,sentence,pmids,context,context_pmids
0,in the absence of sorl1 app fails to be transported out of the endosome and this leads to an increase in generation of aβ in induced pluripotent stem cell ipscderived neurons loss of sorl1 leads to impaired endosomal trafficking and autophagy and ultimately increased aβ levels consistent with these findings loss of sorl1 in ad mouse models leads to an increase in aβ levels in the brain,[16174740 27638701 32492427 34133918 19036982],singlenucleotide polymorphisms snps at the sorl1 locus are associated with ad in genomewide association studies gwass importantly several sorl1 coding variants have been identified in a subset of patients with earlyonset alzheimers disease eoad and variants leading to premature termination codons are found exclusively in alzheimers disease ad cases further reduced expression of sorl1 has been observed in the cerebrospinal fluid csf and postmortem brain of individuals with lateonset ad together these data suggest that sorl1 plays a causal role in ad sorl1 has a major role in intracellular trafficking of various cargos including amyloid precursor protein app which is mediated in part through its role in retromer complexmediated trafficking reviewed in small and gandy,[24162737 35379992 30009200 28537274 15313836 19364929 33667416 17015224]
1,the first compound quercetin is found to have antiinflammatory antiobesity  and cardioprotective action in cardiovascular diseases 53 and antioxidant properties 54 antiarthritic effect 55 antihypertensive effect 56 anticancer properties 57 antidiabetic effects 57 antiallergic effects  and so on,[34101925 29966915 28342364 19307694 27589790 27589790 34101925],"this study reveals the high affinity of quercetin and myricetin towards ache as depicted by their binding energies of -10.6 and -10.5 kcal/mol, respectively, as well as alpha-amyrin and beta-chlorogenin towards buche as depicted by their binding energies of -12.1 and -11.2 kcal/mol, respectively. in contrast, the donepezil revealed the affinity -7.6 kcal/mol with ache protein and -9.8 kcal/mol with buche protein which indicates the lower affinity than spice plant phytochemicals.",[]
2,extracellular circulating mirnas have been investigated as potential biomarkers for ad diagnosis in various studies given their recognized significance in neuronal function and survival,[31659197 36835108 29738527 24827165 36941055],"to date, in tear fluid, approximately 300 different mirnas have been isolated. among these some are newly discovered and their regulatory roles remain relatively unexplored",[31659197 36835108]
3,since then replicative senescence has also been reported in vivo across different mammalian species ranging from the proliferating cells of embryonic tissues 38 92 to many of those in adults including endothelial cells 93 lymphocytes 94 and vascular smooth muscle cells,[24238962 24238961 31109450 18164586 26416809],cellular senescence was first described in the 1960s by leonard hayflick and paul moorhead as the irreversible proliferative arrest of fibroblasts following prolonged culturing in dishes this phenomenon is later known as replicative senescence and has become a major focus in the field of biogerontology,[28688962]
4,the excessive deposition of extracellular aβ is often not accompanied by ad,[ 2897823  2259457 19001171 21280088 33926499],"the mutations of the former lead to the pathological formation of tau tangles and the disease the reverse does not occur the correlation between levels of extracellular aβ and ad is poor
athe excessive deposition of extracellular aβ is often not accompanied by ad 13141516171819bthe occurrence of ad as judged by cognitive symptoms as well as by pet scan and postmortem analysis is not always accompanied by excessive deposition of extracellular aβ",[25307057  2897823  2259457 19001171 21280088 33926499]
5,based on the cholinergic hypothesis of ad the reduced ach levels in the brain and deficits in central cholinergic neurotransmission lead to cognitive impairment which is the main clinical symptom of ad two enzymes are involved in hydrolysis of ach which are butyrylcholinesterase bche and ache and the ache activity is markedly increased in the ad brain ache inhibitors acheis increase the level of ach in the brain and therefore they improve learning and memory and attenuate cognition impairment donepezil is a reversible achei that demonstrates high selectivity toward ache inhibition compared with bche and it has a long duration of action donepezil inhibits ache stimulates nicotinic acetylcholine receptors and prevents cholinergic degeneration which is associated with enhanced synaptic strengthening that is related to cognitive function improvement and reduced spatial memory impairment,[28102474 31773661 18265960 29463072 22114680],"group treated with dpl/ast–solution (ache; 13.70 ± 0.78, 14.29 ± 1.36 ng/mg protein, ach; 15.32 ± 0.65, 18.73 ± 0.91 pg/mg protein) showed similar results to dpl–nlcs, with no significant difference between them in cholinergic parameters. group treated with dpl/ast–nlcs showed significantly lower ache levels (8.13 ± 0.96, 8.76 ± 1.82 ng/mg protein) and significantly higher ach levels (22.17 ± 1.50, 32.90 ± 1.61 pg/mg protein) than the ad-like untreated rats and groups treated with dpl–nlcs, dpl/ast–solution, or dpl–solution in the cortex and hippocampus, and also treatment with dpl/ast–nlcs completely normalized the levels of ache and ach in the cortex and hippocampus.",[]
6,various reports including some from our research group have demonstrated beneficial disease modifying effects of ga in adlike mouse models,[33090673 28860067 34744620 26284939 26049087],these data support the hypothesis that ga treatment does not increase dam found within the vicinity of 6e10+ aβ plaques. due to its ability to induce type 2 responses and its excellent safety profile ga has been one of the candidate therapeutics of interest for repurposed use in ad,[35563884]
7,the 808 nm nir wavelength was chosen for this study because it is at the absorption peak of the primary photoacceptor cco 4791 has optimal penetration through the skull 222324 and has proven effects on cbf 90 and on cognition,[15557336 26346298 23077622 25772014 28186867],"the t-pbm-2.0 device operates in one of five modes: nir continuous low irradiance (50 mw/cm2), nir continuous middle irradiance (300 mw/cm2), nir pulsed middle irradiance (300 mw/cm2), nir continuous high irradiance (700 mw/cm2), and sham. since the proposed average irradiance dose of tpbm at 300 mwcm2 is the most frequently used dose reported in the literature 89 and has been associated with changes in cbf 90 and cognition  for this study we will only employ the nir pulsed middle irradiance 300 mwcm2 and sham modes at 42 hz with a pulsing 33 duty cycle",[34487045 28186867]
8,in addition the aβ40 peptide is preferentially associated with vascular deposits and caa in the human brain resulting in degenerative phenotypes in cerebral endothelial cells31 which culminate in vessel wall dysfunction57 58 contributing to bbb permeability and microhemorrhages,[33155752 19770225 22695614 24670400 34867298],"This cardiac maladaptive remodeling is accompanied by a significant accumulation of Aβ, particularly Aβ40, colocalized in perivascular and interstitial spaces with collagen deposits, as well as caspase 3 activation in cardiomyocytes, suggesting that Aβ deposition in the heart tissue contributes to the development of interstitial fibrosis and apoptotic cardiac cell death (Fig. 2). the preferential accumulation of aβ40 rather than aβ42 in tg2576 mice hearts is in line with previous studies describing the progressive increase mostly of aβ40 levels in both serum and brain parenchyma of tg2576 mice during aging",[11160418]
9,interested readers can refer to review papers eg  for the intricacies of the mechanism,[27274215 25113539 32429229 28781776 31556570],"one reason for this is that the progression of alzheimer’s disease is regulated by a large number of genes, reactions, and pathways which are still under investigation. this work does not aim to illustrate the detail of all genes/pathways known for their involvement in alzheimer’s disease.",[]
10,the rapidly increasing number of studies demonstrates the importance of the ldrsb in resistance to ad pathology and suggests that the development of methods for augmentation of the ldrsb functions may contribute to strong progress in the therapy of ad,[34943796 31452991 32878058 36834631 30046111],"since the treatment of ad is incurable, therapy aimed at reducing the progression of the disease should be applied throughout the life of patients. in this respect pbm technologies are the most promising since they are already widely used in the clinical field for the treatment of various brain diseases",[36061601 29131369 37041790]
11,yu et al suggested that rbck1 promoted the ubiquitination and degradation of p53 the impairment of p53 expression and activity might participate in neurodegeneration as p53 can bind to genes that regulate expression of synaptic proteins neurite outgrowth and axonal regeneration which indicated a neuroprotective role against ad development in addition rbck1 can regulate the proinflammatorycytokinesinduced nuclear factor kappa b nfkb activation which serves as a pivotal mediator of inflammatory responses nfkb activation is a common feature of many neurodegenerative diseases and the increased expression andor activation of nfkb has been largely observed in postmortem studies of ad patients however the two cpg sites were not found to be associated with any neuropathology markers in the current analysis,[30874541 29733887 27382069 25652642 27881951],"scarce evidence related to air pollution has been reported on cg25433380. higher dna methylation levels of cg10495669 in nasal cells have been associated with 1year ambient pm25 exposure among 503 children in massachusetts
rbck1 the gene which cg10495669 is assigned to is involved in carcinogenesis and inflammation pathways",[33872926]
12,ad is neuropathologically characterized by the presence of extracellular βamyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein wnt signaling participates in multiple aspects of cellular function and contributes to synapse formation synaptic activity and neurogenesis in the brain   and dysfunction of wnt signaling may aggravate the pathogenesis and progression of ad,[33667416 28624530 29967987 32616667 31191253],upregulation of wnt2b exerts neuroprotective effect by alleviating mitochondrial dysfunction in alzheimer's disease alzheimer disease (ad) is the most common neurodegenerative disorder leading to dementia in the elderly worldwide.,[]
13,wnt2b has been studied in cancers or tumorrelated diseases while wnt2b is one of the most important components that can induce the particular developing pattern of the fetal hippocampus and related to neurogenesis such as retinal ganglion cells  interestingly wnt2b is also characterized as a mitochondriaexpressed protein which shuttles between mitochondria and the nucleus  however wnt2b has not been studied in ad particularly since it is expressed in mitochondria unlike other wnt family members,[32826863 12271469 21856951 27438855 25356045],ad is neuropathologically characterized by the presence of extracellular βamyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein wnt signaling participates in multiple aspects of cellular function and contributes to synapse formation synaptic activity and neurogenesis in the brain   and dysfunction of wnt signaling may aggravate the pathogenesis and progression of ad we have been focusing on the research and development of blood and cerebrospinal fluid csf markers that can be used for early diagnosis of ad and we have found a variety of proteins that were significantly different in the blood and csf of ad patients and cognitively normal subjects  recently we found that wnt2b a member of wnt family in the plasma of ad patients are lower than in healthy controls,[33667416 28624530 29967987 32616667 31191253 32776690 34044860]
14,in common spatial reference memory test the mwm a wide variety of different protocols are used across studies in congenic 5xfad mice generating divergent data,[29548672 29288735 27542275 27453234 29427384],a recent deep phenotyping study found no deficits in 5xfads compared to wt controls at 6 or 12 months of age in the ymaze  while other studies found deficits at 6 9 and 12 months of age but not 3 months in the cross maze  or at 7 11 and 18 months of age but not 3 months in the ymaze others have also noted deficits in spontaneous alternation as late as 10 months of age,[27453234 29548672]
15,genomewide association studies gwas identified many ad risk genes related to the immune response and microglia including the phagocytic receptors cd33 and trem2,[18976728 21460840 21460841 23150934 23150908],accumulation of amyloidbeta αβ is a defining histological hallmark of the ad brain however failures in αβtargeted clinical trials combined with findings showing no apparent correlation between cognitive decline and overall plaque load in ad patients suggest that additional mechanisms may be crucially involved in ad etiopathogenesis,[32739008 24383468]
16,consistent with the local activation of the amyloidogenic pathway with the generation of aβ species in these transgenic mice  the intensity signal of app figure 1ab and bace1 figure 1cd was inversely increased into synaptic compartments from both tissues hippocampus  p  00001  p  001 retina  p  00001  p  00005 tg2576 versus wildtype,[33750467 32954296 26048669 15917100 16306400],"As shown in Figure 1E,F and regardless of the analyzed area (hippocampus versus retina), the steady state expression level of neuron-specific BIN1 isoform (65 kDa BIN1.1) was significantly reduced in Tg2576 AD mice when compared with littermate wild-type group (hippocampus **** p < 0.0001; retina *** p < 0.0005, Tg2576 versus wild-type). this finding is in line with the evidence that downregulation of bin1 is associated with poorer memory performance in ad cases 77787980 and in this preclinical ad model especially in the concomitant presence of tau neuropathology",[22539578 23226438 33398016 24205320 32719966 31263146 31408457]
17,thrombin cleaves fibrinogen to form fibrin monomers which polymerize to create the fibrin clot,[30323343 33252741 31011700 28101869 17664291],another study suggested that the binding of fibrinogen and aβ in the brain may exacerbate the severity of a tgcrnd8 ad model in vivo 5556 as this association can result in the formation of abnormal blood clots and blockages in the cerebral vasculature similar to fibrinogen fibrin also plays an important role in the process of blood clotting,"[20547128 33551734 30816210 20547128 30323343 33252741 31011700 28101869
 17664291]"
18,heme oxygenase exists in two isoforms heme oxygenase1 ho1 which is robustly inducible by multiple triggers that drive nrf2 expression and heme oxygenase2 ho2 which is considered to be constitutively expressed and modestly inducible by few factors,[10602774 12736340 16459095 25761244 16371440],"regardless the antioxidant and antiinflammatory effects from enzyme activation through the nrf2 pathway have the potential to counteract damage from sustained microglial activation One of the important pathways activated by NRF-2 is the heme oxygenase 1 (HO-1) pathway, which is outlined in Figure 1.",[36316319]
19,for example hypericin can reduce cytokineelicited activation of both stat1 and nfκb in a dosedependent manner it is also able to mediate the activation of the camppkaampk pathway caused by highfatdietinduced metabolic abnormalities further hypericin and other bioactive components in the extract from hypericum humifusum may inhibit acetylcholinesterase and some key enzymes linked to t2d or downregulate homeobox1 pdx1 expression and erk activity  in addition hypericin is found to be an effective inhibitor of αglucosidase a major enzyme that is involved in t2d by altering its structure and microenvironment and reducing its activity,[18226577 33143088 31337977 28147885 34361714],iapp is one of the major secretory products of pancreatic β‐cells and has the ability to aggregate into insoluble amyloid fibrils that are cytotoxic to β‐cells. due to its role in the loss and dysfunction of βcells iapp is suggested to be a therapeutic target for t2d management the deposition of iapp can affect a number of biological processes such as disrupting the structure and function of cardiac myocytes and upregulating the proinflammatory cytokine interleukin1β il1β levels   consistently previous studies have identified some genes and pathways potentially involved in the effect of hypericin in preventing and treating diabetes,[36105173 21742788 27335231 32941692]
20,the different stage of ad models the effect of rapamycin on microglia in the brain and the side effects of rapamycin remain unexplored mtor signaling pathway is not only involved in a variety of cellular functions in the brain but is also present in many types of brain cells such as mature neurons microglia astrocytes and neural stem cells rapamycin lacks specific targeted therapeutic effects and potential side effects may occur with nonselective autophagy induction in vivo to address this issue a rapamycin formulation carried by transferrin decoratednanostructured lipid carriers rapatfnlcs was utilized to target neurons in ad lesions,[34215308 35672148 31690173 35805130 27690737],"thus, the above numerous factors influencing the experiment have led to controversy about the effect of rapamycin on ad. however, mtor signaling has complex effects on the ad brain.",[]
21,we believe that hypomethylation is the key regulatory mechanism responsible for the transcriptional changes of these genes as elevated sah levels and reduced samsah ratios have been confirmed in various experimental hhcy models by us and others,[27992360  9312159 11694601 17698632 14630804],"firstly, hhcy suppresses mg aβ phagocytosis via impaired mg aβ engulfment. secondly, hhcy promoted inflammatory response via activating nf-κb and il-1 pathways.",[]
22,in ad bbb impairments such as changes in the pericyte coverage 11 tight junction tj damage 12 and endothelial cell death 13 are considered as one of the principal causes of cerebral amyloidosis due to their essential role in clearing abundant cerebral aβ,[29453790 22745485 22615835 26005850 29377008],caa is found in over 85 of ad patients characterized by pathological aβ deposits on blood vessels and other vascular abnormalities and it was proposed as a marker of clinical ad the development of caa indicates reduced amyloid clearance from the brain parenchyma 8 impaired amyloid transport across the endothelium and the failure of amyloid degradation,[21205781 23489283 20854368]
23,cognitive impairment due to ischemia is mild to severe and has been seen in approximately 3570 of survivors one year after a stroke,[22311341 23150656 24577459 31712368 37125534],"a focal ischemic episode typically damages the brain cortex, hippocampus, temporal lobe, entorhinal cortex, amygdala and parahippocampus to varying degrees. postischemia, these structures are involved in cognitive and memory deficits, and their progressive degeneration also induces behavioral changes.",[]
24,thus the presented alterations indicated that the dysregulation of the expression of autophagy and apoptotic genes may be associated with a different response of neurons in the ca1 and ca3 areas of the hippocampus and in the medial temporal lobe cortex to transient global brain ischemia,[27472881 27710863 29363901 29128811 31707369],this overexpression was accompanied by the downregulation of caspase 3 gene 2 days after brain ischemia next on days 7 and 30 after ischemia the above gene was impressively upregulated,[27472881 27710863 29363901 27472881 27710863 29363901]
25,several of the critical pathogenic functions of p2x7 could be mediated by p2x7 specifically expressed on microglia including the release of il1β and chemokines and the secretion of taucontaining exosomes see previous paragraphs figure 1 and table 2,[29934546 34391810 34516970 22048123 32811520],"in general microglia exhibit the highest levels of p2x7 in the brain thus, the observed increase in p2x7 in glial cells suggests their potential contribution to the pathogenesis of ad.",[22467178 30691318]
26,cognitive deficits are common in patients with chronic epilepsy particularly in temporal lobe epilepsy tle and lateonset epilepsy,[33279986 33097597 28284559 31834353 32351438],in ad patients with epileptiform activity the minimental state examination mmse score decreased faster compared to ad patients without epileptiform activity furthermore antiseizure medications asms eg levetiracetam lev decreased neuronal hyperexcitability and improved cognition in animal models and in patients with mild cognitive impairment mci and are being investigated in ongoing studies for ad,[27696483 22869752 34332638]
27,previous studies utilizing bisulfite sequencing or pyrosequencing have reported relatively low levels of mtdna methylation in the dloop region and the mtrnr1 gene across different human cell and tissue types with estimated levels ranging from 1 to 34,[36726473 26996456 23656717 27107129 32657220],these findings highlight the importance of considering mtdna methylation as a potential target for further investigation in ad. the existence of methylation in mammalian mtdna remains a subject of debate.,[]
28,bdnf levels are known to fluctuate in response to factors such as age sex hormones lifestyle and stress however chronic alterations in its expression can be indicative of or potentially lead to chronic diseases such as ad,[26788077 32012942 30634650 32825341 17204313],"recently rsg formulated with nanoparticles was shown to modulate bdnf and its upstream signaling pathway substrates in models of diabetes and ad to better understand how rsg may act through this mechanism, alterations to bdnf expression and its pathological involvement in ad must be explored.",[32683650 33860663 25510319]
29,in the present study we conducted additional comprehensive in vitro experiments to assess a potential direct effect of dmf and its metabolite mmf on abc transporter activity a group of transporters associated with ad,[34977908 21460840 36411364 16207713 35477481],"apart from the induction models, only one publication proposed possible positive ad treatment effects of dmf. the authors used a doubletransgenic mouse model app and tau and assessed activation of nrf2signaling by dmf which led to a trend of reduced impairment of motor functions during the disease progress and improved memory through reduced neuroinflammation",[30029164]
30,the strong relationship with these biomarkers suggests that thop1 changes are associated with upstream and downstream mechanisms in ad such as tau pathology neurodegeneration and total aβ load  despite the thop1 increases in response to aβ neurotoxicity the association between aβ42 and thop1 only in the control group suggests that thop1 may not respond to aβ fibril and plaque formation further supporting a relationship of thop1 with normal aβ physiological functioning  altogether the increased thop1 concentrations detected in the mci stage and the significant correlations with ad csf biomarkers may suggest that this protein could be a useful biomarker for detecting an early neuroprotective response against ad pathology,[35026840 16602710 18571100 31431000 11559896],"this suggests that the lack of significance observed in the independent cohorts is probably due to the lower sample sizes and not to the presence of amyloid comorbid pathology in the dlb group. strong correlations between thop1 with t‐tau, p‐tau, and aβ40 concentrations in the total cohort were observed.",[]
31,most studies reported the use of antihypertensive drugs ahds in patients and controls some also reported the use of antidementia medication,[19433892 29844143 24251392 24670396 19433892 29844143 22460326],"mmse score ≤25). in addition to age, sex, and education or cognition, data on bp, medication use, bmi, and vascular risk factors or comorbidities were collected.",[]
32,others have proposed that it is a form of lysosomal storage disorder 36 or a novel form of diabetes 37 or that ad is caused by autophagic dysregulation 38 neuroimmunomodulation 39 or by excess exposure to aluminum,[31482121 19885299 35654956 20134203 21157018],however this only overcomes some of the shortcomings of the original amyloid hypothesis another is the tau hypothesis  which argues for a central role for tau protein rather than aβ in the pathogenesis of ad,[29440986 29440986 20682182]
33,so the hyperaccumulating aβos produce the toxic hptos that actually kill the cells and like aβos are also able to prionlike spread the clinical symptoms,[31157827 30362029 23332364 30355155 29887142],ad is actually a terminal tauopathy in which the currently invisible toxic aβos start the connectopathy by inducing the mislocation of normal tau from the axon to the sdc by stimulating its hyperphosphorylation. this produces the unfolded toxic tau that collaborates with prpcs to destroy synapses,[28864542 30355155 30001506 31524157]
34,since apoe competes with reelin for apoer2 binding in model systems an excess of apoe following injury could potentially compromise reelinapoer2dab1 signaling lastly since reelinsecreting neurons are reported to degenerate in sad reelin depletion could help explain or exacerbate the hyperphosphorylation of tau as well as the accumulations of dab1 pp85αtyr607 plimk1thr508 and ppsd95thr19 observed in the present study,[10571240 10571240 17360894 27031488 31870804 10571241],"apoe particles deliver lipids that are highly vulnerable to peroxidation to neuronal apoe receptors including apoer2 our recent finding that apoe and apoer2 are vulnerable to lipid aldehydeinduced adduction and crosslinking provides a mechanistic link between lipid peroxidation and apoer2dab1 disruption since lipid peroxidation is a common feature of many sad risk factors reviewed in this mechanism could help explain previous observations that lipid peroxidation is markedly increased in the early stages of sad
 astrocytes stimulate repair of injured axons by dramatically increasing local secretion of lipidloaded apoe particles",[35466940 35466940 35466940 35466940 16240347 22137893  2419900  2493483]
35,we observed a high toc in patients with ad consistent with the evidence of cortical thinning as a consequence of ad neuropathology moreover we also observe significant associations with cortical thinning and poor cognitive performance a decrease in csf aβ and an increase in csf ptau  which is also consistent with previous findings atrophy has also been associated with the risk of progression from mci to ad  alongside a combination of other biomarkers importantly these previous studies examined the correlates of common patterns of cortical atrophyyet conversely we considered individual variability in patterns of cortical thickness as opposed to assessing group average relationships,[21504134 23507382 24852682 19439419 32643852],"overall, the results of the present study provide evidence of (1) heterogeneous patterns of cortical thickness between patients with ad, (2) associations of cortical thickness heterogeneity with cognitive performance and csf aβ and p-tau, and (3) the potential of individualized markers of cortical thickness heterogeneity to predict survival time before conversion from the mci stage to diagnosed ad. our findings both complement and offer additional information to the established understanding of ad.",[]
36,more and more experimental evidence including genetic 1213 and epigenetic 14 studies transcriptome analysis of brains of patients with ad 15 and expression quantitative trait experiments in monocytes  supports a contributing role of innate immune mechanisms in ad,[24162737 27088644 25693568 23622250 24786080],"a previous study provided evidence that red ginseng, steamed at higher temperature and pressure, has the major components of these eight rare ginsenosides. alzheimers disease ad is neurodegenerative with various pathophysiological aspects under investigation",[30028503]
37,recently two independent studies reported that a heterozygous rare variant in trem2 pr47h is significantly associated with ad 2829 and multiple variants in the same gene increase ad risk,[23150934 23150908 22312439 22801501  8446617],snps in the trem2 gene modulate protein expression 18 and function possibly resulting in an inactive receptor such single nucleotide polymorphisms snps were identified as risk factors for alzheimers disease ad a central nervous system disease that leads to dementia 19 and it is characterized by progressive cognitive dysfunction memory loss and neuroinflammation,[27995897 25732305 27995897 25792098 23979026 26939933 30406177]
38,the aβfe3 redox interaction mechanism has been validated in aβ amyloid plaque cores from ad postmortem and transgenic mouse brain tissues,[24671940 24559299 28890316 29688240 32587293],our early in vitro study has first demonstrated that aβ can directly reduce fe3 to fe2 initiates the fenton reaction and engenders oxidative stress via a heightened generation of reactive oxygen species ros such as h2o2 and ho radical production we first employed synchrotronbased xray fluorescence microscopy xrfm and detected abnormal iron enrichment in procured aβ amyloid plaques from ad postmortem brain tissues using the laser capture microdissection lcm technique,[15105262 10386999 16503166]
39,in the literature it was shown that both ischemia and inflammation play a role in the pathophysiology of ad vitamin d and nlr were used as a biomarker for inflammation and atherosclerosis in literature,[15850663 22922667 36592816 33013672 24861877],roc curve analysis between fazekas zero and fazekas three groups. abbreviations: ad: alzheimer’s disease. auc: area under the roc curve.,[]
40,the aβ protofibril selective monoclonal antibody mab158 3 27 was recombinantly expressed on a mouse igg2c backbone either in regular igg format or as a bispecific antibody conjugated to single chain variable fragments of the tfr binding antibody 8d3 28 scfv8d3 at the light chain ctermini as previously described  resulting in rmab158scfv8d3,[17623042 20714111  9681691 28042336 28932173],"wild type wt and appnlgf mice expressing mouse amyloid precursor protein app with a humanized aβ sequence and with the swedish km670671nl arctic e693g and iberian i716f app mutations  were used in the study all experimental procedures were approved by the uppsala county animal ethics board (5.8.18–13,350/2017 and 5.8.18–20,401/2020), carried out according to regulations of the swedish animal welfare agency, and complied with the european communities council directive of 22 september 2010 (2010/63/e.u.).",[24728269]
41,we followed the procedure described in a previous study briefly the diffusionweighted imaging data were preprocessed using fsl fmrib software library the nonbrain tissue was removed epi distortion was corrected using epibased field mapping and eddy currents and head motion were corrected,[32035186 21979382 12391568  9469719 26481672],"a b0 field map was collected with matching geometry for use in unwarping epi distortions due to magnetic field inhomogeneity the field map acquisition was performed with a 3d dualecho spoiled gradient echo pulse sequence field of view 240  240 mm matrix size 80  80 isotropic voxel size 3 mm number of slices 48 repetition time 675 ms echo time 1  492 ms echo time 2  738 ms flip angle 60 to characterize the microstructural properties of the human cholinergic system, a diffusion mri-based in vivo model was derived.",[7674900]
42,several studies have shown that ras is a potential contributor to dementia and ace2ang17mas1 axis has been demonstrated to be important it has been proven that in the injury models of central nervous system inducing ace2 or ang17 activation of masr signal has neuroprotective effects on neurogenic hypertension and ischemic stroke our results indicated that the activity of ang17 a critical regulator of ace2ang17mas1 pathways was decreased in the brain tissues of appps1 mice while dize remarkably increased the brain levels of ang17 and mas1,[32701063 34955647 33526381 19923158 23997755],"further high-throughput sequencing indicated that mirna-224-5p expression was drastically upregulated in astrocytes of app/ps1 mice after dize treatment, and mediated the inflammatory response through nlrp3 inflammasome. thus, this is the first study to show that dize mediated astrocyte-regulated neuroinflammatory responses via mirna-224-5p/nlrp3 pathway.",[]
43,in the adcssponsored dha trial 2 g of dha supplementation per day over 18 months was not effective in slowing cognitive decline in persons with dementia particularly among those carrying the apoe4 allele in this trial apoe4 carriers had a threefold lower increase in csf levels of epa and dha after supplementation when compared with noncarriers   with the limited conversion of dha to epa possibly due to oxidation of these omega3 fatty acids in the omegad clinical trial supplementation with 23 g of dha and epa per day over 6 months in persons with mild ad was associated with an increase in markers of inflammation and neuronal injury in csf in contrast in a 12month randomized clinical trial of 327 g epa  dha per day in middleaged cognitively normal individuals apoe4 carriers had the greatest increase in plasma oxylipins following highdose dha  epa supplementation higher levels of these oxylipins in apoe4 carriers may help offset a metabolic and proinflammatory state,[21045096 28733268 17998483 23631810 34604280],each predictive model had an roc auc of at least 0.824. these findings underscore the potential role of systemic lipids in driving the pathology of ad.,[]
44,er stress triggers an unfolded protein response upr and transcriptionally regulates lipogenesis 85 thus playing an essential role in lipid metabolism 85868788 3 stress damage such as dna damage and response play a major role in cellular senescence in vitro,[22195283 22195283 27146479 33398919 36499512 28688962],"interestingly, stress damage and response interlock the immune system and lipoprotein metabolism in multiple ways. some examples are 1 oxidative damage to lowdensity lipoproteins ldl is a wellknown initial step of atherosclerosis inducing inflammatory responses by releasing cytokines and chemokines 828384 2 metabolically linked proinflammatory stress such as endoplasmic reticulum er stress modulates lipid metabolism and mediates the release of cytokines il1α il6 and il8 which are known to participate in agerelated chronic inflammation",[18625445 24903093 30806246 31011483]
45,natural mitochondrial trafficking may transfer injured or degraded mitochondria from the cell body to synaptic terminals,[ 9096346  9115741 15377858  2469224 17696767],to meet cellular energy requirements synaptic mitochondria are first created in the cell bodies of neurons and are then transferred from the axon or dendrite this process is referred to as mitochondrial trafficking,"[ 9096346  9115741 15377858  2469224 17696767  9096346  9115741 15377858
  2469224 17696767]"
46,although reactive astroglia increases trophic support and glutamate uptake isolates lesioned areas favoring regeneration activates immune pathways and promotes bbb repair  45 46 47 astrocytes can become dysfunctional and acquire cytotoxic potential under prolonged stress,[20012068 31583588 25726916 16873533 31110130 20012068 31583588],through the reactive response astrocytes aim to restore regional homeostasis gradually modifying their transcriptional profile and adapting their cell morphology and activity finely tuned morphological changes are driven by an increase of intermediate filament proteins such as gfap and vimentin 15 38 41 42 43 which not only provide mechanical sustenance for the maintenance of astrocyte shape but also support the functional profile of reactive astrocytes through transcriptional modulation of target genes involved in astroglial and microglial responsiveness,"[29351512 20012068 29351512 20012068 18586353 28212850 31583588 25731615
 25726916]"
47,the human p2x7r gene is highly polymorphic with more than 150 nonsynonymous snps the majority of which lead to amino acid substitutions in the extracellular loop or the cytoplasmic cterminal tail 61 affecting agonist binding affinity 62 trafficking to membranes 63 ion channel activity 64 and permeability of the pore,[24928329 15123679 12586825 11150303 20360457],in contrast to other p2x subtypes p2x7r does not undergo desensitisation after activation of the receptor due to permanent stabilization provided by a palmitoylated cysteine rich region in the cytoplasmatic domain this feature of p2x7r activation dynamics likely contributes to the hyperpolarised astrocyte membrane potential that is important for astrocyte physiology and functions,[31587896 34525325]
48,whilst the neuronal localization of p2x7r remains controversial 7576 p2x7r expression in astrocytes 71727780 has been confirmed by the presence of agonistinduced currents and ca2 responses,[28747388 28747389 29934546 34391810 19289154],opening of the p2x7r channel is stimulated by atp concentrations in the higher micromolar to millimolar range in contrast to the lower atp concentrations required for opening of other p2x family members with atp4 being a true agonist atp can be sensed by p2x7rs in rodent or human microglia which show the highest levels of p2x7r expression in the brain 6972 and oligodendrocytes,[23040806 17728465 34054698]
49,until now there have been five antiad drugs approved by the fda namely the ache inhibitor tacrine 9 donepezil 10 rivastigmine 11 galantamine 12 and the nmda receptor antagonist memantine,[27876467 30372021 27094132 11230880 23657927],the pathogenesis of ad is complex involving βamyloid protein deposition neurotransmitter deficiency metal metabolism imbalance overexpression of monoamine oxidase b maob neuroinflammation oxidative stress tau protein hyperphosphorylation etc At present acetylcholinesterase AChE inhibitors NmethylDaspartate NMDA receptor antagonists or a combination of them are used clinically to increase the content of neurotransmitters in the synaptic space to alleviate cognitive and behavioral disorders ,[30095897]
50,the exposition of ad transgenic mouse models to a high fat andor high sugar diet exacerbates the ad pathology,[27863851 29427755 22427376 21762376 27177549],"The connection between T2DM and AD has been studied using different approaches, extensively described in Section 4 of the present review. for instance postmortem brains of ad patients present a deregulation of the insulin receptor ir intracellular signalling",[14769913 15750215 15773910]
51,since 2020 numerous studies have described various effects that sarscov2 has upon the brain       with recent data showing reduced grey matter thickness and increased cognitive decline in people over the age of 51 with infection,[32637987 33399270 33836148 33257876 33031735],in relation to broader health implications our findings may have some relevance and thus warrant some brief reflections in relation to the recent emergence of ace2 as the primary receptor for severe acute respiratory syndrome coronavirus 2 sarscov2  that has caused a global health pandemic since 2020 infection with sarscov2 has been shown to downregulate membraneexpressed ace2 potentially leading to overactivation of cras and elevated production of angii mediated vasoconstriction and inflammation  underpinning pathological processes associated with sarscov2 infection and covid19 disease,[]
52,these brain changes include increased atrophy   brain aβamyloid  and tau pathology  hallmarks of ad as well as reduced brain glucose metabolism,[25186857 25061245 27091528 31209175 24107601],the presence of sleepwake disturbances in dementia due to ad is wellestablished crucially rather than presenting only as a comorbidity mounting evidence indicates that sleep disturbances increase risk of cognitive decline and dementia    by modulating neurobiological brain changes,[14998915 22467987 23905991]
53,the positive effect observed in the souvenaid group alone coincides with the findings presented by other studies showing the efficacy of souvenaid in improving cognitive function in people with mci and mild ad while maintaining a good safety profile,[20129316 22766770 29097166 32920957 31259306],"regarding treatment with souvenaid alone, a significant improvement over achei alone was seen in svft, pvft, and npi after the 12-month follow-up. in addition, the souvenaid group also showed an improvement already at 6 months in svft and npi.",[]
54,consistent with links between the blue module and cancer we find that many blue module hub genes such as moesin msn yap1 tead1 and wwtr1 are well known for their role in cancer and mediate the emt module eigengenes defined as the first principal component of a module can be used to measure the degree of similarity between modules in a network based on principal component analysis pca we find a negative association between eigengenes of the blue cancerrelated module versus eigengenes of the turquoise neurotransmission module e,[28581497 19952108 22190458 19432821 18031580],“hub genes” are defined as the most highly connected genes within a module. we identified hub genes of each module by ranking genes according to their intramodular connectivity kin and selecting the top 15 of the most highly connected genes d,[]
55,s1b of genes that change significantly in braak vvi samples fig 1b and identified three main myeloid clusters homeostatic microglia hmg p2ry12 cx3cr1 activated microglia amg pu1 csf1 cd45 cd74 15 24 35 50 and a third group including nonclassic microglial markers  which we termed cd163 cluster cd163 ifitm3 ccr2 cd68 and msr1,[29346778 28602351 29403371 29310663 30559476],"significance, indicated in the figure, was tested using the kruskal–wallis test followed by the dunn test Next, we performed a hierarchical cluster analysis (Additional file 1: Fig.",[]
56,at2r and masr activation decrease inducible nitric oxide synthase inos and the levels of inflammatory cytokines such as cxc motif chemokine ligand 12 cxcl12 interleukin 1β il1β and il6 produced by m1 microglia while increasing antiinflammatory markers such as il10 and il4,[24487585 27761230 23583926 28192099 26448556],"the upregulation of at1r in m1 microglia is associated with inflammation and cognitive impairment through a tolllike receptor 4 tlr4dependent mechanism 142 thus the at1rmediated activation of proinflammatory m1 microglia exacerbates inflammation eventually causing ad moreover, the activation of at2r shifts microglia toward an m2 phenotype.",[26637556 24487585]
57,nk killer cells leukocytes 117118119 and lymphocytes including human peripheral blood lymphocytes  also contain α1ars but the subtypes are not clearly defined,[18463421 35537053  9119969 10024333 11350496],human neutrophils contain the mrna for all three α1ar subtypes monocytes contain the mrna for the α1band α1dars,[25561369 21771488]
58,a dependence on polymorphisms in both the bdnf gene and related receptors which may increase the risk of developing neuropsychiatric disorders has been described in numerous studies,[22047184 18852698 29102837 21936709 35099506],"these relationships were described in the work of porcher et al., which showed that bdnf may have a differential effect on gabaergic synaptic inhibition depending on factors such as: the stage of neuronal development, the function of a particular area of the brain, or the rate of the delivery of exogenous bdnf. the authors of the study believe that the seemingly opposite effect of bdnf in this regard may contribute to the maintenance of the homeostasis of gabaergic transmission",[30210299]
59,pivotal roles of macrophages at brain surfaces and their significance in brain homeostasis are highlighted in recent literature,[21952260 31358892 36352225 35794106 19164591],"furthermore, this brain drainage system links the health of cerebral vasculature with brain inflammation, stressing critical inter-relationships between brain blood vessels and neuroimmunity. given these recent neuroscientific advances and knowledge on lymphatic diseases in peripheral tissues, a vascular–immune basis for ad is conceivable and evidence in support of specific pathways and mechanisms of brain fluid and metabolite clearance is now emerging rapidly across species.",[]
60,moreover a handful of biomarkers have also been incorporated into the clinical diagnostic process including structural neuroimaging eg magnetic resonance imaging mribased measures of hippocampal volumes 11 12 blood and urine samples 13 cerebral spinal fluids eg tau and betaamyloid levels 14 and genetic risk profiling,[12595205 20139996 22078169 20538373 26312828],As such improving early diagnostics has become a fundamental element in AD research and therapy 5 especially since there are currently no cures for AD  while a definite diagnosis for ad can only be achieved through a postmortem structural examination of the brain clinical diagnosis currently relies on the use medical history and exams such as the minimental state examination mmse 9 and the clinical dementia rating cdr,[18579155]
61,in addition the correlation between blood nfl and aβ deposition was not identified,[31514172 28346578 31572170 32211500 30055655],by comparison it is relatively clear that its levels increased faster in patients with preclinical ad specifically trajectory analyses revealed that mean plasma nfl levels increased 34 times faster in participants who developed ad versus those who remained healthy and that these changes were detectable 96 years before diagnosis,[32206776 31009028 31673598 32206776]
62,comparatively its levels are more likely to reflect csf ttau concentration cognitive level brain atrophy rate metabolic function and white matter alterations,[31514172 31572170 29070659 31009028 32211500],specifically trajectory analyses revealed that mean plasma nfl levels increased 34 times faster in participants who developed ad versus those who remained healthy and that these changes were detectable 96 years before diagnosis in addition the correlation between blood nfl and aβ deposition was not identified,[32206776 31514172 28346578 31572170 32211500 30055655]
63,this dysregulated erca2 signaling disrupted synaptic transmission and plasticity propagated inflammatory responses and drove pathogenic amyloid and tau formation all of which was normalized with ryanodex treatment in the ad models,[19641109 23284867 10764737 20826675 32033164],"bafilomycin (25nm; 4h) did not significantly alter ryr-evoked ca2+ release in either 3xtg-ad (28.47%±16.54% over baseline) or ntg (8.62% ± 2.99% over baseline) neurons, again showing minimized interference of bafilomycin to ryr-evoked ca2+ release. these results are consistent with previous studies that demonstrated altered upstream er-ca2+ homeostasis in multiple ad mouse and human neuronal models.",[]
64,these proteins include 1 singletype proteins such as aβ40 aβ42 aβ oligomers aβo total tau ttau tau phosphorylated at threonine 181 ptau 181 tau phosphorylated at threonine 217 ptau 217 or tau phosphorylated at threonine 231 ptau 231 and 2 combined types such as the aβ42aβ40 ratio the ratio of amyloid precursor protein669771 app669771 to aβ42 aβ42app669771 ratio the aβ42aβ43 ratio the ttauaβ42 ratio or the ptau 181aβ42 ratio,[32806668 32899797 35175385 33910450 35453600],ad predicted to affect more than 152 million people by 2050 is now recognized as common senile dementia with main pathological hallmarks such as extracellular neuritic plaques containing amyloidβ peptide aβ and intracellular neurofibrillary tangles composed of hyper phosphorylated tau some proteins related to the two biomarkers detected in the peripheral blood are attractive candidates for ad diagnosis 89101112 because they are contained in the amyloid cascade hypothesis which introduces the idea that aβ misfolding and deposition are the primary precipitants of ad,[21456963 32806668 32899797 35175385 33910450 35453600 35573283]
65,previous studies have shown that reactive astrocytes can precede early pathological hallmarks of ad such as aβ and tau during disease progression,[22213821 30611668 25893384 26813969 26553227],in pathological situations astrocytes undergo a series of morphological and functional alterations collectively referred to as reactive astrocytes and overexpress proteins such as gfap reactive astrocytes contribute to neuroinflammatory changes in ad by releasing cytokines inflammatory mediators nitric oxide and reactive oxygen species and promoting redox status imbalance,[17090684 19944719]
66,in circulation nearly all igfs are bound to igfbps with only 013 of total igf2 being free to bind receptors the halflife of free igf2 in circulation is 10 min while the halflife is 30 min for the igf2igfbp binary complex and 12 h for a ternary complex that also contains the protein acidlabile subunit als however only the binary complexes are able to cross from capillaries into tissue free igfs can diffuse across capillary pores to act directly within tissue although the physiological significance of these free igfs is not known in addition to producing igfs locally tissues can dynamically regulate the action of circulating igfs by secreting enzymes capable of degrading igfbps thereby liberating the igfs within binary complexes,[18719053  7514998  7523391 15964556 20826314],"additionally, igf1 and igf2 bind six high‐affinity igf‐binding proteins (igfbps), which regulate the action of igfs by sequestering them away from receptors. igfbps generally inhibit the action of igfs, but may in some cases enhance their biological action by protecting them from degradation.",[]
67,a striking manifestation of neurotrophic decline in ad is the reduction in hippocampal neurogenesis that occurs across disease progression in neurologically healthy subjects hippocampal neurogenesis declines with age but this decline is more dramatic in ad subjects  rodent studies have indicated a role of hippocampal neurogenesis in many neurological processes that are impaired in related to ad including memory consolidation  and neuroprotection,[30911133 30911133 29625071 14614143 20204139 12440573],the synaptic compartment is likely to be an early site of igf2 dysregulation in ad. in a rat model of agerelated cognitive decline reduced igf2 expression in the synaptic compartment was associated with cognitive deficits even as overall igf2 expression showed no apparent decline since total igf2 expression eventually declines dysregulation of synaptic igf2 may represent an early event in the typical progression of ad,[27318130]
68,because protooncogenic cells often upregulate igf2 in order to evade apoptosis it is plausible that exogenous igf2 might increase the risk of a precancerous tissue surviving to become tumorous in transgenic mice that overexpress igf2 in specific tissues tumor formation tends to increase in those tissues where igf2 is overexpressed   however such models do not give a clear indication of how systemic administration of exogenous igf2 would influence cancer risk as most tissues also secrete igf2 for use in paracrine and autocrine signaling,[18087038 27140600  7577466 12584565  9571768],the hypoglycemia risk of intranasally administered igf2 is likely to be even lower since a negligible amount of the intranasally administered compound enters general circulation whereas 40 iu subcutaneous insulin would provoke hypoglycemia in humans this same dose of intranasal insulin was not associated with acute or chronic hypoglycemia because igf2 is less effective than insulin in stimulating glucose uptake even a large dose of intranasal igf2 would be unlikely to cause hypoglycemia another potential risk of therapeutic igf2 is increased cancer incidence.,[32568367]
69,sfdi is a relatively new technology designed to quantitatively map tissue absorption and scattering over a wide fov to perform this measurement a typical hardware setup for sfdi includes a camera sensor a light source with one or more wavelengths a digital micromirror device dmd and a computer for triggering acquisition and processing  sfdi uses a dmd to project spatially modulated patterns either from a broadband source or multiple discrete wavelengths onto the tissue and detects the backscattered light with a camera,[15981531 19405742 23764696 29296630 33842666],"despite some of the limitations associated with traditional lsi, it has been extensively used in diseased and healthy rodent brains. in this review, we highlight areas that lsi has been applied.",[]
70,however interpreting these observational associations as evidence of causal relationships between education brain structure and alzheimers risk relies on several untestable and potentially implausible assumptions including the absence of residual andor unmeasured confounding and reverse causation for instance the association of education with brain structural metrics may be confounded by earlylife factors that are common predictors of both ea and brain structure such as childhood socioeconomic status birthweight childhood cognitive ability and maternal smoking during pregnancy confounding may also affect the relationship between mri markers of structural brain reserve and alzheimers risk,[25064373 22880000 25821911 27664981 22180574],"for instance higher education levels have been associated with increased wholebrain and regional grey matter volume cortical thickness and increased surface areas of subregions of the hippocampus and amygdala that are vulnerable to alzheimers disease pathology similar findings have been reported for the association between education levels and white matter microstructure in cognitively intact elderly with more highly educated individuals showing increased white matter tract integrity in several brain regions that are characteristic sites of alzheimers pathology given the observed associations between education and structural markers of brain reserve, it is plausible to hypothesize that changes in brain structure may mediate the protective effect of education on alzheimer’s disease risk, through determining the underlying brain reserve of the individual.",[23796547 27535872 27535407 21853422 19433891]
71,previous reports established that by inhibiting the essential proteins such as cholinesterase monoamine oxidases rock2 calcium homeostasis modulator1 calmh1 glycogen synthase kinase3 beta gsk3β nmethyldaspartate nmda receptor and betasite app cleaving enzyme 1 bace1 or bace can lessen the memory loss and neuronal death,[34944045 34577637 35745697 35741655 36122738],furthermore the deposition of amyloid plaques and oxidative stress can result in the hyperactivation of gsk3β which increases the phosphorylation of tau proteins and potentiate the formation of neurofibrillary tangles moreover the hyperactivation of nmdareceptor nmda in combination with neurofibrillary tangles and amyloid plaques raises the release of glutamate which could lead to excitotoxicity and neuronal death,[34776454 30800052]
72,working memory semantic knowledge attention motor performance and visuospatial ability are among the functions included in the task mode the posterior cingulate cortex entorhinal cortex and hippocampus were evaluated in this mode but the most engaged structure was medial temporal lobe nonetheless fmri is not used in routine clinical evaluation possibly because of its low snr for neuronal activity,[16402259 23497150 10211471 12486265  9106749],the cbf is reduced significantly in ad individuals in temporal frontal parietal thalamus hippocampus and amygdala furthermore lower cbf has been shown to be associated with faster cognitive decline in ad individuals although this modality is noninvasive and nonionizing alterations in signal intensity and the low signaltonoise ratio snr reduce image quality fmri is a bloodoxygenleveldependent or boldcontrast imaging technique individuals can be evaluated for brain activity during the task or resting state studies showed that hippocampal and medial temporal lobe have low activation rates in ad individuals,[21786091 24670395 27334014 29853806 19588145 11449264 22333920]
73,overall jedited fmrs has high sensitivity and specificity for taskinduced lactate modulation and shows the rate of increase in lactate concentration compared with the fixation condition a significant increase was detected in lactate levels the rate of lactate increases significantly between 7 and 15 percent in addition the result shows that lactate increased on activating the visual cortex but did not change on deactivating the posterior cingulate cortex however increases in lactate during motor stimulation are less significant figure  figure,[30201463 24555953 30201463 33472521 31995265 20404151 33472521 24555953],the megapress is a jdifference edited mrs pulse sequence consisting of on and off subexperiments in contrast to the off experiment the on experiment uses frequencyselective radio frequency editing pulses to edit the lactate molecules 132 ppm resonance lactate is separated from overlapping resonances and macromolecules using spectral editing with jmodulation which uses the quantum mechanical characteristics of specific molecules to edit them out of the overall 1hmrs spectrum on the other hand jediting is prone to subtraction mistakes caused by motion which can hide tiny changes in the lactate by using quantum mechanical characteristics of lactate to remove it from the overall spectrum jedited 1hmrs can provide direct insights into the overlapped resonances that occur from numerous molecules such as fatty acids or macromolecules because of considerable suppression of the relatively short t2 for the lipid and macromolecule background signals 1hmrs has demonstrated that physiological modulations of lactate in the visual cortex may be seen even at 15 t using long te,[12815674 30201463 30201463 33472521 31995265]
74,as well as deteriorating cognitive functions 5 47 62 patients with ad show circadian dysfunctions even at preclinical stages that may contribute to disease severity,[21371747 27188934 26921134 29379963 17383938],disturbed circadian rhythm and retinal degeneration in a mouse model of alzheimer’s disease alzheimers disease ad the most prevalent form of dementia worldwide  is characterized by aggregation and accumulation of amyloidβ aβ and hyperphosphorylated tau protein in the patients brains,[]
75,amyloidβ and tau bind iron through histidine and possibly other residues,[20164601 21800824 30174587 12358761 30250423],among the profile of altered enzymes in ad a decreased activity of pitrm1 could contribute to the formation of amyloid and tau deposits in ad since both amyloidβ and tau bind iron  they are likely participants in the sequestration of iron in patients with ad,"[32632204 21750375 24561226 34356897 26697887  9237552 10617129 31927402
 30174587 33532700]"
76,in fact some studies show that the practice of mbi favoring the controlled attention component and therefore the cognitive control of active memory working memory at the present moment without judging the emotional or thought contents could help reduce these adverse factors 27282930 reducing response interference,[28323668 33010903 29466242 23115195 26639952],"in fact, mbis constitute primary prevention interventions for health in general and can be used as secondary prevention in the field of physical and mental health, even in neurodegenerative diseases such as ad. Furthermore stress depression anxiety and neuroticism affect sleep cognition and mental health and wellbeing in aging populations and are associated with an increased risk of AD and further degeneration ",[]
77,genes in green font were prioritized or nominated through integration analyses   thus human genetics evidence strongly suggests that efferocytosis may act as a pathogenetic hub for alzheimers disease in macrophages including microglia in the brain,[33589840 35379992 33712570 35931864 34992268],"adaptation, storage, elimination). with the exception of genes colored in gray, all genes shown in this figure to be involved in the various steps of efferocytosis have also been implicated in the etiology of ad by gwas and post-gwas studies.",[]
78,genes in green font were prioritized or nominated through integration analyses   thus human genetics evidence strongly suggests that efferocytosis may act as a pathogenetic hub for alzheimers disease in macrophages including microglia in the brain,[33589840 35379992 33712570 35931864 34992268],"adaptation, storage, elimination). with the exception of genes colored in gray, all genes shown in this figure to be involved in the various steps of efferocytosis have also been implicated in the etiology of ad by gwas and post-gwas studies.",[]
79,in neuropathology studies similar positive associations were recorded against various aβ staining methods such as thal cerad and thioflavin stain scores,[33585983 34725927 32722745 32720099 35195758],More recently a comparative study that evaluated ptau181 ptau231 and ptau217 in a headtohead manner demonstrated that ptau217 quantified by IPMS technology discriminated with higher accuracy patients with MCI and those who progressed to AD dementia  plasma ptau levels significantly associated with csf aβ42aβ40 as well as with aβpet accumulation in early accumulating brain regions eg precuneus temporal and superiorfrontal areas in preclinical stages which became stronger and extended to lateaccumulating regions eg subcortical structures later in the disease course,[33106600 33169916 33585983 32720099 32123385 33479777]
80,for example ad and especially adrd is often underreported on death certificates  this problem affects the black and hispanic population more than nonhispanic white population the impact of this problem increases with age and is exacerbated by higher misreports of an individuals exact age in these higher age brackets   finally many studies on racial differences in adadrd risk use oversimplified models that cannot account for the complex interactions between risk and protective factors determining what is observed in the data,[10404929 24583403 32852519 29094262 35678407],for example studies have suggested that some of the raceethnicityrelated disparities in adadrd could be caused by healthier individuals within a group who survive past the initial ages of higher mortality risk to older age thus surpassing the average life expectancy of the group  this could lead to the effects such as the hispanic paradox which refers to the comparableorbetter survival in hispanic american groups despite their lowerthanaverage socioeconomic status and education level  the healthy migrant successful migrants have better initial levels of health and salmon agingsick migrants moving back to their home country effects operate through a similar mechanism differences in health especially agerelated comorbidities and adadrd risk factors play an important role in survival and attrition and when these are ignored can lead to misleading findings mismatched linkages and overall quality of mortality data can also present a problem.,[22698043   510638 15074127 23644828]
81,partial aggregated and oligomerized intracellular aβ was documented to be cytotoxic and synaptotoxic in cell culture and in vivo,[11182300 11207825 12834113 10623648 15304237],regarding the interaction with iron it was found that fe3 influences the formation of amyloid fibrils of aβ142 56 and aβ2535 the interaction of redoxactive fe3 with aβ fibrils results in their chemical reduction and concomitant generation of reactive oxygen species ros causing lipid membrane peroxidation dna breakdown and protein oxidation,[15201484 11833745 12689772 14499458 15053949 15231239]
82,adad shares the neuropathological hallmarks of alzheimers disease ie neuritic plaques and neurofibrillary tangles composed of amyloidbeta aβ peptides and hyperphosphorylated tau respectively the order of adad pathologies as measured by biomarker abnormalities in presymptomatic and symptomatic phases of the disease continuum are reported to largely conform to those in sporadic alzheimers disease and also align to the atn aβ tau and neurodegeneration classification these similarities and the deterministic and predictable onset of symptoms in adad mutation carriers mc have made adad an important model for sporadic alzheimers disease in general,[21211070 22784036 30217935 29653606 27371494],"plasma biomarker profiles in autosomal dominant alzheimer’s disease autosomal dominant alzheimer's disease (adad) is caused by pathogenic mutations in the amyloid precursor protein (app), presenilin 1 (psen1) or presenilin 2 (psen2) genes.",[]
83,platelets are one of the major sources of blood circulating amyloid beta 21 22 and plateletderived amyloid beta seems to be involved in the formation of cerebrovascular 24 26 and cerebral amyloid beta deposits,[32681097  7639768 27221710 30341392 33668038],"Females in both experimental groups showed weight loss (Supplementary Table 2), whereas only platelet-depleted males lost weight during the experiment. the efficiency of platelet depletion in the brain was similar between females and males, with platelet-depleted mice showing about 97% lower platelet numbers in the brain compared with sex-matched igg treated mice (hippocampus: females: igg = 920.3 ± 528.9 platelets/mm3 versus αcd42b = 26.6 ± 10.88 platelets/mm3; males: igg = 563.4 ± 473.8 platelets/mm3 versus αcd42b = 16.67 ± 5.51 platelets/mm3).",[]
84,several papers in this field contain uncorroborated behavior endpoints such as acoustic startle prepulse inhibition psychomotor vigilance object in place recognition operant responding and conditioned taste aversion that like our strengthendurance measures would need repetition before meaningful interpretation,[15803624 24611657 24949841 22468701 12793763],other behavior endpoints: our study adds wire hang and grip strength tests to the literature. here we observed small changes of uncertain biological significance in wildtype mice but not transgenic mice.,[]
85,the presented molecular mechanism can be used for building correlations between different enzymebased cellbased animal and clinical studies of alzheimers disease,[21320126 26051801 23308095 22479317 33662398],the second substrate binds to the most dynamic sites in γ-secretase’s structure that can be affected by disease-causing fad mutations and by different drugs. the presented two-substrate mechanism can explain many of the pathogenic changes in γ-secretase activity at the molecular structural level.,[]
86,the presented twosubstrate mechanism is the first mechanism that can explain the apparently conflicting observations that both the c99βctfapp substrate and different aβ products can lead to pathogenic events,[18234110 22537414 30071370 23152608 29867356],"Toxic aggregation between the N-terminal domains of the two substrates can be controlled by the closure of the nicastrin ectodomain (Figure 3, Figure 4, Figure 5 and Figure 6). Closure and opening of the nicastrin ectodomain can be controlled by supramolecular interaction between β-secretase and γ-secretase (Figure 8A).",[]
87,astrocytes are the most abundant glial cells in the brain and play a vital role in maintaining brain homeostasis when ad occurs the deposition of aβ will induce astrocytes to transform from a resting state to a reactive state which is manifested by increased levels of glial fibrillary acidic protein gfap which in turn produce more proinflammatory cytokines and mediators such as interleukin1β il1β tumor necrosis factorα tnfα and interleukin 6 il6 which exacerbates the progression of inflammation additionally recent data found a specific accumulation of astrocytes associated with proinflammatory diseases in ad therefore inhibiting astrocytemediated inflammation may be a potentially effective strategy for reducing cognitive impairment in ad patients,[27443914 23595014 32507685 22727944 32341542],ave 0991 suppresses astrocyte-mediated neuroinflammation of alzheimer’s disease by enhancing autophagy alzheimers disease ad is a progressive neurodegenerative disease characterized by impairments in learning memory and cognition as well as changes in mood previously mainstream research focused on the pathogenic effects of the two main ad drivers aβ peptide aβ and hyperphosphorylated tau hptau protein recently more and more evidence indicated that neuroinflammation plays a central role in the pathogenesis of ad emerging studies have suggested that controlling neuroinflammation mediated by glial cell activation is an important therapeutic strategy for ad and previous reports have also found that the glial responses activated by aβ can promote the release of proinflammatory cytokines to cause neuronal dysfunction and memory impairment therefore targeting neuroinflammation induced by glial activation may be an effective way to slow or prevent the progression of ad,[]
88,since the average age of the control group at the end of the study was around 86 years it is expected that between 20 and 40 of the 25 control cases should be presymptomatic for different neurodegenerative diseases,[35697880 35099509 25988462 31961372 29508259],"by analyzing the data using biomarker panels tailored for these sex differences, a significantly higher percentage of ad cases (96%—all but one male ad case) were identified, where most of these cases could be diagnosed using the earliest available plasma samples (16 out of 25), including 15 out of 24 cases diagnosed pre-symptomatically. Quite notably, diagnosis of AD using the sex-biased biomarker panels detected a higher percentage of AD cases (96% vs. 88%) at an earlier time point (6.3 vs. 6.0 years before clinical AD diagnosis) (Table 4).",[]
89,reduced levels of the hormone have consequently been associated with aβ accumulation tau hyperphosphorylation oxidative stress and neuron loss which contribute to ad progression,[25045655 35021306 26154489 30632505 31746286],the hormone exerts protective effects on neuronal synapses by preserving the production of presynaptic proteins including synaptophysin synaptotagmin and synapsin1 7475 and has thus been reported to contribute towards the maintenance of dendritic spine density synaptic integrity and synaptic plasticity in the hippocampus which underlie learning and memory propensity depletion of testosterone in the hippocampus has been shown to induce oxidative stress and neuronal damage leading to a reduction in antioxidants upregulated expression of caspase3 and subsequent neuronal apoptosis,[25045655 31805308 17132744 27599230 35021306 33691594]
90,the concept that ad and glaucoma may share a common underlying vascular aetiology has been increasingly investigated over recent years and evidence of vascular dysfunction that was related to either disturbed vascular autoregulation or disturbed neurovascular coupling mechanisms has been previously demonstrated at the cerebral 383940 and ocular level  in both conditions but separately,[15140605 16540327 21205781 26498862 29119370],"indeed, the time taken for the retinal arteries to reach the point of maximum dilation following the onset of flicker light stimulation was found to be significantly greater in both ad and poag patients in comparison to healthy controls, on the final flicker cycle. furthermore, the sequential changes in the rt of the retinal arteries on progressing from flicker 1 to flicker 3 was found to vary significantly between all study groups with healthy controls showing a significant faster rts on heading into the final flicker cycle, which was not replicated by any of the diseased groups.",[]
91,an in vitro study reported that mesenchymal stem cells mscs from c57b6 mice exposed to pbm therapy presented an increased phagocytic state toward aβ whereas yang et al observed a pbmdriven normalization of inflammatory responses through the downregulation of proinflammatory factors in primary astrocytes exposed to aβ accordingly pbm animal studies have detected a decrease in proinflammatory markers in ad transgenic and nontransgenic models such as interleukin 1β il1β tumor necrosis factor α tnfα and transforming growth factor β tgfβ   with some studies also demonstrating reduction of hyperactivated glial cells accompanied by decreased aβ andor tau load,[24994540 20884337 21116053 27815990 28255783],"moreover two vs protocols led to a significant decrease of levels of hyperphosphorylated tau assessed by different tau phosphoepitopes in the visual cortex of p301stau mice  hence despite the preclinical evidence reporting the beneficial effect of pbm and vs on tau pathology no pbm or vs clinical study has monitored tau pathology in the human brain among the 43 included articles, 12 of them reported alterations in immunological activity induced by light stimulation.",[27929004 31076275]
92,vr technology has also been reported to be used for people with mild cognitive impairment mci  people at high risk of cognitive decline  memory rehabilitation patients with noncommunicable diseases ncds  patients with ncds due to traumatic brain injury  stroke patients   and patients with severe ncds due to ad,[33101098 24998488 26158918 26029101 29507261],additionally people also want to know what they can do to delay the onset or reduce their risk of developing ad virtual reality vr technology has been widely used in rehabilitating older adults with medical conditions to enhance their ability to perform activities of daily living in the last years,[34354619 31547137 34318524]
93,many studies 625 met the criteria for moderate immersion   with the remainder being 125 high immersion  125 low immersion experiences  and 125 information unavailable for immersion,[22261206 30409202 28655135 31409559 32349413],"virtual reality (vr) levels of immersion, characteristics of the vr programs, and user experience. shows the objective level of immersion based on the five criteria developed by slater et al",[]
94,in addition neuroinflammation caused by glial cell activation plays an essential role in ad,[25792098 27179961 26984188 30349474 33318676],"however, how toxic conformers contribute to the progression of ad pathology has not been studied in detail. this study investigated age-dependent phenotypic changes related to ad pathology in nl-p-f mice.",[]
95,it should be noted that oxidative stress alters lipidlipid interaction leading to impaired membrane permeability 76 and high levels of markers of oxidative stressinduced lipid peroxidation and cytotoxicity such as 4hydroxynonenal mda or thiobarbituric acid reactive substances are increased in ad 77 78 and diabetes  supporting a synergistic effect when both diseases coexist,[28212725 28098243 35227014 35245527 24999379],"likewise advanced glycation end products resulting from hyperglycemia in t2d alter the structure and function of bbb proteins 62 and diabetesinduced inflammation leads to astrocytic feet swelling in small vessels separation of the plasma membrane and accumulation of hypertrophic microglia our in vivo observations were also confirmed by postmortem assessment of oxidative stress and an overall increase of lipid peroxidation was observed in ad-t2d animals, when compared with ad alone.",[30618559 35299293]
96,recent studies have suggested that bbb dysfunction is correlated with human cognitive impairment 239 including the early clinical stages of ad and is considered as an early biomarker of the disease,[30643288 29377008 25611508 27243267 27459939],vascular dysfunction in ad accelerates bbb breakdown 237242 degeneration of pericytes 237 240 243 244 and reduction of bbbassociated cells that maintain integrity the presence of vascular aβ pathology also called cerebral amyloid angiopathy caa predisposes toward neurovascular impairment and sometimes stroke,[23126372 22857991 30340601 30643288 22857991 33567873]
97,during obesity the expanded adipose tissue secretes proinflammatory factors and the ffas which reach the bloodstream and lead to tonic activation of the innate immune system and to maladaptive responses such as fibrosis necrosis and altered secretion of local proinflammatory factors which cause significant tissue damage in multiple organs including pancreas liver skeletal muscle heart and brain,[15677759 24593134 20035279 17578888 21633177],"in the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in t2d and ad, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives. lowgrade chronic systemic inflammation is an established hallmark of lipotoxicity",[14679176 25729921 28045402]
98,interestingly as opposed to microglial large evs neuronal and neuroblastoma cell line small evs seem to promote amyloidogenesis of soluble aβ through the binding of the amyloid peptide to the glycosphingolipid glycans 616292 and to the cellular prion protein prpc  present on their surface,[22303002 25037226 25741766 19242475 26710111],indeed the amyloid precursor protein app and its metabolites including the aβ peptide have been shown to be secreted within neuronderived small evs in addition sardar sinha and colleagues  demonstrated that the impairment of the formationsecretion of small evs can suppress the diffusion of aβ oligomers to other neurons,[16837572 18171695 17468104 19773092 28956068 29934873]
99,glp agonists such as liraglutide and exendin4 have been shown to increase insulin sensitivity in the periphery 979899100 and the brain,[30371206 31034184 32139381 28572610 29435980],more recently a phase iii clinical trial to assess the efficacy of pioglitazone in protecting against progression to mci was terminated when a futility analysis revealed that there was no likely benefit in preventing a cognitive decline more recent interest has been in evaluating glucagonlike receptor glp agonists as these agents offer the advantage of crossing the bbb and exerting direct neuroprotective effects,[34146512 29412810]
100,similar findings have been reported on another glp1 agonist exendin4 as it has been shown to increase brain insulin synthesis 109 to restore cerebral insulin signalling 110 to attenuate aβ and tau pathology as well as neuroinflammation 111112 and to improve cognition,[34587885 28573460 32737929 31256135 31082410 31082410],this glp1 agonist has also been shown to reverse memory impairment and synaptic loss in aβ mouse models 106 with similar findings in nonhuman primate models similar findings were observed in ad mouse models in the presence of t2d  suggesting multiple mechanisms underlying liraglutides neuroprotective benefits,[25107586 29435980 33467075 34975451]
101,there is data indicating direct associations between plasma adipoq levels and the expression of adiponectin receptors in peripheral blood mononuclear cells pbmc,[15897298 21284833 20178558 23510830 25392268],as mentioned adipoq binds to 3 receptors adipors adiponectin receptor type 1 and type 2 g proteincoupled receptors and tcadherin cadherin family adipor1 is primarily associated with adiponectins metabolic functions while adipor2 is also engaged in the antioxidative and antiinflammatory actions of adipoq,[15897298 16380487 17618856 31377319]
102,considering the multifactorial nature of ad a promising therapeutic approach is the development of multitarget drugs having a complex effect on several biological targets responsible for the pathogenesis of this disease,[24533013 28358144 26281952 24493627 24851088],moreover cu2 and fe2 support the production of reactive oxygen species and increase of oxidative stress thus promoting neurotoxicity therefore selectively reducing brain concentrations of metals with chelating agents is one of the therapeutic approaches proposed for the treatment of ad,[15105262 26343967 21414382 23685572]
103,one of the design strategies for multitarget drugs is to use a molecular spacer to link together two pharmacophores that are active against two or more different biological targets and a wellknown anticholinesterase drug molecule is often used as one of the pharmacophores,[26797191 29768996 31735356 30744931 33342413],therefore selectively reducing brain concentrations of metals with chelating agents is one of the therapeutic approaches proposed for the treatment of ad considering the multifactorial nature of ad a promising therapeutic approach is the development of multitarget drugs having a complex effect on several biological targets responsible for the pathogenesis of this disease,[21414382 23685572 24533013 28358144 26281952 24493627 24851088]
104,"in humans divergences between
different brain areas have been shown the decrease in bdnf both protein and
mrna has been confirmed in numerous studies but the
putative changes in ngf were not being confirmed although the
cholinergic theory of ad presupposed a decrease in ngf",[ 9387865 10867782 19625522  9387865 10867782 15935057  1742020],"here,
we present what we consider to be some of the most interesting of
these:(a) one possible therapeutic strategy is to compensate the
deficits in neurotrophins (mainly nerve growth factor –ngf- or
brain derived neurotrophic factor - bdnf) caused by the
dysfunction or involution of astroglia. studies on changes in
neurotrophic factors have given rise to controversial results
for years, both in the study of human brains and in the study of
experimental models of ad.",[]
105,"in humans divergences between
different brain areas have been shown the decrease in bdnf both protein and
mrna has been confirmed in numerous studies but the
putative changes in ngf were not being confirmed although the
cholinergic theory of ad presupposed a decrease in ngf",[ 9387865 10867782 19625522  9387865 10867782 15935057  1742020],"(a) one possible therapeutic strategy is to compensate the
deficits in neurotrophins (mainly nerve growth factor –ngf- or
brain derived neurotrophic factor - bdnf) caused by the
dysfunction or involution of astroglia. studies on changes in
neurotrophic factors have given rise to controversial results
for years, both in the study of human brains and in the study of
experimental models of ad.",[]
106,microglia perform preventive actions including the removal of aβ the inhibition of tau hyperphosphorylation and the production of neurotrophic factors which delay the onset of ad symptoms,[27091843 30572908 25630253 33008458 29740062],aluminum causes damage to nerve cells mitochondria 108 apoptosis and programmed necrosis 109110 aβ deposition 111 abnormal tau protein phosphorylation  changes in synaptic plasticity and glial activation microglia activation happens before ad manifests according to in vivo pet imaging studies,[26944603 25971159 28211326 23574527 23219964 26984188]
107,numerous neuropathological changes that occur during ad     likely contribute to this altered pain experience,[16951408 21257326 23277361 10976641  1300498 16951408 23277361],this represents substantial numbers because there are 65 million people living with ad in the united states us  and over 55 million with dementia globally preliminary neuroimaging studies indicate that major brain regions involved in pain processing continue to demonstrate activation in response to painful stimuli in ad  but it remains unknown how this activation contributes to the pain experience in ad,[16951408 28222526]
108,both histopathological and ultrastructural shifts were detected in the cerebral microvasculature and in neurons which was supported by results of previous studies,[22792182 23404118 16039562 18305170 19725828],"the tol2 plasmid used to generate this transgenic zebrafish contained a zebrafish promoter, exogenous human cdna, and a cmv promotor and egfp tag. egfp expression was used to examine the time and location of expression of the transgene. the zebrafish telencephalon, which is comparable to the mammalian hippocampus, was morphologically altered in this transgenic model.",[]
109,hence genomic studies of the human gitract microbiome indicate that this microbial repository currently represents about 1 thousand times the genetic complexity of all proteincoding sequences found in the entire human genome  httpswwwhmpdaccorghmpoverview last accessed on 10 october 2022,[26338727 17943116 32690973 31415755 27190214],"as a complex microbial repository i this compartment includes a broad spectrum of microbes which represent mostly facultative anaerobes or anaerobic bacteria followed in abundance by archaebacteria fungi protozoa viruses and other microorganisms 123 ii represents the largest source and highest density of microbial species found anywhere in nature 45 and iii comprises about 13 of the human body mass 2 to 6 pounds of microbes in a 200pound adult collectively constituting the largest diffuse organ system in the human body and at least as metabolically active as the liver relatively recent data from us national institutes of health (nih)-funded interdisciplinary human microbiome project (hmp) initially classified over ~200 thousand diverse, non-redundant prokaryotic genomes in the human gi-tract microbiome comprising about ~5 thousand different gi-tract microbial species, which together encode about ~200 million different protein sequences.","[26338727 17943116 32690973 31415755 26338727 17943116 32690973 31415755
 27190214]"
110,interestingly oa structures which represent the outermost and most immunologically exposed component of bacterial lpss are extremely diverse and approximately 200 different serogroups have been identified for escherichia coli alone,[17943116 32690973 31415755 27980292 16953973],the microbial om is not a phospholipid bilayer but is instead a highly asymmetric capsule containing phospholipids in the inner leaflet and lps molecules in the outer leaflet noncovalently bound and ultimately shed from the om matrix into surrounding biofluids large lps species of approximately 1000 kda per subunit consist of a hydrophobic lipida domain also known as the lps endotoxin attached to a core oligosaccharide coreos and a distal oantigen oa also known as an opolysaccharide  httpspubchemncbinlmnihgovcompoundlipopolysaccharide last accessed on 20 september 2022,"[34457996 18194336 12045108 27980292 16953973 34457996 18194336 12045108
 27980292 16953973]"
111,the oxidative stress produced by preoxidants in neurons and neural cell lines can be counteracted by saponins via their antiradical effects,[19447300 19185022 17659841 19138476 18809438],"sources, bioactives and underlying neuroprotective mechanisms of saponins. The antioxidant potentials of saponins are linked with the neuroprotective effects of these compounds (Figure 7).",[]
112,"a1 astrocytes can enhance local neurodegeneration or conversely they may help
remove unrecoverable neurons in an attempt to repair neuronal circuits",[28099414 31136698 30276955 26232154 32819809],"a1 astrocytes can be identified in vivo by c3d complement upregulation other
suggested markers are h2t23 fkbp5 and ligp1 these neurotoxic astrocytes
can enhance local neurodegeneration or conversely they may help remove
unrecoverable neurons in an attempt to repair neuronal circuits a1 astrocytes
also produce different neurotoxins not well identified until now dserine no and
proinflammatory cytokines tnα and so on these substances produced in
different quantities in the different subtypes of a1 astrocytes induce neuronal
apoptosis and different alterations in oligodendrocytes including
prooligodendrocytes and microglial cells different local physiological
or pathophysiological scenarios can reactivate the neuroinflammatory process that
has started or that is ongoing or on the contrary to initiate an
antiinflammatory response tending to restore normality of the cns although
unfortunately it is the rarest possibility tgfβ and fgfs have been reported to
reduce neuroinflammation caused by activated microglia and astrocytes liddelow et al 2017
further found that tgfβ1 downregulated several genes related to the a1 phenotype","[33803478 34048845 28099414 31136698 30276955 26232154 34048845 34048845
 21234816 24616125 30210273]"
113,"the plasticity of glial cells particularly in terms of reactive gliosis
includes modifications to the structure of glial processes changes in cell
motility andmore importantlymodifications in the production of diverse
neuroprotective neurotrophic factors gliotransmitters etc and neurotoxic
substances cytokines chemokines free radicals prostaglandins no or other
neurotoxins the expression of different gfap isoforms in
astrocytes as well as the different reactive forms of these normal
neuroglial cells or subsets of astroglia must also be kept in
mind",[30158892 12909295 11137576 22912745 33589835],"perhaps the most important justifications of the involvement
and the simultaneous or exclusive neurotoxic and/or neurodegenerative effects of
neuroglial cells in ad are indicated below.1) differences in the response of different
neuroglial families or subtypes. 1) differences in the response of different
neuroglial families or subtypes.",[]
114,in our study the periodontitisrelated salivary microbiota treatment reduced gut microbial richness and diversity a ubiquitous indicator of diseaseassociated dysbiosis in addition an increased abundance of bacteroidetes was observed in mice gavaged with periodontitisrelated salivary microbiota compared to that in healthy mice in accordance with gut microbiota alterations in patients with ad the phylum bacteroidetes consists of a diverse group of gramnegative commensal bacteria in the intestine and is more predominant than firmicutes in the elderly according to spearmans correlation analysis with adrelated parameters lactobacillus sutterella oscillospira ruminococcus rikenella and helicobacter at the genus level might be crucial for gutbrain bidirectional communication in ad pathogenesis lactobacillus is a probiotic that ameliorates brain inflammation by participating in gastric vagus nerve activity compared with the healthy control the mice in the p group exhibited decreased lactobacillus abundance although not significantly this may be due to the limitation of gavage time,[22411464 29051531 24861948 19508720 21876150],"furthermore, the increased plasma concentrations of tnf-α and il-1β reflected systemic inflammation, which might be attributed to gut-associated lesions. under pathological conditions the oral microbiota can colonize in the gut and disrupt the intestinal gut microbiota since intestinal inflammation and gut microbiota dysbiosis have been considered prominent features in the progression of ad periodontitisrelated salivary microbiota might produce cascade effects on the intestine of pap mice",[31471351 33504065]
115,our findings were also consistent with the structural racism and discrimination srd literature and supported the framework of srd patients with adrd,[10936998 25632292 25626224  8450822 35659469],several sdoh are associated with cognition and adrd diagnosis such as low socioeconomic status low levels of education economically disadvantaged regions with limited physical resources and food security among other factors results of our study suggested that acos aimed at improving access to necessary timely care may help decrease existing disparities resources can be directed toward sdoh to improve the well-being of older adults.,[33756057 34103175]
116,in addition rothia haemophilus and alloprevotella are normal in the oral cavity  anaerostipes and weissella are common in the intestine with anaerostipes facilitating acetate formation   whereas weissella is an emerging genus with potential health benefits capable of inhibiting pathogenic microbial growth through the production of bacteriocins,[22698087 24215821 34870576 33565028 32017095],it is boldly speculated that the altered microbiota may be associated with a systemic inflammatory response. to further support our speculation we correlated systemic inflammatory markers with microbiota and found that a specific oral and gut microbial composition was associated with inflammatory markers fusobacterium and selenomonas have been reported to be associated with unhealthy microbial characteristics in patients with gingival and periodontal disease whereas fusobacterium may be a major indicator of microbial transformation into inflammatory pathogenic bacteria   and a potential biomarker of periodontitis and gingivitis episodes,[34204609  2777378  9495607  9495612]
117,the kv21 channels are the main α subunits mediating the delayed rectifier k currents idr in hippocampal and cortical pyramidal neurons where they are present as large highdensity clusters on the pm of somata and proximal dendrites,[10024359 14977411 16988031 22648171 30712450],mediating k fluxes across the plasma membrane pm k channels are crucial determinants of neuronal excitability Among them voltagegated K channels KV are the largest family of K channels expressed in both the central and peripheral nervous system where they participate in different biological processes including the regulation of action potential conduction neurotransmitter release synaptic plasticity and apoptosis ,[]
118,activated microglia and astrocytes play an important role in the clearance step of aβ phagocytosis,[31973106 18701698 21757877 28666707 20552234],"therefore, our results support the hypothesis of early plaque formation appearing before the onset of decline in neurogenesis. accumulation of aβ plaques induces inflammatory responses.",[]
119,we measured this plasticity through in vivo singleunit recording which although labor intensive and timeconsuming compared to intrinsic optical imaging or visually evoked field potentials 46 is a gold standard in quantifying vc plasticity,[22674275 25164659  8627365 32594561 16195464],"ODP may be a more sensitive readout of abnormalities in circuit functions than pathological or behavioral phenotypes  we show that after monocular visual deprivation, 5xfad mice lack odp in vc during the normal critical period.",[]
120,recent studies based on neuropsychological tests or brain imaging data identified other mci subtype classification systems in which different subtypes of mci have different conversion rates to ad,[32142126 27239533 31128864 29455029 29323751],"this classification system divides mci into amnestic and nonamnestic mci, each further divided into a group with impairment in a single cognitive domain (single-domain mci) and a group with impairments in multiple cognitive domains (multiple-domain mci). it has been reported that amnestic mci regardless of whether it is single or multipledomain mci comparatively highly converts to dementia mainly ad dementia at a rate of 10  to 15  per year",[19752306]
121,affinity measurements of the copper complexes with aβ and tau indicated dissociation constants in the range from nanomolar to attomolar values 110111112 and from micromolar to high picomolar  respectively,[20974842 10465554 10936205 18803399 31820933],"a better understanding of their relationship at a molecular level, could be beneficial for elucidating ad pathogenesis. in this regard, determining the affinity of metal ions for tau and aβ proteins is essential to understand the biological relevance of these metal complexes and predict which biomolecule could effectively compete with aβ and/or tau for metal ion complexation.",[]
122,although loss of financial capacity is a common consequence of ad 2 parkinsons disease 3 vascular dementia 4 frontotemporal dementia  and amnestic mild cognitive impairment 6 only one study has investigated what caregivers of frontotemporal dementia patients believe,[29504530 31115356 32366802 33818175 33136558 33818175],"what biological factors, social determinants, and psychological and behavioral symptoms of patients with mild alzheimer’s disease correlate with caregiver estimations of financial capacity? bringing biases against older women into focus neurocognitive disorders such as alzheimers disease ad are often diagnosed in later stages due to its insidious onset and particularly in greece this can be explained by the fact that the general public is not able to recognize the early symptoms of this disorder attributes the symptoms as part of the normal aging process and shows general ignorance regarding this disease",[]
123,all participants provided written informed consent in accordance with the helsinki declaration and approval for the studies was obtained by the local ethics committeestable 4characteristics of the cohorts included in the studyadnijadniaibladdneuromedstudy designlongitudinal multicenter cohortlongitudinal multicenter cohortlongitudinal multicenter cohortlongitudinal multicenter cohortdata collection period2004present201820142006present20042010countryusa and canadajapanaustraliafinland france greece italy poland sweden and united kingdominclusion criteriammse 2026 cdr 051 age 65 nincdsadrda criteria for probable ad gds  6mmse 2026 cdr 051 age 65 nincdsadrda criteria for probable ad gds  6mmse 1826 cdr 05 nincdsadrda for criteria for probable ad icd10mmse 1228 age 60 nincdsadrda for criteria for probable ad and dsmivfollowup intervals312 months612 months18 months12 monthsstructural mri field strength15 t and 3 t15 t15 and 3 t15 tbiomarkers availableyesyesyesnocsf platform cutoffelecsys 880 pgmlaluminex 333 pgmlpet cut offfbb suvr  108av45 suvr  111bav45 suvr  111 pib suvr  148pib suvr  15mmse minimental state examination cdr clinical dementia rating gds geriatric depression scale nincdsadrda national institute of neurological and communicative disorders and strokealzheimers disease and related disorders association icd10 classification of mental and behavioral disorders suvr standardized uptake value ratio av45 florbetapir pib 11cpittsburgh compound b fbb florbetabenathe upenn biomarker batch 9 was used to quantify adni csf positivitybcomposite suvrs for fbp  111 or fbb  108 were defined as positive as described on the adni website httpsadnibitbucketioreferencedocsucberkeleyfbbucberkeley_fbb_methods_041119pdf,[29499171 29753531 29753531 23166389 29753531 27966045 20472326],"this study includes 891 ad dementia patients and 319 cu individuals from four international multicenter cohorts alzheimers disease neuroimaging initiative adni httpadniloniuscedu japanese adni jadni httpshumandbsbiosciencedbcjpenhum0043v1 addneuromed httpsconsortiapediafastercuresorgconsortiaanm and the australian imaging biomarkers and lifestyle study aibl australian adni httpsaiblcsiroau table the ad inclusion criteria of the four cohorts were similar since the research protocols of j-adni, aibl, and addneuromed were designed to be comparable with adni (supplementary material, p. 1–2).",[29753531 19470201]
124,obesity as measured by body mass index bmi has been reported to be associated with an increased risk of dementia in middle age and may reduce the risk of dementia in later life   one hypothesis to explain the situation is a pattern of the socalled obesity paradox in which excess weight traditionally considered detrimental to health may be beneficial in older adults to reduce the disease risk however although bmi is widely accepted as an indicator of general adiposity in populationbased studies it cannot distinguish between fat and muscle mass which is highly variable at the same bmi level  furthermore body composition is more informative than bmi because changes in bmi lag behind changes in body composition with dementia progression,[25866264 25030513 19273752 19273752 12117701 32803916],"total and regional fat‐to‐muscle mass ratio and risks of incident all‐cause dementia, alzheimer's disease, and vascular dementia dementia including alzheimers disease ad and vascular dementia vd is the fifth leading cause of death globally affecting approximately 44 million people worldwide due to the current lack of diseasemodifying therapies dementia prevention has become an urgent public health priority",[]
125,alzheimers disease ad the most common cause of dementia is a progressive neurodegenerative disorder that causes deficits in memory thinking decision making and social skills the pathophysiological events of ad begin years before the onset of clinical dementia the national institute on agingalzheimers association niaaa proposed three subsequent stages of ad including the preclinical stage of ad mild cognitive impairment mci and ad dementia   the primary hypothesis on the progression of ad pathologies stated that the initial deposition of amyloidβ peptide aβ leads to subsequent tau hyperphosphorylation neuron and synaptic loss and cognitive decline however the continued failure of clinical trials aimed at decreasing aβ plaques implies that there may be alternative causes of disease progression or the neuronal injury of the late mci and ad dementia may be irreversible the long preclinical phase with mild neuronal damage provides a potentially crucial opportunity for exploring the potential pathogenic mechanisms of ad and preventing or delaying the progression of this disease,[21371747 21514250 21514249 21514248 21514248 32568197],impaired type i interferon signaling activity implicated in the peripheral blood transcriptome of preclinical alzheimer's disease,[]
126,positron emission tomography petcomputed tomography ct was performed using pittsburgh compound b for amyloid and flortaucipir for tau and individuals were considered a using a threshold of standardized uptake value ratio suvr  148 centiloid 22 and t using a temporal lobe meta region of interest roi at a threshold of suvr  125   biomarker subgroups were based on the recently proposed research framework for a biological diagnosis of ad and included participants with negative amyloid and tau pet biomarkers at and participants with preclinical ad at,[25443857 18263627 27697430 28138510 29653606],"two participants (7%) in the a+t+ group were diagnosed with mci during at least one of their follow‐up visits (2–4), whereas <1% of a–t– participants were diagnosed with mci. for validation diagnosis followed typical mcsa procedures and was based on consensus among the neuropsychologist study coordinator and examining physician",[18259084]
127,mice with complete or partial enos deficiency enos or enos respectively display increased levels of app βsite app cleaving enzyme 1 bace1 and aβ amyloid angiopathy and altered neuronal p25 an aberrant activator of the tau kinase cyclindependent kinase 5 cdk5 in the brain as well as memory deficits,[21127294 23745722 30614363 27601478 26104027],such agerelated enos deficiency may be an important early event contributing to later neurodegeneration in ad a number of animal studies have explored the link between enos deficiency and ad pathologies.,[24589433 16181125 22842871]
128,the oral cholinesterase inhibitor class of drugs is effective for improving the cognitive and global functioning of patients with ad and is the main pharmacological intervention used in the clinical management of ad however the incidence of adverse events aes associated with donepezil eg abdominal pain nausea and vomiting anorexia and diarrhea increases with the administered dose which can lead to difficulty in achieving and maintaining high therapeutic doses in clinical practice these dosedependent adverse symptoms linked to cholinergic hyperstimulation are related to plasma concentration fluctuations a novel therapeutic approach using a transdermal delivery system may be a solution to the abovementioned limitations,[ 9443470 15596605 23462265 28590369 15804207],"a multinational, multicenter, randomized, double-blind, active comparator, phase iii clinical trial to evaluate the efficacy and safety of donepezil transdermal patch in patients with alzheimer’s disease alzheimers disease ad is the most common type of senile dementia affecting 68 of people aged 65 years and nearly 30 of people aged 85 years every 5 years there is a twofold increase in the number of people aged 60 years affected by ad and so ad is expected to affect more than 115 million people worldwide by 2050 donepezil an oral cholinesterase inhibitor is widely used in clinical practice to treat mildtosevere ad symptoms",[]
129,the fact that shared risk factors for ad and brain disease such as hypertension 73 74 are also related to motor performance such as gait speed 75 and the fact that there are sex differences in motor performance 76 neuroanatomy 77 neurobiology 78 and agerelated neuropathology  warrants studying sex differences,[31381518 21391929 29771288 29287628 30927602],"lastly, the reviewed studies did not look at sex differences in the relationship between motor function and brain measures, but merely adjusted for its effect statistically. it is therefore uncertain if the relationship between motor differences and brain differences in mci and ad differ by sex.",[]
130,currently prs seems most applicable to estimate risk in lateonset forms of ad 28 64 and has proven useful to stratify patients for clinical trials to reduce variability 65 66 and for genes that show reduced penetrance eg psen2 prs might influence clinical expression as has been shown for other diseases such as hereditary breast cancer,[34099642 29555425 34621978 31363735 32820175],"although a few families showed higher risk, this currently seems insufficient to justify clinical action — similar to apoe — until disease-modifying therapies or cost-effective preventive measures become available. as a result, although the prs will likely improve when more variants are added to it, we foresee it will not change this view on its clinical utility in familial eoad in the near future.",[]
131,alzheimers disease ad is a progressive neurodegenerative disorder manifested by cognitive and memory deterioration in addition to progressive impairments of activities of daily living and behavior and neuropsychiatric symptoms  commonly used approved ad treatments are acetylcholinesterase inhibitors donepezil rivastigmine and galantamine and a noncompetitive nmethyldaspartic acid receptor blocker memantine however these do not slow the progression of the disease   and only demonstrate modest efficacy to symptomatically improve or stabilize the clinical trajectory for most patients aducanumab an amyloidtargeting monoclonal antibody has been shown to remove amyloid plaques and holds promise for producing modest clinical benefits in early ad but requires monthly infusions and substantial safety monitoring including magnetic resonance imaging mri the modest efficacy and side effects of current treatment options along with a growing elderly population provide an impetus to develop more effective therapeutic agents with a wider range of application,[30704681 30704681 19724715 17466645 30925615 34585212],"effect of masupirdine (suvn‐502) on cognition in patients with moderate alzheimer's disease: a randomized, double‐blind, phase 2, proof‐of‐concept study",[]
132,arachidonic acid derivatives and other immune regulators are regulators of the neurogenic outcome and neuroregeneration in zebrafish,[23168169 23138980 27760324 31905199 31719242],notch signaling is an important determinant of neurogenesis in vertebrate brains 31 and is related to glial cell proliferation arachidonic acid and its derivatives are among the key regulators of the immune system,[26932669 32476207 23863484 34064238]
133,in addition to bactericidal effects amps are also antiviral antifungal 33 antitumor 34 and immunomodulatory 22353637 and are involved in autoimmune diseases,[19217824 16257969 30314800 15892627 21178486],these two modes of action do not allow bacteria to develop resistance unlike what happens to conventional antibiotics amps also inhibit bacterial protein nucleic acid cell wall synthesis and enzymatic activities,[28083516 31438824 11958294 25220491 25113635]
134,we present data on the detoxifying effects of gal201 on oligomers formed from aβ142 and on pyroglutamatemodified aβ aβpe3,[21965666 23747948 12354296 17029395 21903077],"a detailed understanding of the formation of toxic aβ oligomers and their effects is essential to develop urgently required new treatments for ad patients. this manuscript describes pharmacological characteristics of the new drug candidate gal-201 as an aβ aggregation modulator based on data from binding experiments, from a rat pharmacokinetic study and from patch clamp and ltp experiments.",[]
135,in the literature it is widowhood of the patient that is reported as a risk factor of nhp  as well as the fact of living alone being cared for by an adult offspring caregiver can be considered as a proxy report of living alone or being widowed and as such our finding is consistent with the literature some evidence suggests that spouses regard caregiving as part of their marital duties whereas for adult children such caregiver tasks require an important change in their lifestyle,[18606052 22759566 26658776 20723154 20374966],we found the status of “offspring caregiver” to be a risk factor of nhp. the literature reports difficulties in life balance among adult offspring caregivers especially with regards to work workfamily life balance in the group of offspring caregivers the incidence of nhp is however similar independently of the patients marital status,[20723154]
136,our study also demonstrated that pathogenic genes such as csmd1 rbfox1 ptprd cdh13 and wwox were significantly related to ad,[25024348 32568366 30648269 29771432 34359949],"then, we used the top 10 bonferroni-corrected genes for gene identification. The significant common genes in the three groups are listed in Table 3.",[]
137,however the concentrations of these biomarkers in human blood are very low which is motivating the development of ultrasensitive assay technologies,[17499942 19204155 25086887 25300247 26136856],a trend to evaluate the risk of alzheimers disease ad is the assay of biomarkers in blood the most recognized biomarkers related to ad are amyloid β 140 aβ140 and aβ142 peptides and total tau protein tau,[23470193 23850333 27870940 30922367 29653606 32390633 32784025 33075193]
138,several studies exhibited that picomolar concentrations of aβ42 can act as an agonist of α7nachrs 80 81 resulting in increased acetylcholine production in hippocampus 51 activated pi3k 33 and elevated expression of map kinase which eventually led to an increased level of ltp,[15009674 11983690 19749407  8916088 18832563],"aside from the positive correlation reported between low concentrations of aβ and ltp aβ has also been shown to target nicotinic acetylcholine receptors nachrs 76 77 which are known to promote synaptic plasticity neuroprotection learning and memory and regulate transmitter release in several brain regions including hippocampus interestingly, mounting evidence points to the possibility that this interaction too operates under hormesis.",[12436426 19126755 30471405  8878480  9736631]
139,a decrease in the volume of these brain regions in patients with depression may be associated with both a decrease in astrocyte density 8485 and neuronal atrophy 8586 and a decrease in the number and functioning of synapses,[26742791 23469922 23469922 15522247 25582786 31801966],"atrophy of these brain regions is considered as a significant predictor of the development of clinical dementia consequently, atrophy of the medial pfc and hippocampus may be associated with pre-existing depression and/or with early stages of dementia development.",[20375138 18258339 26306871]
140,depression is also associated with the suppressed expression of astrocytic s100b 114 aquaporin 4 85 as well as connexins 30 and 43 and the transcription factor sox9 regulating the expression of connexins,[20386568 23469922 10392848 21571253 27516431],"along with a decrease in astrocytes density, possibly occurring only in the most severe cases of depression, there are data indicating changes in the functioning of astrocytes in patients with mild depression. in the cortex lc and hippocampus transcriptomic analysis revealed a depressionassociated decrease in the expression of astrocytespecific glutamine synthetase and glutamate transporters which are involved in glutamateglutamine cycle between neurons and astrocytes and play an important role in the functioning of synapses",[ 1881516 20386568 16230605 26519765 19668376]
141,neuropsychiatric inventory npi 384649 was used to assess the behavioral symptoms while the wordrecognition task  was used to assess recognition memory function,[24678298 31529691 24262299 18525028 24262299 21840288],for the memory domain the assessment included the wordrecall task 4151 instructionremembering task 4651 rivermead behavioral memory test 38 rey auditory verbal learning test 38 tinetti balance scale 38 tinetti gait scale 38 word list memory test 41 nback 41 wechsler adult intelligence scale 4144 rey complex figure test 42 seoul verbal learning test 42 frontal assessment 43 category verbal fluency test 46 digit cancellation task  and wordlist learning task the language was assessed by using the boston naming test 4142 picturenaming task  and battery for analysis of aphasic deficits,"[31285793 21840288 31529691 21840288 24678298 24678298 24678298 24678298
 31285793 31285793 31285793 25346688 31196835 31196835 31555109 31529691
 24262299 24262299 31285793 31196835 24678298 24678298]"
142,as a result it disrupts the differentiation and maturation of precursor nerve cells inhibits the formation of new synapses and reduces the plasticity of neurons,[27725817 29520228 26509334 24711006 27179961],"in ad, however, there is chronic inflammation caused by continuous stimulation with pro-inflammatory agents. this causes the neurodegenerative action of microglia with uncontrolled production of pro-inflammatory cytokines through nf-κb activation and ineffective phagocytosis, preventing effective clearance and promoting β-amyloid production and deposition.",[]
143,from our initial list of potential publicly available datasets we selected six datasets based on the data availability the species and the presence of values for a fold change and adjusted pvalue figure 1 table 3,[31908000 22728825 23430253 26139848 20041192],"the presence of three signalling pathways known to be important for locomotor function in our analysis, strongly suggests a central role for bace1 in the regulation of axon guidance and axonogenesis, beyond that of the cleavage of chl1. we explored the literature for proteomic datasets of proteins differentially expressed (de) in response to changes in bace1, through overexpression, knockout, knockdown, or inhibition.",[]
144,conversely epilepsy especially lateonset epilepsy of unknown etiology no cause identified after completing etiological study has been described as a risk factor for the development of ad,[25484360 34117482 33097597 32150220 17182059],"ad dementia and epilepsy frequently coexist, and there are reciprocal relationships between the two diseases. ad is an independent risk factor for epilepsy with an increased risk ranging from 2 to 10 times compared to agematched healthy controls","[33097599 32488295 32116260 28826176 29941211 25484360 26008894 28397967
 34117482 29710705 31532186]"
145,dna damage occurs in response to various endogenous biological activities in cells in which dna doublestrand break dsb is a predominant damage and can lead to cell death if not repaired,[26462757 21055985 19847258 32394945 19847258 22197993],dna repair failure is a severe phenomenon for neurons since they lack cell division moreover dna damage accumulates in addition to the aging process and failure of dna repair affects transcription and translation resulting in breakdowns for genomic integrity,[26462757 32394945 26462757 15734677 31101070]
146,they suggest decreases in excess neuronal activity   improved cognitive functions  reduced amyloid plaque load in some cases  or a rescue from the depletion of neuronal stem cells due to network hyperactivity  see  for a review,[25878292 22869752 22869752 23889921 23889921 31242408 33741601],furthermore it appears that asms including lev do elicit such a positive effect on cognition even with chronic treatment in loeu patients without ad  especially in patients diagnosed with focal seizures although the amount of randomized casecontrol studies remains too low for further conclusions  preclinical results of antiepileptic treatments in ad are promising reviewed by  and,[31726425 33314010 33741601 33929683]
147,global estimates of pain vary substantially across countries ranging from 10 to 50 country level factors associated with pain include income inequality gini index higher population density gender inequality lower life expectancy and region about 34 of adults in lmics reported chronic pain compared to 30 of adults in hics although there is increasing literature on pain as a potential risk factor for cognitive decline  and adrd risk    sex and gender differences have not been studied widely and even less so across cultures,[22697274 28586818 34155725 28586818 31694670 30543173],few studies have assessed whether the relationship between tbi and adrd risk differs by sex and the evidence has been mixed      this may be because adverse health and psychosocial factors throughout the lifespan moderate the risk of adrd following tbi      for example greater exposure to adverse childhood experiences earlier in life has been observed as a risk factor for both tbi and other poor health behaviors and outcomes that interact throughout life to increase adrd risk  many of the overlapping adverse psychosocial risk factors for tbi disproportionally affect women whereas sports and occupations two of the biggest risks for tbi differentially impact men   in addition women are at greater risk for poorer healthrelated outcomes including adrd even at equivalent levels of these psychosocial risk factors few studies of tbi and dementia have been conducted in lmics where tbi rates are often higher than hics and few resources for treatment are available for example in pakistan domestic violence against women which sometimes results in head trauma is a significant problem in addition poor safety conditions frequent incidents of terrorism and political violence also contribute to the high rates of tbi in pakistan,"[30541865 29801145 30852157 11071494 29381704 29653873 32719017 31806487
 25122029 23117388 32031646 32383452 33992149 32031646 30317219 32741501
 17615903 22514667 32887574 32425875 32425875]"
148,several measures have been developed to examine neurocognitive function in populations with high rates of illiteracy andor low levels of formal education including the rowland universal dementia assessment scale neuropsi or the figure memory test although additional tools and normative data to be used in diverse cultural and geographical populations are still needed female advantage on verbal memory tests has critical implications for early detection and intervention because clinical tests of cognitive function in older adults often do not consider sex differences thus the verbal advantage for females could lead to a delayed diagnosis of mci compared to males and subsequently to a more rapid rate of deterioration and diagnosis of dementia for females,[32146910 10439587 34345358 31511111 34719502],"similarly, performance on neuropsychological tests is influenced by an individual's lived experiences and education and learning opportunities. low education levels have been identified as a risk factor for dementia   with known gender disparities in access to educational opportunities in both hics and lmics",[31722961]
149,indeed the symptoms of the disease typically begin with mild memory difficulties 19 such as episodic memory loss due to the changes in the hippocampal volume 223 and to the disconnection of the hippocampus from the associative neocortical regions,[29653606 28164766  7745409 29147068 21086049],nevertheless there is still no agreement about which cognitive screening instruments could be more sensitive and specific enough to detect ad in the early phases of disease several neuropsychological tests using long word lists have been usually administered to differentiate the subjective memory complaints which is a common symptom in an aging population 21 with the objective episodic memory impairment which seems to be unique of admci,[30819244 15450043 21594655]
150,the minimum clinically important difference mcid in cognitive efficacy was used for clinical significance defined as a mean change of 26 points for the adascog and 14 points for the tmse despite having less evidence regarding mcids for the remaining tests were used cutoffs of 5 points for the adcsadl 1 point for the cdrsb and 8 points for the npi,[33637039 21671540 31417957 20848576 11528012],the primary endpoint figure  in supporting information was the effectiveness of wme treatment versus placebo for enhancing cognitive function and nps as assessed by the neuropsychiatric tests at any visit improvements were measured by examining the mean score change and the proportion of participants who reported beneficial score changes.,[]
151,as antiseizure drugs we chose levetiracetam lev and lamotrigine ltg which are most often recommended for ad patients with epilepsy in addition we tested three experimental drugs for mechanistic purpose minocycline min an antiinflammatory antibiotic that has proven anticonvulsive in several seizure models 2 semagacestat sgs a gammasecretase inhibitor that failed to improve memory in a phase 3 clinical trial but proved effective in reducing amyloidβ aβ production in both mouse models and patients and 3 istradephylline ist an adenosine a2a antagonist based on its overexpression in ad patient and appps1 mouse hippocampus and its coupling to nmdamediated overexcitation we chose the doses based on the literature so that they should not cause motor side effects,[28327340 22366182 23883379 19519664 29950682],"the tested drugs and their vehicles and doses are summarized in table they included current ad drugs, donepezil (dpz) as a representative angiotensin‐converting enzyme (ace) inhibitor, and the n‐methyl‐d‐aspartate (nmda) receptor antagonist memantine (mem).",[]
152,previous studies have reported that activation of immune mediators is an important regulator of the ad pathology and dysfunction of immunemicroglia molecular network is one pathogenesis of ad 7 as well as of depression 8 trem2 is an immunerelated gene expressed in microglia promoting microglial phagocytosis chemotaxis and survival 9 10 and regulating the transition of microglia from homeostatic to diseaseassociated microglia dam,[31564456 26442697 32531244 30266932 28602351],Recent evidence suggests that depressive symptoms together with aberrant Aβ accumulation could result in cognitive impairment and the development of dementia  and the minimal depressive symptoms mdss a symptom prior to subclinical depressive symptoms were associated with abnormal amyloid pathologies and cognitive impairment,[32980133]
153,some studies showed that aβo and tauo impair synaptic plasticity and memory independently 16 17 while others reported that aβo acts upstream of tauo to drive ad pathogenesis,[21421841 28877993 26718979 17478722 18568035],Low concentrations of AβO and TauO that would not normally perturb synaptic function effectively suppress longterm potentiation LTP and impair memory function when administered together  the colocalization of aβo and tauo at the synaptosomes isolated from ad brains has been observed,[18467692]
154,lipid metabolism is closely related to the production metabolism and aggregation of aβ an important pathological product of ad abnormal sphingolipid metabolism occurs in the urine plasma brain tissue and cerebrospinal fluid of ad patients,[20303415 18547682 21957010 20953867 22293144],"although countless investments have been made in the war against ad, there is currently no known way to prevent or cure this disease. most of antiad drugs have a single molecular target and are mainly acetylcholinesterase inhibitors which is not an optimal choice for ad patients with multipathogenesis",[33579351]
155,in addition we found associations of rs9877502 in gmnc previously associated with ttau levels in this and other datasets 44 63 64 with levels of 696 csf proteins in ad individuals gmnc is involved in neuronal plasticity and regulation of gene expression,[33223526 23562540 28247064 26395491 20383140],while markers in apbb2 do not show strong evidence for association with ad risk in gwas comparing controls with individuals with addementia  the gene represents an interesting functional candidate as apbb2 binds aicd alternative splicing of apbb2 increased the aβ42 aβ40 ratio 87 and overexpression increased aβ140 app and aicd levels and changed gene expression,[30617256 23485396 14527950 23485396 12089154]
156,metaanalysis using the random effects model with the dersimonianlaird method of studies reporting relative risks rr  a forest plot effect sizes are represented as red squares with 95 confidence intervals,[19634208 19387105 21757907 21490316 18289451],however chronically insulin receptors at the bbb are downregulated and the amount of insulin that enters the brain decreases this phenomenon is called brain insulin resistance and gives prominence to the key role of gsk3β in ad pathogenesis in particular gsk3β is hyperactive and can phosphorylate tau which aggregates to form neurofibrillary tangles,[22820012 20420491]
157,more recently ccs have also been used to determine the role of some neurodegenerative diseaserelated proteins in the regulation of cell excitability ion channel currents bulk exocytosis and the fine kinetics of singlevesicle exocytotic events,[19641596 17108165 16087704 24366265 28259758],the ccs are integrated into the sympathoadrenal axis which helps to maintain the body homoeostasis during both routine life and acute stress conditions these cells are widely used to explore neurotransmitter release and synaptic transmission and are considered to be the amplifying arm of the sympathetic nervous system the sudden and fast exocytotic release of their catecholaminesstored in noradrenergic and adrenergic cellsplays a fundamental role in the fightorflight response to stress,[22249377 22249377]
158,autophagic receptors such as nbr1 and p62 directly bind to atg8 homologs on autophagosomes for the degradation of protein aggregates,[21189453 16286508 18524774 19250911 17580304],"the receptor sqstm1-p62 (p62), the neighbor of brca1 gene 1 (nbr1), and the large junction protein alfy are important in aggrephagy. a deficiency of alfy or p62 is associated with neurodegeneration",[12598614 18346206]
159,the involvement of sdcs in the pathogenesis of ad has also been confirmed in several human studies the colocalization of sdcs with amyloid plaques has already been observed along with the correlation between ad pathology and sdc gene expression pattern,[34671250  2140065  2974240  1488123 30016411],"according to our studies, overexpression of sdcs, especially the neuronal sdc3, creates favorable conditions for the cellular accumulation and subsequent aggregation of misfolded proteins. seeding and spreading of pathological protein aggregates on the other hand has paramount importance in inducing neurodegeneration",[21624403 21045796]
160,another key mediator uncovered in our gsems is pa a factor positively affecting brain health neuroimaging studies on humans show brain atrophy with age that is mitigated in older adults who exercise exercise promotes neurogenesis in aged mice by stimulating mitochondrial regeneration and expression of vascular endothelial growth factor vegfa a growth factor supporting neuron proliferation brainderived neurotrophic factor bdnf a key mediator in brain connectivity and plasticity both supports growth and differentiation of new neurons and protects existing ones exercise in mice increases brain bdnf levels ubiquitously including with cognitionrelated regions although bdnf plays a critical role in ad controversial findings from human and animal studies question its precise role,[18094706 12586857 25002036 12086747 12086747 32052374],"noteworthy is the mediating effect of nutritional biomarkers, particularly among men, and that of diet quality among women. in fact several antioxidant vitamins including vitamins a and e as well as carotenoids and folate were previously found to directly impact brain function     a recent trial vitacog carried out among patients with mild cognitive impairment indicated that brain gray matter regions vulnerable to ad eg medial temporal lobe benefited from highdose b vitamin supplementation by slowing 2year brain atrophy rates an effect detected only among hyperhomocysteinemic individuals the trial also suggested that b vitamin supplementation can stabilize executive function and reduce decline in global cognition and episodic and semantic memory moreover among carotenoids lutein or lutein  zeaxanthin may have beneficial cognitive effects in older men and women as indicated by a recent randomized controlled trial more generally a recent study examining multiple nutritional biomarkers including plasma n3 fatty acids 25hydroxyvitamin d and homocysteine found that participants presenting without nutritional risk factors exhibited cognitive enhancement 003 standard units suy whereas each nutritional risk index nri point increase associated with an incremental acceleration cognitive decline nri1 reduced n3 fatty acids β  004 suy p  03 nri2 reduced 25hydroxyvitamin d β  008 suy p  0001 and nri3 elevated homocysteine β  011 suy p  0008 a recent study examining gender and race differences in the association between diet quality and cognition using more recent waves of nhanes 20112014 found that a 1 unit increase in the mediterranean diet score medi was associated with a 0039 95 ci 0016 to 0062 higher global cognitive zscore with the effect being stronger among nhw and in men conversely we found that diet quality is a stronger mediating factor in women than in men for racial disparities in dementia particularly for the nhb versus nhw contrast","[28130638 23690582 23321337 21780182 18510807 23690582 21780182 18510807
 31921969 33614896]"
161,the participants classification was accomplished according to a neuropsychological evaluation ad cooperative study adl scale for mild cognitive impairment adcsadlmci 24 clinical dementia rating cdr 25 functionality assessment questionnaire faq 26 minimental state examination mmse 27 repeatable battery for the assessment of neuropsychological statusdelayed memory rbansdm 28 and csf biomarkers ßamyloid42 total tau ttau and phosphorylated tau ptau following the recommendations of the national institute on agingalzheimers association niaaa,[ 9236950  7104545  7069156  9845158 21514249],the latter group consisted of patients diagnosed with ftd or dlb. it should be noted that the study protocol was approved (approve number: 2019/0105) by the ethics committee (ceic) and all the participants gave their prior consent.,[]
162,in 2018 a national institute on agingalzheimers association niaaa working group developed a research framework to biologically define alzheimers disease ad similarly to previous clinicobiological criteria  the research framework recommends dichotomization of ad biomarkers that is the use of normalabnormal status based on a single threshold to define biomarker profiles for amyloid tau and neurodegeneration proposing the atn system  although this practical approach has enabled systematic characterization of ads preclinical phase  and facilitated recruitment for clinical trials of diseasemodifying therapies  the niaaa research framework acknowledges that dichotomization is context dependent and that continuousvariable modeling might be more appropriate for many studies in fact it also suggests that a threerange approach might also be a useful strategy in ad research,"[29653606 21514248 24849862 29653606 21514248 24849862 23229078 30958413
 29653606]",a three‐range approach enhances the prognostic utility of csf biomarkers in alzheimer's disease,[]
163,while treatments such as trazodone 21 40 60 risperidone 53 70 and suvorexant  showed some promise in improving clinical and caregiver symptoms further data from larger prospective trials are required,[24495406 30689583 15157345 26279176 31944580],as a result there remains uncertainty about the balance of benefits and risks associated with common sleep treatments when used in ad few studies evaluating the use of sleep medications in ad patients were identified and were generally small.,[29067350]
164,while no significant adverse events were reported in the studies included in this review antipsychotics can cause residual sedation confusion and falls and have metabolic and cardiovascular side effects,[26834500 24846773 12670415  7579786 19187704],the use of antipsychotics in the treatment of sleep and other behavioral disturbances in ad has been extensively discussed while they may be useful in the treatment of sleep disturbances and to alleviate neuropsychiatric symptoms  they are not without risks,[26834500 24846773 18346674 12670415 11602004 26279176]
165,over the last 10 years advances in technology have led to innovative solutions for the diagnosis 1617181920 management 21 and treatment  of pwad,[28574362 27855415 29512255 27148050 28798682],"This screening finally yielded 8 articles for evaluation (Figure 1). two independent reviewers (d.m.c. and g.c.) extracted data of interest, and disagreements were discussed until a consensus was reached.",[]
166,enrolled individuals were outpatients in two cases 1618 in other cases they were recruited from memory clinics 17 alzheimers day centers 2022 or social senior centers,[28574362 29512255 27855415 27148050 28798682],two studies 1618 based the ad diagnosis on the national institute on agingalzheimers association niaaa criteria 24 and three studies 171923 based it on the national institute of neurological and communicative disorders and stroke and the alzheimers disease related disorders association nincdsadrda criteria 25 with the supplement of the diagnostic and statistical manual of mental disorders fourth edition dsmiv 26 criteria in one case heterogeneity among participants was also found.,[28574362 29512255 21514250 27855415 28798682  6610841]
167,regarding animal models in spite of a convincingly demonstrated crosstalk between i gut microbiota perturbation and peripheral immunomodulation impact of microbiota on peripheral inflammation immunity and  impact of microbiota on neuroinflammation ii peripheral inflammation and neuroinflammation 7 26 27 34 and iii neuroinflammation and neuronal activity  the impact on synaptic activity of modulating microbiota has not been explored so far particularly when considering the presymptomatic changes in ad,[33582183 32340575 33381913 26048578 29735654],targeting the gut microbiota and restoring its balance could represent a promising therapeutic strategy in ad. several approaches can be considered such as prebiotics food components typically nondigestible fiber compounds with the capacity of inducing growth or activity of beneficial microorganisms probiotics live microorganisms which confer a health benefit on the host when administered in adequate amounts or fmt which consists in transferring a solution of fecal matter from a healthy donor to restore the gut microbiota of a patient suffering from a microbiotarelated diseases,[33246175 32791113]
168,the finger population characteristics 24 trial protocol details 25 main relevant findings 26 and neuroimaging substudy have been previously published in detail,[25211775 23332672 25771249 29263220 31164160],samples are sorted by apoe genotype apoe3/apoe3 (e3/e3) and e4/e4. student t-test was used to analyze the differences between groups. *p < 0.05; **p < 0.01; ****p < 0.0001,[]
169,our bioinformatics strategy is based entirely on publicly available genomic datasets including genotype data gwas results and functional genomic datasets such as annotation of enhancer elements encode chromatin state position probability matrices for tf motifs encode  homer factorbook hocomoco gene expression gtex portal and cardiogenetics and chipseq data,[22955616 29126249 20513432 22955990 23175603],"b, single tissue eqtls for various tissues including brain. eqtl, expression quantitative trait loci; gwas, genome‐wide association study; load, late‐onset alzheimer's disease; snp, single nucleotide polymorphism; tf, transcription factor in this article, we developed a new bioinformatics analysis pipeline to characterize and prioritize snps in enhancers located in load gwas regions based on their predicted effect to alter tf binding sites.",[]
170,while newer mechanisms and potential targets for diseasemodifying treatments are being explored      there remains an urgent need for novel symptomatic drugs that can reinstate damaged or dysfunctional neurotransmission to provide sustained and clinically meaningful benefits for patients regardless of the outcome of the disease modification strategies,[30450030 31062825 31367008 32339611 29441009],"over the last two decades, many of the drug discovery strategies for alzheimer's disease (ad) have focused on disease‐modifying treatments targeting amyloid beta (aβ) pathology. despite extensive research and large numbers of clinical trials these as well as other targeted approaches have generally failed to show clinical benefit in the future it seems probable that multiple therapeutic approaches will be necessary to successfully treat ad",[30610216]
171,knowledge from the fields of oncology and genetic testing may offer a good starting point,[28317644 30507575 32393330 24179789 23578568],nonetheless others did not consider biomarker information medically meaningful a dozen papers addressed the need for guidance regarding who to test what findings signify whether to disclose and how,[30154216 28891443 22550984 32393330]
172,for example cholinergic receptors may be adversely affected by beta amyloid peptides 15 but cholinergic neurotransmission also influences amyloid processing 16 17 and may protect neurons from amyloid toxicity,[17039298  7605915  1411529 26979166 33571523],further support for the role of the cholinergic system in cognition comes from observations that cholinergic antagonists worsen attention and memory whereas procholinergic treatments provide modest symptomatic improvement in patients with ad dementia relationships between cholinergic system dysfunction and other ad pathologies are complex and bidirectional.,[29850777 22232050]
173,there are additional complex links between cholinergic system dysfunction and tau processing 2123 neuroinflammation 18 24 cortical volume loss 25 26 and apolipoprotein e ε4mediated neuronal alterations in the medial temporal cortex,[26979166 33921376 27312991 27811848 27707979],for example cholinergic receptors may be adversely affected by beta amyloid peptides 15 but cholinergic neurotransmission also influences amyloid processing 16 17 and may protect neurons from amyloid toxicity tau pathology is prominent in the basal forebrain early in the ad process 4 and may initiate distant cortical degeneration,[17039298  7605915  1411529 26979166 33571523 23852922 32203580]
174,a total of 27 studies qualified with 26 of these studies being included in the ad blood gsh metaanalysis 3661 and 7 of these studies being included in the mci analysis,[18780972 18297609 18073509 31356205 26690564],"The search returned 299 unique records (Fig. 2). of the records screened, 40 studies were excluded as they were non-clinical studies (including reviews, editorials, and or conference abstracts); 70 studies were excluded because these studies involved non-human subjects; 81 studies were excluded as they were not conducted in ad or mci patients; 23 studies were excluded as they were post-mortem studies; 9 studies were excluded as they did not include a healthy control group; 47 studies were excluded as they did not measure gsh in whole blood, plasma, or serum; and 2 were excluded as full results could not be obtained.",[]
175,in studies examining blood gsh in ad 7 studies used the hachiniski ischaemic score his  4 to differentiate those with ad from those with potential vascular causes 41 46  and 5 of those studies further used neuroimaging to support diagnosis  table 2,[15202788 18073509 30443289 12094909 30611996 30443289 12094909 30611996],ad patients were identified primarily using the diagnostic and statistical manual of mental disorders dsm 63 andor the national institute of neurological and communicative diseases and strokealzheimers disease and related disorders association the national institute on agingalzheimers association diagnostic guidelines 65 the dementia rating scale2 66 international classification of diseases 10th revision 67 and the consortium to establish a registry for alzheimers disease 68 neuropsychological battery were used in 5 gsh studies respectively,[ 6610841 21514250 18631955 29560372 17069783 26295825 25316430]
176,neuroinflammation is a key mechanism contributing to ad pathology  previously it has been shown that appps1 mice express higher levels of proinflammatory cytokines and inflammasome   we therefore investigated nob effects on cytokine gene expression and inflammasome formation using cortex samples figure,[25792098 34067173 27511018 25756590 33257576],metascape analysis of these circadian deps revealed several enriched pathways including protein membrane localization and autophagy pathways in wtcntl receptor tyrosine kinase signaling in appps1cntl and behavior and mrna metabolic process in appps1nob figure c overall these results indicate nob restored protein landscape in app/ps1 mice in a circadian time‐dependent manner.,[]
177,the two most commonly used preclinical behavioral approaches in the evaluation of antipsychotics are the quantification of locomotive behavior hyperkinesis being an analogue of behavioral disorganization in psychosis and sensorimotor gating integrity with prepulse inhibition ppi of acoustic startle deficits of which have been reported in psychotic conditions  currently approved typical and atypical d2receptorblocking medications used in the treatment of psychosis have been extensively studied in mice and consistently inhibit locomotive velocity rescue ppi deficits driven by psychotomimetic compounds and even increase sensorimotor gating integrity in otherwise untreated wildtype mice  though there is evidence that pimavanserin which does not antagonize dopamine receptors can rescue ppi deficits and increase locomotion driven by psychotomimetics  its ability to impact these behaviors has not been previously reported in transgenic models of ad,[31278012 19900963 19900963 17097724 21921840 22750845],"there is evidence that pimavanserin a medication approved for the treatment of parkinsons disease pd psychosis may be effective in treating psychosis in ad and other dementias   pimavanserin is novel among antipsychotics as it does not antagonize dopamine receptors as all other available antipsychotics do rather it acts as an inverse agonist primarily at neuronal 5ht2a and to a lesser extent 5ht2c receptors with no appreciable activity at other targets including dopamine receptors   this unique binding profile avoids the extrapyramidal side effects such as dystonia tremor and akathisia associated with dopamine blocking antipsychotics although the phenomenology of psychosis is a strictly human construct, a common strategy in the development of novel antipsychotic medications involves screening candidate compounds in preclinical models using behavioral outcomes established in human psychosis that can be observed in animal models.",[24682754 29452684 30298184 24682754 27503570]
178,these markers showed high diagnostic accuracy for established ad 4249 and identified ad before onset of dementia at the mci stage evidenced in single center 150 and largescale multicenter studies,[31884486 31526625 29558986 31201098 29287745],the framework of ad diagnosis and research has changed dramatically through the development and application of biomarkers. core ad biomarkers include 1 cerebrospinal fluid csf low levels of aβ42 or the aβ4240 ratio and brain amyloid deposition evidenced by pet imaging 2 increased total tau ttau and phosphorylated tau ptau representing cortical neuronal loss and cortical tangle formation respectively and 3 hippocampal atrophy shown on mri,[27931796]
179,in this regard compelling evidence including geneticimaging studies suggests that genetic variants of the dlg1 gene are functionally linked to abnormal cognitive patterns in scz patients,[22225629 28990294 30319465 32692143 33133161],"conversely, no changes were observed in the expression levels of the protein encoded by the dlg1 gene, sap97, in both brain regions. taken together these results are puzzling since it has been demonstrated a pivotal role of this synaptic element in regulating the trafficking of the glutamate ampa receptors whose expression and function have been reported to be altered in scz",[32513544]
180,this test battery includes 10 different computerized tasks and eeg on a wide range of cns domains    and is also sensitive to cholinergic effects  all eligible patients entered the challenge phase consisting of two study days during which the effects of galantamine or placebo were measured according to a predefined time schedule with a 1 week washout period in between,[19648218 20142308 21306419 18187530 28217868],"before entering the study, all patients were screened for eligibility, including evaluation of diagnosis, use of medication, presence of contraindications for the use of galantamine, electrocardiogram (ecg) and laboratory investigations. also, a training session for the pharmacodynamic measurements performed with the neurocart® cns test battery was planned.",[]
181,interestingly tg2 also interacts with various other proteins strongly associated with the pathophysiology of ad such as apolipoprotein e heparan sulphate proteoglycans heat shock proteins gelsolin various mitochondrial proteins and proteins of the ubiquitin system,[26088696 23122413 16385579 29382685 26702927],in addition tg2 and its crosslinking activity are present in sps and caa in post mortem tissue of ad cases and in glial cells associated with these lesions apart from tg2 association with ad brain lesions it is known to directly interact and posttranslationally modify soluble aβ monomers inducing neurotoxic protein multimers,[18673368  9797004  8103081  7922559 21300794 18055545 31923381 18397883]
182,recently researchers have identified elastin degradation as a potential contributor to aging oxidative stress and ad pathology,[10216959  1466664 19560218 22099332 29992983],several reports demonstrate that oxidative stressinduced increases in metal ion redox potential also stimulate the upregulation of tau kinases amyloidbeta aβ is also implicated as a contributor to the cascade of molecular events that result in tau hyperphosphorylation and the inhibition of tau binding to microtubules by promoting glycogen synthase kinase 3 gsk3 activation,"[22528780 12358761  9890432 24954411 10617124 17662457 28269780  7718249
 19782073 19246243 15867159  9809590 18258852]"
183,numerous studies have reported that ghrelin agonists improve diverse adrelated neuropathological features    similar to asm inhibition,[33381011 31434007 33103129 31413143 22005105],"the effects on mitigation of hippocampal neurogenesis could also result from ceramide reduction by asm activity inhibition, and these combined effects of kari 201 contributed to an overall effective improvement of hippocampal memory impairment of ad mice (si appendix, fig. s23b",[]
184,for example after tbi ischemia and in neurodegenerative disease astrocytes enter a hypertrophic state characteristic of astrogliosis 31 117 and this process can contribute to impairments in gliovascular connections bbb permeability and cerebral blood circulation,[33589835 20012068 25828533 15846805 26671410],this observation suggests that high concentrations of human aβ present in the tg mouse brain confers susceptibility for chronic dysfunction of perivascular astrocytes in the context of btbi exposure. astrocyte dysfunction has been reported in multiple models of cns insult.,[]
185,fibronectin is the adhesive protein that connects cells with collagen fibres in the ecm binds to cellsurface integrin regulating cytoskeleton reorganization and facilitates cell migration,[20944663 15250583 12732238 28092265 20690820],this protein can bind to fibrinogen fibronectin laminin type v collagen and integrins alphavbeta1 hsamir1323p and hsamir2123p inversely related to cd44 which was previously found upregulated in severe alzheimers disease 46 hsamir30e5p and integrin beta1 itgb1 a receptor for collagen is another interaction and it was suggested to undergo plasticity through interactions with ecm proteins modulating ion channels intracellular ca2 and protein kinases signalling and reorganization of cytoskeletal filaments ecm and integrin aberrations are likely to contribute to imbalanced synaptic function in epilepsy alzheimers disease mental deficiency schizophrenia and other brain conditions  hsamir13p hsamir4253p and hsamir12373p are all downregulated and all show the upregulated fibronectin fn1 as potential target,[22233753]
186,in this group of families we also found variants in app psen1 and psen2 usually associated with familial earlyonset forms of ad and mapt grn and c9orf72 usually associated with frontotemporal dementia ftd     the most frequent variants were found were psen1 pa79v 046 of the families and the c9orf72 expansion 048 of the families,[26433351 29486463 22312439 29091718 29688227],"however, a number of other loci, labeled on the manhattan plot below, were nominally significant. many of these loci supported several large metaanalyses that included other cohorts",[24162737 30820047 30617256]
187,homoor heterodimers exhibit potent enzyme inhibition efficacy as assessed using computational and preclinical studies,[12369973 18517184 26325402 31132435 33930191],cheis such as donepezil can inhibit ache activity via transitory binding to the pas andor the catalytic site of the enzyme potential control of ache activity via dual inhibitory binding site occupancy has led to the generation of hybrid ligands separated by suitable linkers or spacers.,[23478436 32096991]
188,recent evidence points towards autophagy as a key player in postischemic hippocampal neurodegeneration,[27472881 29363901 29128811 31707369 17035724],"according to the first option, the aforementioned lysosomal degradation of the cytoplasm’s own structures provides the neuron with substrates for energy production and protein synthesis. the second option is blamed on autophagyprogrammed neuronal cell death",[27472881 29363901 29128811 31707369]
189,clinical diagnosis for probable ad dlb and ftld was made according to international guidelines,[21325651 28592453  6610841 21514250 21810890],"our data strongly support a critical role for sorl1 in ad and related diseases and highlight sorl1 as a potential therapeutic target for drug development. This retrospective study was carried out on DNA from a total of n = 697 patients (n = 282 AD, n = 114 DLB, n = 301 FTLD) and n = 251 subjects with normal cognitive function (CTRL) (Table 1).",[]
190,plasma aβ42aβ40 was measured using a mass spectrometrybased assay araclon biotech phosphorylated tau ptau217 cerebrospinal fluid csf and plasma was measured on a meso scale discovery platform using an assay developed by eli lilly plasma neurofilament light was analyzed using a simoabased assay csf aβ4240 and neurofilament light were measured using the elecsys platform roche main analyses were performed using plasma biomarkers with findings using csfbased biomarkers reported in etables 3 to 5 in the,[27567833 32123385 32246036 31009028 33336877],"ethical approval was given by the regional ethical committee in lund, sweden. approval for pet imaging was obtained from the swedish medicines and products agency and the local radiation safety committee at skåne university hospital in sweden.",[]
191,each modification may be associated with activation of the target gene as in lysine acetylation 141142143144 and in other cases with repression and inactivation of a gene,[18628954 26136662 26159193 30559478 18234899],"the diversity of ptm-hs includes methylation, acetylation, o-glcnac modification, adp-ribosylation, the phosphorylation of serine and tyrosine residues, ubiquitination and the binding of molecules of the small ubiquitin-like modifier class (sumo) system via sumoylation. the methylation of lysine serine or arginine by the enzymatic action of histone methyltransferases hmt and demethylases hdmt and their acetylation by acetyltransferases hat and deacetylases hdac are among the beststudied epigenetic events with modifications controlled by fluctuations in the total histone levels and the enzymatic activities of several functionally distinct histones  figure 2",[25484284]
192,several tau pet tracers label nfts including 18fflortaucipir 2 18fgtp1 3 18fro948 4 18fmk240 5 and 18fpi220,[26505746 31254035 30635637 29880509 31712323],baseline [18f]gtp1 tau pet imaging is associated with subsequent cognitive decline in alzheimer’s disease neurofibrillary tangles nfts comprised of hyperphosphorylated tau protein are one of the defining neuropathological characteristics of alzheimers disease ad,[]
193,although astrocyte reactivity has so far been considered mainly a process aimed at resolving tissue damage the functional consequences on astrocytes are still controversial and studies have pointed out that the impact on surrounding cells might be beneficial or detrimental,[31429127 28099414 34616039 27027288 25014177],"concerning gfap, it is a key constituent of intermediate filaments in astrocytes and the most widely used marker of astrocyte reactivity. gfap immunoreactivity characterizes astrocytes in many cns disorders including ad 4789 however it does not necessarily characterize all reactive astrocytes and its upregulation varies depending on the pathology",[22553043 24269023 33908669 20185032 31429127]
194,of these seven articles five  showed very good quality and low risk of bias supplementary materials table s6,[28201726 22541366 23179169 26680338 16323253],out of eight ma 1017182122242628 only five 18192225 detected publication bias using funnel plots 36 and another one  also applied kendalls tau correlation coefficient seven articles  concluded that the achei donepezil galantamine rivastigmine and tacrine have little or poor riskbenefit ratio in improving cognitive status and overall patient outcome by clinical interview supplementary materials table s5,"[27582220 28201726 17154660 18686744 16081444 10713577 16323253 28201726
 22541366 18686744 26680338 12517232  9310563 12517232 28201726 22541366
 12391943 23179169 16081444 26680338 16323253]"
195,there are however several studies reporting lack of alterations in the aforementioned regions,[11255451  2908095  2975188 10908891  2252449],the third main finding of this study pertains to the different vulnerability of the two main dopaminergic pathways in ad. previous in vivo and postmortem studies focused mainly on the nigrostriatal dopaminergic pathway reporting alterations in the sn 26 and in its major subcortical targets ie putamen 8 11 15 16 23 41 and caudate nucleus,"[ 6204013  8742039  2870131 10908891  6155966  6200784  8742039  2870131
 10908891  6155966]"
196,as transcription regulates the abundance of metabolites  metabolites also transfer the information back to the transcription network directly or indirectly interacting with a transcription factor,[21685093 31578326 24658329 27498839 20461071],to further infer causal relationships among a large collection of dissimilar variables at different omics layers we can conduct bayesian probabilistic causal network bn analysis    as we and others have previously done in ad   and other complex traits  moreover the static state bn analysis can be expanded to model dynamic and timedependent regulation changes in a longitudinal or timeseries dataset for example a dynamic bn dbn framework had been used to model the dynamic causal network of blood gene expression in response to food intake over multiple time points where intratimeslice bn structure from a large dataset generated at static states was combined with intertimeslice structure inferred from the time series data the datadriven causal networks will provide a systemswide context for understanding the mechanisms of known regulators and discovering novel key causal regulators among mrna protein and metabolite levels,"[17432931 18552845 30283032 19270708 23622250 33238137 32770063 22806142
 18822406 20168994]"
197,recent studies  used initialization or feature extraction by cnnbased tl architectures such as resnet deep resnet caffenet alexnet densenets vgg16 and inception with or without finetuning followed by an extended network architecture,[31853655 32275915 30598877 32210685 31132373],"however, the training process consumes considerable time, and the size of neuroimaging datasets is restricted, which may lead to overfitting. as we have seen in the previous discussion of dl architectures, tl is less time-consuming and shows better performance in comparison to training from scratch.",[]
198,several studies used different combinations of biomarkers to improve the accuracy of ad detection 9293pet images were used in,[28721928 30028955 29502031 29454006 32210685],it is mainly beneficial for the early detection of ad as it can demonstrate the distinctive patterns of ad earlier them mri for mci subjects another type of pet is amyloidpet which is used to assess brain amyloid deposition one of the main neuropathological milestones of ad with an elevated sensitivity and specificity in patients with established alzheimers disease who underwent an autopsy within one year of pet imaging,[33098804 33098804]
199,dietary dha intake can modify the dha status of peripheral tissues such as blood and adipose tissue 79808182 dietary dha correlates with hippocampal volume in vivo 83 and neurological deficits of dha deficiency resolve with supplementation,[18435934 12612178 12499320 17574755  2139096],similarly greater erythrocyte dha content corresponds with reduced risk of cognitive decline more recently a metaanalysis has shown that altered blood fatty acid composition is evident in individuals with mci and ad versus controls with individuals with ad showing the greatest number of altered fatty acids and degree of change of these fatty acids including dha,[12663275 32194194]
200,asc specks in microglia are hallmarks of inflammasome activation and seed new aβ plaque formation,[23254930 29293211 25629724 27091843 27196974],"microglial function in ad is complex having both detrimental 8081 and neuroprotective activities in early ad, microglia in aβ models work to clear amyloid plaques but also release pro-inflammatory cytokines and produce apoptosis-associated speck-like protein containing a card (asc specks).",[23254930 29293211 25213090 25629724 27091843 27196974]
201,alzheimer disease pathology is associated with morphologic molecular and functional remodeling of astrocytes a process termed reactive astrogliosis however few astrocyte imaging and fluid biomarkers have been investigated blood levels of glial fibrillary acidic protein gfap a reactive astrogliosis biomarker are higher in individuals with preclinical ad constituting a promising candidate biomarker for this early stage of the disease a recent metaanalysis demonstrated that gfap levels were consistently altered in the cerebrospinal fluid csf of symptomatic patients with ad but studies of blood gfap present relatively high variability,[33589835 20880504 30611668 33431793 33952650],differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the alzheimer disease continuum currently the most promising blood biomarkers for detecting ad are the phosphorylated tau species ptau and amyloidβ 4240 aβ4240 ratio however it is still desirable to have more sensitive blood biomarkers for preclinical ad,[]
202,for instance a few studies found csf ptau was associated with wmh 38 global mean diffusivity in white matter 57 and hypertension 40 two pet studies found pet measures of brain tau  were related to vascular health variables,[29572277 30239611 24225352 29023983 29799981],"for example a few studies based on the adni cohort reported significant associations of csf ptau or plasma ptau with wmh 25 37 56 and hypertension in addition, some non-adni studies reported similar findings although without specifically examining relationships in aβ- individuals.",[29387348 26747881 25822631]
203,in most studies participants were persons without any cognitive decline or dementia diagnosis at baseline except one of them that included individuals with subjective memory impairment 33 three of them 101116 that included mci persons and three studies  that included ad patients at the beginning of the study,[27421618 30698630 30390881 23032941 30390881 23032941 19671904],mean age of the participants in most studies was over 60 years old except five of them  in which younger participants were included according to nationality fourteen studies 1378101317202733353638 included american participants four studies 9153132 included australian participants one study 34 shows results of swedish individuals one study 11 is based on brazilian results other one the participants were german 30 and only one study was performed in france,"[29574441 29653991 19671904 25599008 29574441 29653991 29889074 30698630
 19204158 19671904 25237654 25681666 27421618 25599008 20847399 16622828
 17030648 34153553 29616707 25062901 30390881 33952652 19671905]"
204,ferulic acid has also been involved in enhancing the cell stress response by regulating heme oxygenasehsp70 95 heme oxygenasebiliverdin reductase hobvr system 9697 superoxide dismutase sod catalase 98 erk ½ and akt 99 and inhibiting caspases,[16634068 16386335 26340979 16038626 17007737],most importantly it directly alters the kinetics of aβ fibril formation and can directly inhibit plaque formation in vitro however the oral administration of ferulic acid was unable to display any significant effect on aβ oligomers or aβ deposition in vivo  which could be due to poor absorption or difficulty in crossing bbb in the body,[16153607 20406252]
205,among patients with pd decreased olfactory performance was reported to be associated with lower gray matter volumes in the piriform and orbitofrontal cortices amygdala left putamen right caudate and right thalamus,[24482154 21846992 20007465 28522171 21330398],patients with impaired olfaction due to nonneurodegenerative causes had decreased gray matter volume in the piriform cortex orbitofrontal cortex nucleus accumbens medial and dorsolateral prefrontal cortex anterior and middle cingulate cortices insular cortex hippocampus parahippocampal gyrus and cerebellum among patients with ad diminished olfactory performance was shown to be associated with atrophy of the primary olfactory cortex parahippocampal and entorhinal cortices left precentral and inferior frontal gyri overall medial temporal lobe and reduced left hippocampal volume,[20231262 25240014 25633674 25934852 12666770 29936148 31474819 31242486]
206,second findings in ad patients were mostly in line with previous reports about which regions are involved in olfactory information processing,[31339489 28443000 29301613 28195241 12666770],"the slightly but not statistically significantly worse odor identification performance among patients with ad is also in line with previous findings that higherorder olfactory function impairment is present in both ad and pd but is relatively more pronounced in ad we also found age-related odor identification performance decline among patients with ad, which may indicate both the direct effect of aging, and the effect of more advanced ad pathology in older patients.",[20437286 22414849 29988355]
207,a classic ad subgroup was identified by multiple approaches      typified by initial atrophy in hippocampus and amygdala followed by mtl atrophy and primarily memory deficits and underlain by apoe ε4,[30323170 31344486 30514930 30830917 30278855],"all subtypes had an excess of genetic risk for ad and did not differ in disease severity or presence of co‐pathologies. converging evidence from multiple angles—neuropsychological, imaging, blood biomarkers, genetics, and proteomics—points to substantial heterogeneity underlying disease progression.",[]
208,the long association fibres for motor control especially in the inferior frontooccipital fasciculus pass through the periventricular white matter and this tract is more susceptible to wmh burden than other fibre tracts wmh are highly variable disease processes with growth and shrinkage especially in ad subjects with a considerable amount of wmh a recent study indicated that controlling blood pressure was associated with a reduction in wmh and preserving white matter integrity in subjects with minor stroke additionally poor glucose management in diabetic patients with ad has been shown to be associated with frontal wmh therefore management of vascular risk factors potentially leads to better brain tissue outcomes and could lead to the maintenance of gait function,[14645885 27432800 27047377 28794252 30258360],"the subcortical occipital region has longitudinal fibres that link frontoorbital areas motor areas and visual conceptualization and deficits in this tract could affect visuospatial processing in gait   our study evaluated gait function under conditions that did not require visuospatial processing therefore, gait parameters may be predominantly associated with pvh in the anterior region rather than posterior lesions.",[14645885 21872363 27721745]
209,dextromethorphan is a sigma1 receptor agonist which has some moodmodulating properties it is also a low affinity nmda antagonist a serotonin and norepinephrine reuptake inhibitor a histamine h1 receptor agonist and a neuronal nicotinic alpha3 beta4 receptor antagonist quinidine and deuteration appear to prolong dextromethorphans plasma halflife reduce first pass metabolism and facilitate brain penetration deuterated d6dextromethorphanquinidine avp786 is currently being evaluated as a treatment for agitation in people with ad two phase iii trials evaluating efficacy safety and tolerability have been completed nct02442765 february 2020 and nct02442778 august 2020,[ 8901003 32848775 32052375 27936965 33615952],some associated cognitive decline and cardiac side effects qtc prolongation however hamper its longterm use results suggest that citalopram needs to be given at least nine weeks to allow enough time for a full response the evidence for its use for this indication nevertheless remains compelling and potentially could be a class effect for all ssris some additional novel and/or repositioned agents are being studied as treatments for agitation in dementia.99 four will be discussed here.,[21328305 31288974]
210,moreover mounting evidence from preclinical and clinical studies suggests that oxidative stress is linked with etiopathology of ad 6263 which includes mitochondrial dysfunction 64 increased aβmediated neurotoxicity 65 and synaptic dysfunction and neuronal apoptosis,[14500988 21376020 19245786 10880853 10491580],"oxidant-level-related dysfunctions have been reported in ad patients, which could be attributed to either hyperproduction of oxidants or deficit in antioxidants. Higher levels of MDA are one of the known pointers of oxidative damage in the brains of rats, and MDA levels were quantified in the rat brains as indicated in Figure 6.",[]
211,"the largest
abc
gene subfamily is abca which consists of a lot of amino acids

abca full transporter is divided into two groups abca1 like abca1471213 and abca5 like abca56810


abca1 and abca2 proteins which play a role in apolipoproteindependent cholesterol efflux sterol homeostasis lipid transport and metabolism share 50 sequence homology",[12456012 19403462 11441126 17266523 18996096],"abc transporters similarly function as a second selective permeability barrier in neurons and glial cells. because of all of these properties of abc transporters they have essential detoxification and neuroprotective roles in the brain


changes in abc carrier expressions or functions lead to β clearance disturbances causing adassociated cerebral amyloid angiopathy caa",[26187753 12415123 15717060 19319544 19061857]
212,growing evidence suggests that hbot can induce the neuroplasticity and improve the cognitive function in patients suffering from neurocognitive impairment due to stroke and brain injuries4546 moreover hbot cannot only improve cognitive functions and ameliorate the brain glucose metabolism in ad and amnestic mci amci patients447 but also induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging individuals,[25384125 25206655 32548235 30713673 33206062],"given that hypoxia contributes to the pathogenesis of ad, the development of prevention and treatment targeting hypoxia is promising. hbot is a safe, effective, and routinely used medical procedure.",[]
213,this hyperphosphorylation of tau is especially caused by the increased activity of kinases namely glycogen synthase kinase3 gsk3 cdk5 and the mapmicrotubule affinityregulating kinase mark which are activated by aβ oligomers,[29561798 28386764 26149638 28464981 21456963],however under pathological conditions the accumulation of hyperphosphorylated tau in neurons leads to protein misfold and aggregation in intracellular nfts reducing their affinity for microtubules the loss of normal tau protein function leads to a pathological disturbance in the structural and regulatory functions of the cytoskeleton of neuronal cells causing alterations in the morphology neuronal plasticity axonal transport and provoking synaptic dysfunction and neurodegeneration,[30657599 30531004 30980111 31022830 26149638]
214,aripiprazole is approved for use in patients with various psychotic disorders including schizophrenia bipolar disorder depression and autism 121314 and it has been reported that some clinical studies showed beneficial effect of aripiprazole for adrelated psychosis such as aggressiveness or anxiousness,[19505266 22447196 21254788 18591574 24389877],however amyloid remains the most compelling therapeutic target 8 and efforts to find novel therapeutics for ad using new technologies including in silico drug repurposing 9 or fdaapproved drugs  are ongoing aripiprazole is a secondgeneration atypical antipsychotic with high affinity for d2 d3 2ht1a and 5ht2a receptors and moderate affinity for d4 5ht2c 5ht7 alpha 1 adrenergic and h1 receptors,[32939050 31116390 20361061]
215,3nitrotyrosine is a product of oxidative damage on proteins generated when a superoxide radical reacts with nitric oxide no to form peroxynitrite which cause nitration of proteins on tyrosine residues 3nitrotyrosine and protein carbonyls these last produced mainly by the action of free radicals on the peptide chain or by oxidation of amino acids are used as biomarkers of oxidative damage in the brain of ad and mci,[30737462 27626216 20084018 27143416 23044265],it has been hypothesized that tissue injury aging ischemia increased metal levels or energy metabolism deficit can induce ros generation independently from aβ deposition even if ros generation is secondary to other initiating causes it plays an important role in the events that lead to neuron death in ad,[9165306 9165306]
216,lastly reactive astrocytes also express chitinase3like protein 1 chi3l1 also known as ykl40 61 62 63 64 and the 18 kda translocator protein tspo  although their function remains to be fully elucidated these two proteins are commonly interpreted as evidence of inflammation when measured in csf and detected via pet imaging respectively,[21035623 28599675 29126445 32066474 19077109],multiple studies report increased immunoreactivity for a wide variety of inflammatory cytokines including the inflammasomeactivating enzyme caspase1 casp1 37 interleukins such as interleukin1 beta il1b 37 38 interleukin6 il6 37 39 40 interleukin18 il18 41 interleukin33 il33 42 and its receptor interleukin1 receptorlike 1 il1rl1 42 as well as tumour necrosis factor tnf 43 chemokines such as cc motif chemokine ligand 2 ccl2 40 cc motif chemokine ligand 4 ccl4 44 cxc motif chemokine ligand 10 cxcl10 45 and stromal cellderived factor 1 cxcl12 46 cell adhesion molecules such as intercellular adhesion molecule 1 icam1 47 eicosanoid metabolism enzymes such as prostaglandin gh synthase 2 ptgs2 also known as cyclooxygenase2 48 cytosolic phospholipase a2 pla2g4a 49 and haematopoietic prostaglandin d synthase hpgds 50 while the microsomal prostaglandin e synthase ptges was reported to be decreased in adra 51 and the immunomodulatory receptor sphingosine 1phosphate receptor 3 s1pr3 52 but not sphingosine 1phosphate receptor 1 s1pr1 in addition some studies have shown increased immunoreactivity for transcription factors known to mediate immune and inflammatory responses such as nuclear factor of activated tcells cytoplasmic 2 nfatc2 54 nuclear factor of activated tcells cytoplasmic 4 nfatc4 54 transcription factor p65 rela also known as nuclear factor nfkappab p65 subunit 55 56 adipocyte enhancerbinding protein 1 aebp1 57 ccaatenhancerbinding protein delta cebpd 58 and glia maturation factor eg gmfb,"[27090093 27090093  2529544 27090093  9449432 17658666 24413615 24413615
  9665462 10900358 12834106  8337942 11754989  9173912 17549007 27662305
 23551178  8905182 23616440 15212823 22035352 23640177]"
217,to overcome this limitation isobaric peptide labeling methods such as itraq 121 tmt 122 and dileu 123 have been developed to generate isobaric ms1 peaks and enable multiplexed tagging eg 11plex 16plex 18plex and 27plex tmt,[17177251 12713048 25405479 32203386 33900084],"the stable isotope labeling methods have begun with chemical protein labeling such as cysreactive icat 117 aminereactive dimethyl labeling 118 and then metabolic protein labeling like silac  in which peptideprotein quantification is attained by ms1 peaks from the pooled samples with differential labels however, the pooling increases the complexity of ms1 spectra, reducing the efficiency of peptide identification.",[10504701 14670044 12415544 17139335]
218,"one approach
has been immunotherapy with antiamyloid antibodies despite promising preclinical
studies demonstrating central nervous system cns aβ clearance and improvement in
cognitive deficits in transgenic mice several antiamyloid immunotherapies have
failed in clinical trials
possible reasons for this lack of clinical translation include their low bloodbrain
barrier bbb penetrance failure to target the appropriate aβ species or safety
concerns such as amyloidrelated imaging abnormalities aria to address these concerns at
the preclinical level we have recently developed a biomarker platform that allows
longitudinal assessments of the effects of an antiamyloid therapy on imaging and
cerebrospinal fluid csf biomarkers using the app transgenic rat model",[24450890 24450891 27582220 24450890 24450891 26938442 27025652],"preclinical in vivo longitudinal assessment of
kg207-m as a disease-modifying alzheimer’s disease therapeutic amyloidβ aβ aggregates remain an attractive therapeutic target for alzheimers
disease ad based on a multitude of genetic and cellular evidence supporting the
central role of aβ in ad pathophysiology consequently there have been
great efforts to develop therapeutics that target aβ and its clearance",[]
219,this separation of local and network mechanisms has been shown to be informative in previous applications to epilepsy,[25393751 27384316 28817568 31632339 27501083],"future work should involve integration of multi-modal neuroimaging data, including functional data (eeg/meg/fmri), structural mri, and pet, to quantify the relationship between spatial patterns of ni and alzheimer’s pathologies, cortical atrophy, vascular dysregulation, metabolic alterations, inflammation, etc. on an individual level. a limitation of the modelling methodology is the use of a static functional network which is independent of cortical excitability.",[]
220,prior studies have shown that the concentration of a single protein such as aβ and a tau protein is increased in the csf or blood in ad,[20413866 32310175 33609478 29420472 30857558],"although these methods have been used to predict pathology before clinical symptoms have developed, their invasiveness and cost have limited their use to well funded research settings in academic centers. using our novel assay, we identified ttr, aβ, tau231 and α-syn as constituents of the aggregates seen in adts exposed to sera from patients with ad and mci.",[]
221,a high blood cholesterol level is a wellknown risk factor for ad moreover polymorphism in the apolipoprotein e gene apoe is a major risk factor for ad development animal studies have shown that high blood cholesterol disrupts autophagymediated amyloid β clearance cholesterol binds to amyloid β peptides and aids the formation of neurotoxic oligomers statins lower cholesterol levels by inhibiting hmgcoa reductase and improve neurovascular dysfunction by modulating oxidative stress nitrosative stress and inflammation therefore the major benefits of statins in ad might be attributed to these 2 mechanisms,[19715550 31367008 29862881 25000142 24231510],"most degs were downregulated in the statin-treated group. gsea, gene set enrichment analysis; kegg, kyoto encyclopedia of genes and genomes; ad, alzheimer's disease; nes, normalized enrichment score.",[]
222,other studies have shown that rta408 increases nrf2 and decreases nfκb,[33017422 28851867 29435098 29925185 31487581],propofol decreases consciousness and memory and is used as a general anesthesia. rta408 protected against propofolinduced memory impairment assessed with the mwm and increased activation of nrf2 and the inhibition of nfκb p65 nuclear translocation,[33295701]
223,this notion has been confirmed by computational studies in which up and down states can be reproduced by models of neural populations with recurrent excitation and slow adaptation eg activitydependent k current or synaptic depression a,[30602773 15537811 19499317 12351744 12612051],earlier studies showed that slow oscillations can be generated in isolated cortical gyrus  a cortical slab  and cortical slice  suggesting that cortical circuits are sufficient for the generation of slow oscillations subsequent studies have consistently demonstrated that recurrent excitation of layer l 5 pyramidal cells is a source of slow oscillations,[ 8985908 11073868 11017176 19914188 20200108 11017176 23313909]
224,to achieve this we performed timetoevent analyses controlling for lifestylerelated markers of obesity diabetes hypertension and inflammation as lifestyle factors affect both dementia progression 33 35 36 and tl dynamics,[32992046 32996171 32979926 18391173 26785477],this suggests that ltl may predict ad and cognitive decline differently among carriers and non-carriers of apoe ε4. the present study aims to investigate whether baseline ltl alone or in interaction with apoe ε4 predicts the onset of ad in a wellcharacterized populationbased sample of older individuals followed for 25 years,[32992046]
225,regular exercise is associated with a delay in onset of ad and our groups recent crosssectional research has demonstrated crf is positively associated with several indices of brain and cognitive health  although exercise and crf appear to be beneficial randomized controlled trials have not provided strong evidence that structured exercise can substantially impact the pathophysiological processes of aging and ad eg neurodegeneration an intrinsic limitation to exercise trials is the relatively short durations the typical 6 to 12month intervention may be insufficient to significantly impact the slow progressive pathophysiology of the disease but see also erickson et al,[16418406 28293467 30852709 29113943 21282661],"however, we did not observe significant three‐way interactions; therefore, the genetic specificity of our findings are uncertain. the impact of exercise on brain and cognitive health has received considerable attention in recent years.",[]
226,the apolipoprotein e apoe omim 107741 ε4 allele is the most established genetic risk factor for sporadic ad and has been consistently associated with earlier ad symptoms and pathology in the general population,[ 8346443  8446617 20186853  8592548 29672664],recent estimates indicate a lifetime dementia risk of more than 90 and identify alzheimer dementia as the leading cause of death in this population this elevated risk has led to the conceptualization of ds as a genetically determined form of ad that is similar to autosomal dominant forms this idea is further supported by a recent study that showed that the pattern of ad biomarker changes follows a similar temporal profile in ds as in autosomal dominant forms with a long preclinical phase and pathophysiological processes that are qualitatively comparable to sporadic ad,[30452522 32593336]
227,it has been previously described in some studies of diadmc   but many studies have relied on surfacebased methods that exclude the cerebellum from analysis,[24049139 20858974 23137948 29397305 24194552],while cerebellar gm volume in diadmc with dementia was reliably lower than that of asymptomatic diadmc regions typical of sporadic ad were on average more atrophic and together contributed more to the risk score table cerebellar atrophy is generally understudied in ad and diad.,[]
228,skeletal muscle undergoes prominent remodeling during aging  and exercise powerfully opposes these local deleterious effects activating metabolic   and proteostasis pathways to accommodate increased bioenergetic demands,[31642809 12783983 27304505 28011087 31980607],skeletal muscle has been proposed as a central regulator of organismal metabolism communicating metabolic and proteostasis stress to distant tissues including brain via secretion of circulating myokines in agreement with this multiple epidemiological studies suggest that skeletal muscle aging is a risk factor for the development of ageassociated disease   including those of the cns,[26527185 24797482 26527185 27304505 30700801 24742458]
229,many accelerated ageing diseases such as xp at cs and ws and neurodegenerative diseases such as ad are closely related to the mutation of ddr proteins and dna damage in both the nucleus and mitochondria,[27732836 27181190 30666569 27686631 25552414],the accumulation of mtdna damage and the reduction of mitophagy are also hallmarks of premature ageing diseases such as xp and at although organisms have a large number of responses to dna damage not only will dna lesions increase during ageing but the efficiency of ddr will also decrease,[31923475 22144182 24813611 26956196 25456739 29141944 31364066]
230,furthermore patients with cushing syndrome an endocrine disorder of hypercortisolism present with wholebody insulin resistance 2324 and are more prone to develop a dementialike phenotype,[20829623 10700481 27515536 27986873 18801622],additional studies in ad patients have demonstrated an association between insulin levels and cerebral amyloid deposition and importantly hyperinsulinemia doubles the risk of developing ad moreover chronic glucocorticoid exposure is well known to result in wholebody insulin resistance,[15477536 25043908 27861636 27614803]
231,in recent studies where hcd or beam type cid were used with a ramp of ms fragmentation energies energyresolved hcd stepped collision energy scehcd informationrich fragments from both the glycan and peptide moiety resulted in peptide identification and glycan sequence as well,[25582509 26729457 26481991 24440233 28874712],"however, cid preferentially cleaves glycopeptides at the glycosidic bonds, which facilitates glycan characterization but leaves the peptide intact yielding only a blind mass. hcd and beam type cid (q-tof) ms/ms have in previous studies demonstrated peptide identification and partial glycan information but less information about glycosylation site.",[]
232,"reactivation of hsv seems to have a stronger correlation to ad than hsv1 carriage alone   furthermore populationbased cohort studies indicate that the genetic background and allele 4 of the apolipoprotein e gene apoe ε4 in particular interact with hsv1 infections to increase the risk of ad  
apoe ε4 carriers have an increased risk of cold sores and animal studies have indicated that spread of hsv1 in a host is facilitated by the presence this allele  independently of apoe ε4 hsv1 carriage also seems to interact with other genes for ad development and a genetic variant affecting the development of efficient immunity toward hsv1 gm1717 was recently shown to almost double the risk of later ad development together these studies indicate that not so much hsv1 carriage alone but hsv1 together with certain genetic susceptibility factors increases the risk of ad which might explain the relatively modest penetrance of hsv1 carriership itself",[18982063  9014911 14534428 16699018 32709662],"alzheimers disease ad is a common cause of a major neurocognitive disorder that affects millions of people worldwide a growing body of evidence suggests that herpes simplex virus type 1 hsv1 might play a considerable role in the development of ad  hsv1 is common worldwide and its prevalence is estimated at 80 in the swedish population longitudinal cohort studies have shown that reactivation of hsv, measured as immunoglobulin (ig) m‐positivity for hsv, increases the risk of developing ad approximately 8 to 10 years after hsv reactivation.",[28491117 26510007]
233,positron emission tomography pet studies have demonstrated that the ad patients with apathy had glucose hypometabolism in the acc ofc ventral striatum and medial thalamus 53 54 higher neurofibrillary tangles burden in the acc 55 56 and higher amyloidβ aβ deposition in the bilateral frontal lobe and right acc,[17620493 15705358 16391476 11261510 24133289],gray matter studies on apathy showed that gray matter atrophy in the bilateral acc and left medial frontal cortex moreover decreased gray matter density in the bilateral acc frontal cortex head of the left caudate nucleus and bilateral putamen 46 and decreased cortical thickness in the left caudal acc left orbitofrontal cortex ofc left superior and ventrolateral frontal region 48 and inferior temporal region  were all correlated with the severity of apathy,[17570907 18669506 20872914 23890751]
234,more importantly one single csf analysis with fully automated assays can allow simultaneous investigation of all of the atn biomarkers table  thus dramatically accelerating diagnostic prognostic and therapeutic decisionmaking,[32573951 30902090 29499171 31914216 31759396],"however, at the current stage, blood‐based biomarkers are still under development, and both analytical validation and standardization efforts as well as much more research is needed to establish their utility in clinical trials and clinical practice. comparing the two more established modalities while pet offers unique insights into the spatial and temporal evolution of ad pathophysiology csf analysis is more costeffective is less resourceintense provides evidence on several pathophysiological processes and is more accessible globally compared to pet brain imaging  the number of pet scanners and cyclotrons is limited and existing scanners likely have limited timeslots to accommodate additional patients who need aβ andor tau pet assessments",[31205802]
235,"downregulated mrnas include those encoding complement
factorh cfh of the innateimmune system 8399 an sh3prolinerich
multidomainscaffolding protein of the postsynaptic density shank3 98 and the triggering receptor expressed in
myeloidmicroglial cells trem2 surface glycoprotein immune receptor",[31588707 22509485 31354434 27378912 32531244],"over the last five years lps andor bflps have been shown i to associate
with the periphery of neuronal nuclei in sporadic alzheimers disease ad
brain 38394 ii to promote the
generation of reactive oxygen species ros the inflammatory transcription factor
nfkb p50p65 complex in human neuronalglial cells in primaryculture 7125783 iii to efficiently enter neurons with the
assistance of aβ42 peptides perhaps as a consequence of aβ42
peptides poreforming capabilities 9596 and iv
to strongly induce the upregulation of the proinflammatory transcription factor
nfkb p50p65 complex and transcription of a selective family of proinflammatory
nfkbsensitive micrornas mirnas that include mirna9 mirna34a mirna125b
mirna146a and mirna155 these mirnas in turn
ultimately bind to the 3’-untranslated region (3’-utr) of multiple
target messenger rnas (mrnas) in brain cells and thereby reduce their expression
post-transcriptionally.","[31588707 27784770 32670176 27725817 31588707 31866832 32792144 27725817
 31588707 30568571 31354434]"
236,to better understand the funding landscape for ad clinical trials we interrogated our database of information from clinicaltrialsgov and our annual reviews published over the past 5 years     to determine what agencies and companies were involved in funding current ad clinical trials,[32695874 29067309 29067343 29955663 31334330],ad drug development represents an urgent unmet need there has been no new drug approval in the united states since 2003 and only one agent has been approved globally in that period  an important disincentive to engage in ad drug development is the high cost of development programs a 2014 analysis showed that the outofpocket cost of ad drug development including phases 1 2 and 3 is 413 million when the cost of failures and the cost of capitalization of the funds are included the total cost is 57 billion per drug there are many organizations that support ad drug development including the national institutes of health nih clinical trials funded by philanthropies such as the alzheimers drug discovery foundation addf support for trials from the alzheimers association eg part the cloud initiative and biotechnology and pharmacology companies increasingly trials include publicprivate partnerships ppps involving the nih and biopharmaceutical companies to allow more trials to be conducted while distributing the cost and risk,[25024750 32695874 24673372 24673372 30175227 28899416]
237,anticancer drugs for which a publication was available were bexarotene 52 54 masitinib 51 nilotinib 53 and thalidomide,[26822146 29067298 21504563 32468646 28124585],"four phase ii and one phase i studies were identified. for one study, results were also posted on clinicaltrials.gov as mentioned in the previous section.",[]
238,the most popular hypothesis to explain the origin of ad proposes that deposition of aβ in senile plaques leads to inflammation and neuron death however attempts to decrease the aβ load or to prevent its formation have had no effect on ad no cure whatsoever exists or seems to be on the horizon these facts together question the validity of this mainstream hypothesis therefore new and bold avenues of research need to be pursued to unravel new pathomechanisms leading to successful prevention andor treatment of ad however integrating the unavoidable aβ cascade hypothesis,[24052108 29562511 31564456 30087609 31297054],"because of the abovementioned relationships, inflammaging is one of the most important links between aging and the age-related neurodegenerative diseases. therefore in this context the production of aβ represents most probably the consequence of the neuroinflammatory process induced by several chronic situations including chronic infection as suggested by the amp nature of aβ",[25376108]
239,positive associations were observed between percentage residential green space derived from land use data and spatial working memory and between distance to the nearest natural outdoor environment and visual attentionexecutive processing greater amounts of forest surrounding the residence were associated with greater amygdala integrity whereas amount of neighbourhood urban green space was not associated with mri measures of brain integrity percentage green space and private gardens based on land use data was inversely associated with odds of cognitive impairmentdementia tree canopycover vcf was not associated with attention in children lastly selfreported amount of residential natural environment was not associated with visual attentionexecutive processing,[30187470 28254708 28931835 28082001 28934095 28254708],the third study found no associations between neighbourhood park area and cognition other measures measures of time spent in green space based on objective gps tracking or selfreport were not associated with cognition,[21515547 27179137 28254708]
240,this inclusion criterion may explain why our results show a greater or risk from depression to ad than previous metaanalyses,[32469813 31173329 23637108 22815126 26692556],furthermore our study includes recent references  and it did not analyze data from studies of patient groups with mixed psychiatric histories or all types of dementia even though the metaanalysis of kuring et al  analyzed 36 independent studies for all types of dementia they only pooled k  8 studies for ad or  223,[32469813 32469813]
241,damlike cells or mgnd phenotypes have been characterized in the aβproducing 5xfad and apppsδe9 ad mouse models 51171172 the tauproducing p301s ad mouse model 173 mouse models of amyotrophic lateral sclerosis 51174 and mouse models for multiple sclerosis,[28602351 31061494 32008854 28602351 28930663 23850290 28930663],"the majority of these genes are associated with the production of proteins involved in lipid metabolism phagocytosis clearance of apoptotic cell bodies and the immune response interestingly, the mgnd phenotype is consistent across various neurodegenerative mouse models.",[30206328 29775591]
242,although one of the strongest risk factors for alzheimers disease both eoad and load is being a carrier of the e4 allele of the apoe gene recent genomewide association studies gwas have shown that variants in more than 50 loci are implicated in load defining load as a polygenic trait genes within alzheimers disease risk loci are enriched in multiple diverse biological pathways such as the immune response cholesterol metabolism amyloid protein processing and app metabolism however the mechanisms involved in the misregulation of gene expression that leads to alzheimers disease have not been elucidated,[ 8346443 32112059 26490334 32112059 21085570 30820047],alzheimer’s disease can occur sporadically in the population or may be inherited. earlyonset alzheimers disease eoad that accounts for 5 of alzheimers disease cases can be caused by autosomal dominant mutations that may be inherited or occur de novo in the app presenilin 1 psen1 or presenilin 2 psen2 genes however most cases of alzheimers disease are late onset load and occur after the age of 65 years,[1671712 7596406 8817335]
243,other studies show that sleep fragmentation with increased n1 and the corresponding decrease in sws appear to be widely associated with sleepiness in osa patients,[ 3383654 15222989  9731004 10351907 11399708],the results of a study evaluating the relationship between eds and aβ accumulation  showed that informantreported apnea witnessed apnea was the only sleeprelated symptom that differed between participants with and without eds it suggests that there is a higher prevalence of osa in individuals with eds.,[29532057]
244,indeed there have been clinical trials targeting general cytokine milieus using sargramostim 20 a small molecule rage inhibitor 21 nsaids 22 23 and etanercept 24 in patients with ad or mild cognitive impairment,[28421558 22406537  9065537 27716676 30265513],"therefore, the duration of cytokine-induced microglial response (i.e., transient vs. chronic) is the distinguishing feature of the functional roles of microglia in ad pathogenesis. given the role of chronic neuroinflammation in ad pathogenesis, targeting cytokine milieus to modulate microglial functions is an attractive therapeutic approach for ad.",[]
245,it was well known that females showed more intense nps than males,[24887405 28216088 15939839 19581570 11378178],"nps such as anxiety and depression is typical features of ad effect of music therapy on anxiety and depression moderated ad
phenotypes",[30935215 26049034 21889116 19628939]
246,the insights from mechanistic studies of biphasic doseresponse can help to achieve reproducible results and sustained progress in future drugdevelopment efforts,[23308095 16548522 16595682 18024430 17556361],"biphasic drugs and fad mutations favor an increase in the production of the longer more hydrophobic aβ catalytic intermediates Presented results indicate that the increase can be attributed to the selective interference with the dynamic conformational changes at the cytosolic end of TM6, TM6a, and TM7 (Figure 7, Figures S1, S4 and S5).",[28978478 18574238 23308095 16548522 22323718 22479317 22505025 18024430]
247,inhibition of amyloidogenic or tau fragments aggregation was targeted by dopaminebased hybrid molecules 149 by the reactive catecholaldehyde intermediate of dopamine metabolism dopal 150 multifunctional dopamine d2d3 receptor agonists 151 dopamine appended derivatives of naphthalenediimide ndi 152 and by other rationally designed structural derivatives based on dopamines oxidative transformation,[33523571 33398040 32828429 30285025 29782798],"in ad transgenic mice models eeg modifications in but not restricted to 5xfad mice were associated with alterations in dopaminergic transmission 147 and reduced dopaminergic innervation in the tg2576 hippocampus resulted in reduced synaptic plasticity and excitability of dorsal subiculum pyramidal neurons the lack of causality between brainstem dopamine system failure and ad did not hinder pharmacologists to investigate the possibility of molecular dopamine therapy in ad, with efforts accelerating in the past five years.",[31177214 29778899]
248,"mutations in human c2cd3 cause skeletal dysplasia caused by defective assembly of the primary cilium a microtubulebased cellular organelle involved in developmental signaling
kif2a encodes the kinesin family member 2a which is required for normal mitotic spindle activity and normal brain development most likely via its atp dependent mtdepolymerase activity like c2cd3 kif2a has also been implicated to affect ciliogenesis relating to its role in the cell cycle kif2arelated cortical development defects have been attributed to decoupling between ciliogenesis and cell cycle a kif2a his321asp missense mutation was identified in a subject with defective cortical development owing to impairment of kif2a microtubule depolymerase activity several members of the kinesin family are overexpressed in the brains of ad patients and kif2a expression is specifically upregulated in axons spinal neurons and oligodendrocytes adjacent to spinal cord injuries finally apc encodes the adenomatosis polyposis coli regulator of wnt signaling pathway as a negative regulator and serves as a major tumor suppressor",[27094867 29077851 29077851 31919497 29060936 31041455],"all three adlinked prkca mutations displayed increased catalytic activity by live imaging versus wildtype prkca and potentiated the ability of aβ to suppress synaptic activity in hippocampal slices it will be interesting to determine whether mutations in prkch have similar aberrant effects on receptor activity the three other genes implicated in the spatial clustering–based analyses included c2cd3, which encodes the c2 domain containing 3 centriole elongation regulator that is expressed at relatively high levels in the brain.",[27165780]
249,our findings are in agreement with previous studies that peripheral inflammation triggers a neuroinflammatory response characterized by sustained glial activation with detrimental consequences for learning and memory in neurodegenerative condition  thus supporting the view that the gutmicrobial inflammatory response might represent the earliest events of neuroinflammation in ad,[32032696 27776263 24807189 31284126 23531500],"in the present study, we also found that 5xfad mice exhibited age-dependent increased nlrp3 inflammation activation in the gut tissues along with increased expression levels of asc,caspase-1, and gasdermin-d, which are positively correlated with increased production of proinflammatory cytokine il-1β. interestingly, increased peripheral inflammasome activation is positively correlated with activated microglia and astrogliosis in the hippocampus of young and aged 5xfad mice.",[]
250,with standard dti axd was higher across multiple regions consistent with prior literature,[30687081 20371138 29922120 23145075 21872362],"for example, lower fa in the cc and fornix is indicative of altered wm integrity (e.g., demyelination) in the ad group; these changes were driven by both higher axd and rd with standard dti, while fw correction showed that these changes in fat may be driven by underlying lower axdt. using fw-dti, lower fw-axdt (ad < hc) were found in wm locations corresponding to lower fat, while the fornix showed simultaneous lower fw-rdt (hc > ad) in a small cluster.",[]
251,plasma soluble ssaovap1 is increased in various systemic diseases in diabetes atherosclerosis 107108109110 congestive heart failure 91 and nondiabetic morbidity obesity,[10064104 10892891 12135815  9074703 12800092],experiments performed in adipocytes evidenced that soluble ssaovap1 could be shed from the membranebound form depending on a matrix metalloproteinase mmp activity in diabetic and obese animals it seems that under pathological conditions soluble ssaovap1 originates from adipocytes endothelial cells and smooth muscle cells  but given that various cellular sources can secrete different types of mmps such as neurons cerebral microvascular endothelial cells astrocytes and inflamed neutrophils which kinds of mmps participate in the shedding of soluble ssaovap1 still warrant future investigation,[14968297 15178639]
252,most recognized eofadcausative mutations have been found in the genes psen1 psen2 and app 9 the majority of these mutations  63 occur in the gene psen1 10 the zebrafish orthologs of these genes have been identified as psen1 11 psen2 12 appa and appb,[27060961 22472873 10521267 12424519 11862463],"it is easily manipulated genetically and has the capacity to produce large families of siblings which can then be raised together in the same environment to limit the effects of environmental and genetic noise in molecular analyses moreover, zebrafish possess orthologs of the human genes mutated in eofad.",[25071820]
253,wholeexome sequencing studies have identified robust ad associations with rare missense variants in trem2 akap9 unc5c znf655 ighg3 casp7 and notch3  and it is expected that more adrelated rare variants will be identified by wholegenome sequencing wgs studies because some rare variants including those in noncoding regions likely contribute to ad risk,[23150934 25172201 25419706 31636380 30924900],ad is highly heritable h  5879  but common variants explain only onethird of the genetic portion of ad risk highly penetrant rare variants may account for some of the missing heritability,[16461860 16461860 28714976]
254,these results are consistent with clinical evidence indicating that diabetes is associated with reduced white matter volume as well as with reductions in hippocampal volume  and gray matter volume in addition diabetes is associated with aberrant functional connectivity of the posterior cingulate cortex with the temporal gyrus and frontal gyrus suggesting white matter abnormalities occur in diabetes,[23939539 24647028 23939539 24448784 24658392 24203723],"however, we observed upregulated expression of a subset of genes in app;ob/ob mice, which might illuminate the molecular mechanism underlying the interaction between obesity/diabetes and ad. genes specific to oligodendrocytes and microglial cells were downregulated in both ob/ob and app;ob/ob mice (i.e., mice on the ob/ob background).",[]
255,endothelial dysfunction has also been implicated in cerebral vascular diseases however despite a general appreciation of the role of vascular dysfunction in stroke and atherosclerosis the involvement of endothelial dysfunction in the pathophysiology of ad is not fully understood ad patients display reductions in cbf in various regions of brain including the cortex and the hippocampus in conjunction with cognitive dementia whether the contribution of capillarytoarteriole signalingand therefore cbf controlis affected during ad has not been explored,[31248555  9329032 10944232 11129782 31203725],in 5xfad mice systemic injection of dic16pip2 05 mgkg significantly increased the cbf response to ws 20 min postinjection  by enhancing the ba2sensitive component accumulating evidence has established a crucial role for the endothelium and particularly the capillary endothelium in mediating neurovascular coupling and thereby regulating cbf,[24926076 32076269 28319610]
256,bche was found in amyloid plaques and neurofibrillary tangles nfts suggesting that the protein may be involved in ads pathogenesis,[22157615 25931333  7979218  8534419  8004445],nevertheless bche is also found in specific neurons mainly localized in the amygdala hippocampus and thalamus The primary source of BChE in the CNS is nonneuron cells such as astrocytes and microglia which also express nicotinic acetylcholine ACh receptors indicating that BChE might play a regulatory role in the functional status of these cells via its AChhydrolyzing activity ,[ 9548556 12811800]
257,the group also included parkinsons disease pd subjects n  128 fulfilling the criteria by gelb et al 25 pspn  17 fulfilling the criteria by litvan et al 26 and höglinger et al 27 multiple system atrophy msa n  27 fulfilling the criteria by gilman et al 28 and cbs n  3 fulfilling the criteria by armstrong et al,[ 9923759  8710059 28467028 18725592 23359374],"ad dementia patients (n = 137) fulfilled the diagnostic and statistical manual of mental disorders-5 (dsm-5) criteria for major neurocognitive disorder (dementia) due to ad. the non-ad group (n = 253) included patients with vascular dementia (vad, n = 12), parkinson’s disease dementia (pdd, n = 25), dementia with lewy bodies (dlb, n = 21) and frontotemporal dementia (ftd, n = 5), all fulfilling the respective dsm-5 criteria.",[]
258,in the human tau protein htau transgenic model the mice tau gene is replaced by the human gene correlating with nfts development and neurodegeneration,[28025715 33176118 25927677 12859672 23948912],"pathogenic ps1 or ps2 mutations increase the levels of aβ1-42 form in vitro, but do not promote aβ plaques aggregation in vivo in mice. several doubletransgenic 2xtg mouse models have been developed by crossing app and ps1 transgenic mice demonstrating accelerated aβ accumulation leading to the impairment of cognitive functions",[28304309 25927677 27930341]
259,many components of pge have a variety of activities in the brain,[28610929 17873848 29375565 19433075 32008007],"in addition ethanol extract of pg has been reported to inhibit acetylcholinesterase ache activity considering the previous studies, pge may exert the neuroprotective effect through the regulation of the imbalance between e/i neurotransmitters in the ad brain, such as activating the excitatory cholinergic and inhibitory gabaergic transmission.",[20521984]
260,pla has been used previously to detect both heterotypic 58 as well as homotypic protein interactions  which shows the reliability of the pla approach,[17072308 20923550 32025699 25732184 30721406],"the molecular basis of prion and prionlike disorders is the ability of certain proteins to acquire a selftemplating amyloidogenic state in which protein multimerization is a required step for molecular seeding here, we describe tau-pla, a technique that enables the specific histological visualization in situ of the tau–tau interactions, regardless of tau phosphorylation state and conformational changes, with preservation of the cellular and subcellular morphology.",[9759504]
261,deep brain stimulation targeting the fornix region fxdbs is currently under investigation for the treatment of alzheimers disease ad    a recent paper reported on acute flashbacklike phenomenathe involuntary recall of autobiographical memories described by earlier authors as reminiscences that were experienced by a subset of ad patients during initial postoperative fxdbs programming these were associated with specific stimulation settings and appeared to be unrelated to intrinsic wholebrain or hippocampal volume pioneering 19th and 20th century experiments involving intraoperative direct electrical stimulation of the exposed cortex     provided tremendous insight into the causal relationships between cortical areas and reminiscences and these insights still stand  however the relationship between these memory phenomena and deep brain structures has not been systematically investigated and it remains unknown which specific structures give rise to the flashbacks reported in the aforementioned fxdbs population,[18232017 20687206 29914028 28445741 31914177 28445741 31914177],brain structures and networks responsible for stimulation‐induced memory flashbacks during forniceal deep brain stimulation for alzheimer's disease,[]
262,previous studies reported in early onset ad that left superior temporal and cuneus 44 lateral temporal 40 45 46 parietal 4648 and occipital  regions demonstrate increased aβ,[23507771 16894106 21479849 21709608 21479849 21709608 22265212],"we found high amyloid binding in posterior cingulate/precuneus, lateral temporal, anterior cingulate, and parietal regions in ad. in accordance with prior studies highest amyloid binding was seen in the precuneus 10 4043 and anterior cingulate  in typical ad",[17499392 17065593 18263627]
263,other rodents including transgenic rats have also been used as animal models of ad although ad pathology does not develop naturally in most rodent brains one exception may be the aged octodon degus a grounddwelling diurnal rodent from the upper mountain regions of chile this rodent shares features of neurodegeneration including production of extracellular aβ deposits and intracellular tau and replicates other characteristics of the ad brain its utility as a translational model for drug development however is at a very early stage and new data suggest that degus raised in captivity do not reproducibly demonstrate the hallmarks of ad reported previously similarly guinea pigs are a developing animal model of ad featuring a humanlike aβ sequence with agedependent diffuse accumulation of amyloid pathology,[19432812 29514054 15748782 27566602 24360504],"critically, there are also substantial differences between mouse and human immune systems. reliance on a singular model an underappreciation of background strain influences and a tendency to anthropomorphize outcomes in behavioralcognitive evaluations may model responses to disease factors that insufficiently translate beyond the specific model utilized this must be addressed to adequately model human disease",[]
264,furthermore studies investigating the impact of trem2 signaling on the inflammatory response have produced contradictory results demonstrating either an antiinflammatory or a proinflammatory role for trem2,[16887962 28100745 25732305 23301011 16951310],nhd is a rare autosomalrecessive earlyonset dementia characterized by behavioral changes and cognitive decline with or without pathological bone fractures the mechanism by which trem2 influences to neurodegeneration remains obscure.,[23318515 23150934 12080485]
265,two studies identified an inverse correlation between retinal vessel density and the fazekas scale a radiographic measure of white matter lesions in the brain often used to assess patients with dementia yoon et al also reported that inferolateral ventricle volume was inversely corrected with scp vessel density and perfusion density furthermore some groups have demonstrated significant associations between retinal vd and neurocognitive testing results including moca and mmse scores though the association between octa findings and clinical ad is not fully understood the fact that ad neuroimaging and neurocognitive tests are associated with octa findings supports the value of octa in the evaluation of ad,[31193094 30507577 31755970 28600299 31118186],"in particular robbins et al recently reported that temporal measurements were the least repeatable among peripapillary octa parameters further research is needed to evaluate the utility of peripapillary octa in ad other studies explored the correlations between octa findings and well-established ad metrics, providing further insight into the biological underpinning of these retinal microvascular abnormalities and their clinical significance in ad.",[]
266,our baseline data differ quantitatively from reports by other authors since the bmd obtained in our sample was 0506  0150 gcm2 whereas the data from other authors in patients with ad ranged from 1110 to 2124 gcm2,[19661621 20164583  9855465 15337610 15759247],clinical trials aimed at the effects of exercise in older people or postmenopausal women are more frequent although the evidence appears to support the assumption that exercise has positive effects on bone status not all studies provided clear evidence of increased bmd with exercise interventions,[31498937 23775701 31925473 32055889 19196369]
267,plasma aβ42 andor aβ40 levels were previously shown to be elevated with age in both crosssectional 23 31 32 and prospective studies,[12873852 17914065 30349853 14610118 17055615],"among the biological variables tested as potential modifiers of plasma biomarker levels (age, sex, apoe
ɛ4 dosage, and mapt h1 haplotype dosage), age, apoe
ɛ4 dosage, and sex showed significant effects. older age had significant associations with elevated plasma levels of aβ42, tau, and tnfα.",[]
268,tdo is of particular interest in this regard as it is expressed in the hippocampus and is involved in the regulation of adult neurogenesis in mice neurogenesis within the hippocampus plays a crucial role in memory formation and is affected early in the course of ad hippocampal tdo expression was found to be activated by aβ oligomers and tdo expression was increased in hippocampal regions of ad patients inhibition of tdo prevented neurodegenerationrelated phenotypes in caenorhabditis elegans and drosophila melanogaster models of ad in c elegans this protection was independent of kyn metabolites while in drosophila protection was established by increasing relative levels of ka,[20205802 19323847 27190010 22927396 27114543],the kyn pathway could be a potential drug target in ad. augmenting cerebral ka production by inhibition of kyn metabolism in the blood thereby increasing kyn transport to the brain prevented synaptic loss and improved memory function in a mouse model of ad in addition kyn pathway enzymes in the brain might be targeted directly,[21640374]
269,of interest in this regard is the fact that tdo seems to be integrated in damage response mechanisms in the brain that are regulated by stress signals such as glucocorticoids and prostaglandins which might be activated by aβ finally 680c91 could elevate a global measure of brain extracellular csf serotonin concentration and thereby influence cognitive function,[29241670 27142940 26708701 27190010  7539265],"we, therefore, speculate that tdo might have a role in brain physiology that is independent of its enzymatic function. indeed tdo inhibition reduced aβ toxicity independent of kyn metabolites in c elegans alternatively as tdo expression is highly restricted to subregions in the brain tdo inhibition could impact cellular function without causing measurable changes in metabolite concentrations at a regional level",[22927396]
270,this is particularly relevant for the interplay between aβ and the various surrounding cell types which is considered to be crucial in plaque development,[10794847 22398730  2677252 23610434 27196974],"fonseca et al detect lipidrich cellsized depositions surrounding mature plaques using raman microspectroscopy however, as the transferability of findings between mouse models and humans remains unclear, we investigate aβ plaques in human brain tissue here, in order to resemble the disease course and pathology in human brains.",[31657367]
271,several groups have applied vibrational imaging to human ad brain tissue before,[26621077 25415602 25600495 23586070 28127051],"however, as the transferability of findings between mouse models and humans remains unclear, we investigate aβ plaques in human brain tissue here, in order to resemble the disease course and pathology in human brains. this is particularly relevant for the interplay between aβ and the various surrounding cell types which is considered to be crucial in plaque development",[10794847 22398730  2677252 23610434 27196974]
272,consistently genetic studies have revealed the prominent link of mutations in h3k4 methyltransferases or demethylases to diseases with cognitive impairment  including wiedemannsteiner syndrome kmt2a mutations  kabuki syndrome kmt2d mutations  xlinked claesjensen syndrome kdm5c mutations  and autism spectrum disorders kdm5a5b mutations,[25135975 22795537 20711175 15586325 25363768],methylation at lysines in histone h3 can serve to both activate and repress gene transcription. histone methylation is uniquely suitable to be part of the molecular underpinnings of memory storage because of its tight association with distinct transcriptional states of genes and its active regulation during memory processes,[24045506 23729618]
273,only 39 20 of the reviewed studies present class balance that is the number of participants is evenly distributed across the two three or four diagnostic categories,[31427959 28088191 25417086 28436388 29018636],"this section offers insight into another aspect in which lack of consensus and uniformity is obvious. using accurate terminology (i.e., abiding by diagnosis categories) when referring to each of these groups could help establish the relevance of this kind of research to clinical audiences.",[]
274,some reported a significant enlargement of the faz in individuals with ad compared to controls 11 12 15 whereas others reported no difference in the faz area,[31408108 28600299 31174670 30507577 31193094],this finding would also suggest that the use of octa may be more sensitive in detecting changes in ad and mci participants than fundus camera. previous octa studies have quantified the faz area within the scp region automatically using the octa software and reported conflicting results table 4,[31193094]
275,functional pathway analysis showed that adrelated genetic variants were mainly enriched in app metabolism inflammation lipid metabolism tau protein binding endocyticvesicularmediated transport and synaptic function pathways,[29740579 29562532 30820047 28666525 29971646],"a review article by raghavan and tosto summarizes studies of genetogene interactions in ad the concept of functional genomics attempts to link omics data such as genomics, transcriptomics, proteomics, and metabolomics to explain the complex process from genotypes to phenotypes at a comprehensive level.",[28825204]
276,the latter causes recruitment of extrasynaptic nmdars  and neuronal excitotoxicity   resulting in progressive neuronal and memory loss,[21543591 23270879 28209726 27809304 23776240],however nmda receptors nmdars seem to be particularly important in both animal ad  and ms models the alteration of synaptic plasticity in ad models has been linked with oaβinduced increase in glutamate concentration at synapses    and its spillover out of the synaptic clefts,[23665072 23295855 21446020 22304707 22894822 23776240]
277,the top transcriptional regulators identified by ismara motif enrichment analysis coalesced into the same general categories of diseasecausal endotypes identified by ontology enrichment analysis with consistent activation of transcriptional regulators related to pluripotency including sox2 and sox3 gata2 and gata3 and klf4   cell cycle e2f family members and foxm1  inflammation interferon regulatory factor irf signal transducers and activators of transcription stat and nuclear factor κb nfκb transcriptional regulators   and dedifferentiation including tead factors snai2 and prrx2,[26389663 30517869 23842645 21102550 16979567],s2c). to characterize the transcriptional regulation of these altered gene programs we performed two complementary transcriptionfactor tf activity analysis approaches motifcentric tf activity analysis by ismara integrated system for motif activity response  to characterize the tfs and micrornas mirnas whose motif activity most significantly changes between the psen1 mutant and ndc neurons and tfgene targetcentric activity analysis by dorothea discriminate regulon expression analysis  which uses the viper activity inference algorithm with a curated tf target regulon generated from consensus chipseq expression signatures and tf motif studies to predict tf activity based on the directional regulation of target genes by tfs,[24515121 31340985]
278,notably the ratio of csf aβ142aβ140 has been found to predict cortical amyloidpet positivity more accurately than csf aβ142 alone 909192 improving the discrimination of ad vs nonad demented patients table 2,[32123386 28073379 29614646 30352211 19268916],therefore this biomarker is currently integrated in the diagnostic criteria of ad it is used for subject selection in clinical trials and approved in medical practice as well on the contrary csf aβ140 peptide alone albeit prevailing over the other aβ species in both cns and periphery showed no relevant correlation with ad dementia,[24849862 21514250 29653606 31833025 32123385]
279,cerebrospinal fluid levels of ptau mirror changes in the brain tau metabolism and are elevated in all disease stages of ad including the asymptomatic phase when taupet is still normal taupet tracers bind to insoluble paired helical filaments of tau in neurofibrillary tangles and taupet measures become abnormal mainly in symptomatic ad and correlate with brain atrophy and cognitive function together these findings suggest that fluidbased measurements of ptau may be more sensitive than taupet in the earliest stages of ad,[28743782 32426454 31961372 29053874 30626656],"in autosomal-dominant ad, plasma p-tau217 levels started to increase approximately 20 years before the estimated onset of mild cognitive impairment (mci). although both csf p-tau and tau-pet are considered as biomarkers of ad-related tau pathology, new findings suggest that they are not completely interchangeable.",[]
280,they develop deficits in spatial reference and object recognition memory correlating with robust neuron loss in the ca1 pyramidal layer in a gene dosedependent manner 65103104 as well as motor deficits 105 and reduced neurogenesis,[23685882 24252153 27138799 31156407 31818124],a transgenic mouse model (tg4-42) expressing only aβ4-42 under the control of the neuron-specific thy1-promoter has been developed as a tool to assess the in vivo toxicity of this peptide. in good agreement with the abovementioned results in models expressing only specific aβ peptide variants these mice do not develop overt extracellular amyloid pathology  but robust intraneuronal aβ accumulation mainly in the hippocampus figure 2,[23685882]
281,as pd can prime macrophages either through microbial factors eg lipopolysaccharide or by activation of other immune and nonimmune cells microglia priming activation and polarization due to pd may be plausible,[28890719 28472719 22696147 28912533 24946875],"the risk of developing pd increases with age; however, pd has a peak rate of occurrence in middle age that may result in priming microglia to a significantly activated state increasing the brain vulnerability to aging and to additional immune challenges or diseases. while microglia in wt mice was impacted by the experimental pd as shown by increased iba1 expression the level of inflammatory cytokines was also impacted suggesting a defective immunological process due to pd that would lead to a disrupted inflammatory response",[30555774]
282,several studies have shown that hyperforin activates trpc6 and increases its expression 106133 leading to a decrease in the aβ level and an improvement in cognitive performance in ad models,[22815087 18818211 25039785 16880827 19939230],When applied intracerebroventricularly to rats immediately after MCAO hyperforin preserves TRPC6 activity reduces infarct volumes promotes functional recovery and increases neurologic scores at 24 h after reperfusion  there is a lot of evidence that hyperforin and its derivatives are highly selective towards the trpc6 channel and do not exert similar effects on its closest relative the trpc3 channel,[22815087 17666455 20008516 22832522]
283,the action of aβ and app on mitochondria would explain the abnormal amount of free radicals and oxidative stress the impairment of the activity of the enzymes of the intermediate metabolism and the mitochondrial dysfunction observed both in the disease and in the cells intoxicated with the toxic peptide,[28059794 18725189 29029390 23583906 23562762],autoptic studies on brain tissue of ad patients have confirmed the presence of numerous signs of oxidative stress such as an increase in lipid peroxidation oxidation of proteins and glycides and reduction in antioxidant enzymes furthermore in vitro studies have shown that the neurotoxic properties of aβ can be mediated by ros,[28314935 25944987 24683437 29080524]
284,so βamyloid deposition is the reason behind pathological alterations in ad and its clearance when patients are immunized does not stop this disorder,[25231068 23560052 23610434 22993126 18640458],however the tastpm animal model study pointed out that the concentration of cu in the alzheimers brain does not link to plaques deposition the affinity of cu2 ions for aβ peptides is very high 122123 and it also increases the portion of betasheet and alphahelix in aβ proteins which may be the cause of its aggregation,[26449834 28586203 26178596 17091193]
285,thus the available results are generally not comparable since they target different mirna molecules which further increases the complexity of the subject,[30734227 30689565 26527155 32973449 29800558],another important group of ad biomarkers is the micrornas mirnas which are small noncoding rnas with an average length of 22 nucleotides involved in gene expression at the posttranscriptional level regulation through binding to mrna targets and the subsequent translational repression or degradation of the target by the rnainduced silencing complex although recent studies have been intensively focusing on mirna deregulation associated with ad the lack of standardization in the quantification methods and protocols used is considerably challenging for establishing the discrimination power of mirnas as biomarkers for ad,[31792281 30734227]
286,low csf aβ40 levels might also be indicative of frontotemporal dementia ftd 29 30 cerebral amyloid angiopathy caa 31 hiv 32 multiple sclerosis 33 or normal pressure hydrocephalus nph,[21135556 21709372 20028512 30084711 28486988],this is a useful approach for reducing preanalytical aβ42 biases 2325 and improving the diagnostic performances of csf biomarkers 26 especially in discordant cases this ratio can also be used to account for interindividual amyloid variations in the baseline csf level,[31010420 26034513 17254013]
287,previous studies have reported relationship between different neurotransmitters and ad pathology most of them used plasma or csf samples while only a few used noninvasive samples such as urine from murine animal models,[28211810 25751428 23700429 28039808 30316910],physiologically a reduction of synapsis occurs and neurotransmission is altered in this sense the study of different compounds involved in neurotransmission systems could be useful,[22491782 24410566]
288,in contrast to normal ageing excessive accumulation of autophagy vesicles avs autophagosomes and lysosomes has been observed in postmortem brain of ad patients 101102103 raising the question of whether the av accumulation is a result of autophagy dysfunction 102104 or due to excessive autophagy,[16874045 17396135 17118264 17396135 17362839 15528435],growing evidence shows that soluble aβ42 oligomers are the main toxic species while plaques which mostly contain insoluble fibrils are considered relatively inert secondary contributors to the onset of cellular dysfunction and sometimes even a protective mechanism to limit oligomer toxicity dysfunctional autophagy is implicated in the disruption of cell signalling pathways 98 and increased accumulation of aβ and tau protein aggregates in ad,[26541462 32682953 28923312]
289,several risk factors for ad in ds have also been identified including age and the presence of an apoe ε4   however much less is known about the relationship of sex to risk of ad or to rates of progression in adults with ds and the few existing reports have been inconsistent  one communitybased study of  100 individuals with ds found that men had an earlier onset and an almost threefold greater risk for ad than women however another similarly powered study found that females had a higher risk for developing ad,[10402500 20946940  8957023  9566384 10430422  9566384 10430422],these factors may provide potential targets for intervention to delay or prevent onset of ad. major known risk factors for load are age the presence of an apolipoprotein ε4 allele apoe ε4 which has been associated with an increased risk for load and sex where the risk of ad appears to be greater in women compared to men independent of the longer life expectancy for women the literature is inconsistent with respect to the differential effects of sex on ad with several studies finding either no difference between men and women in incidence of ad or a significant effect of age and sex on risk of ad as the incidence of ad is higher in women in the older age range  several lines of investigation have shown a protective role for estrogen in load  and the loss of estrogen has been identified as an important factor in the increased risk of ad in women after menopause  sex may also have an effect on rate of cognitive decline after onset of ad and it appears that women with ad have worse cognitive impairment than men at baseline and may decline faster a recent review on the differential effect of sex on ad highlights knowledge gaps in many aspects of risk factors of progression and biomarkers for ad in the general population and the need for further study,"[23296339 20442496 10851365  9008508 11445258 20167003 27870425 27692800
 24418360 29189302 29324460 29985474]"
290,previous studies have demonstrated that microglia instigates tau pathology in diverse ways inducing tau aggregation by proinflammatory cytokine release 404142 and spreading hyperphosphorylated tau oligomers or nft through exosome secretion,[29951498 19289607 20920788 26436904 30227881],"once the balance is weighted on m1 conversion, it cascades into further neuronal deterioration in the presence of tau proteins, not to mention external aβ oligomers. like the pathological conversion of aβ hyperphosphorylated tau oligomer causes microtubule collapse then forms neurofibrillary tangle nft leading to brain atrophy and cognitive decline",[22487856]
291,csf pt181 tau has also proven useful in differential diagnosis of dementia 213214215 and to predict cognitive decline in preclinical and prodromal disease stages  with specificity for ad,[20157306 29554190 22170879 20157306 22213792 24012374],from a neuropathological perspective analysis of postmortem brains has shown a certain degree of correlation between the neocortical tau burden and csf ptau tau phosphorylated at threonine 181 pt181 ttau and aβ42 have been extensively validated in the csf as biomarkers of ad and are currently widely used as diagnostic benchmarks in clinical and research studies,[19273758 17012293 24849862 21514249 30488277]
292,in ad patients and ad animal models aβ accumulation induces ec dysfunction and reduces the expression of tight junctional protein in brain ecs thus resulting in decreased bbb tightness,[16644119 26143259 23855502 29154819 31047972],"endothelial cells in the brain form the blood–brain barrier (bbb), which tightly regulates solutes exchange between the lumen of blood vessels and the interstitium of the brain parenchyma. bbb breakdown causes accumulation in the brain parenchyma of bloodderived neurotoxic proteins such as fibrinogen thrombin haemoglobin ironcontaining hemosiderin and free iron contributing to neurodegeneration",[20944627 21040844]
293,one of the major obstacles for the early diagnosis is related to the complexity of ad etiology and pathogenesis,[30617256 27050320 21304480 27025652 29653606],Data from The World Health Organization indicate that AD is the fifth cause of death worldwide and predict a dramatic increase in AD incidence in the next years reaching 52 million people affected by 2050  this scenario is worsened by the absence of an effective therapy as well as by the absence of an early diagnosis as it is usually made after symptoms manifestations when neural impairment and brain injury damages are already severe,[30617256 27050320 21304480 27025652]
294,opposite to apoeε4 apoeε2 confers a reduced risk of ad 456 although apoeε2 is associated with more severe caa and hemorrhages,[ 8346443  8350998  8446617 26341746 25716356],the allele frequencies of ε2 ε3 and ε4 are 7 78 and 15 respectively in most caucasian populations  showing that apoe3 is the most common isoform in humans and apoe2 is the least common however in patients with ad the frequency of the apoeε4 allele is markedly increased to 4050,[3283935 8533168]
295,however oxidative stress mitochondrial dysfunction and glucose hypometabolism have been well documented in mci and ad brain,[30737462 22037588 10811879 17222480 19142633],the high metabolic need of the brain cannot be met by glycolytic activity. rather neurons rely on the tricarboxylic acid cycle and oxidative phosphorylation housed in mitochondria to produce atp,[29752396 16285865]
296,indeed removal of aβ by the csf lymphatic and glymphatic systems decreases in ad 88 142 possibly with contributing factors including increased stiffening of the arterioles with age 179 and ischaemiainduced changes of other key components such as decreased lymphatic function and aquaporin 4 localisation away from astrocyte endfeet abutting blood vessels,[31104026 27234656 18363936 30046111 31104026 21891870],a detailed analysis of these proposals has been provided in ad when cbf decreases decreased pulsatility of the middle cerebral artery has been reported  and so if this extends to penetrating arterioles less aβ removal by pulsationdriven mechanisms would be expected,[30340614 31908463]
297,blood amyloid biomarkers results have been somewhat inconsistent in the literature  however plasma aβ4240 ratio measured by mass spectrometry has been shown to provide a sensitive and reliable measure of amyloid status that predicts future progression to positive amyloid pet and correlates with csf aβ42405152 plasma ttau is elevated in persons with ad as well as other brain disorders   and plasma ptau has been shown to be a sensitive and specific predictor of elevated brain aβ which suggests it may be useful for screening although more research is needed on the topic,[27534714 29420472 28692710 29487167 29626426],several studies have shown that plasma nfl correlates with csf nfl and neuroimaging markers as an indicator of neurodegeneration across the ad continuum is higher in people with both mci and ad even after correcting for age and is associated with cognitive decline and neuroimaging biomarkers of ad   serum nfl concentration increases 5 to 15 years prior to clinical disease onset in familial ad and may thus be an easily accessible biomarker for onset of neurodegeneration other plasma biomarkers have also shown some promise.,[30055655 28346578 30664784 26870824 30664784]
298,given the wealth of research implicating the transentorhinal region   selective vulnerability of the alec to agerelated alterations in processing and structural changes associated with agerelated cognitive decline we hypothesized that alec structure specifically ct might provide a suitable biomarker for early ad detection,[ 6474172  1669339  1669710 29518359 28578804],"overall, these results indicate that relative to hippocampal volume, raw alec thickness is a better predictor of ad status and is at least as good a predictor of mci status. future research may consider combining alec ct with other predictors within a machine learning algorithm to better predict ad onset.",[]
299,the vt has been employed as an index of tspo binding in multiple studies in alzheimers disease,[25649991 25412766 23775979 25766898 27318133],"thus, it is possible to estimate the density of tspo by calculating the radioligand distribution volume (vt) that takes into account the number of radioligands in the plasma and the presence of metabolites. the vt refers to the relationship between the amount of tspo radioligand in a defined brain area and its concentration in the plasma at steady state.",[]
300,as compared to the individuals without amyloid pathology a faster deficit in brain glucose metabolism brain volume and cognitive performance was experienced by individuals with amyloid deposits at baseline,[24012374 23477989 27450471 26595683 28609533],it has been revealed by postmortem analyses that healthy elderly individuals can possess extensive amyloid pathology Moreover brain imaging analyses showed that Aβ pathology was observed in up to 44 of cognitively healthy older people ,[16801647]
301,the receptor for mar1 is thought to be lgr6 and rorα of a nuclear receptor 737475 figure 1 mar1 exerts a potent antiinflammatory effect and promotes the macrophage phagocytosis and efferocytosis of apoptotic cells,[31657786 32360520 30855276 19103881 22253477],the following sections will focus on mar1 rvd1 and npd1 which are produced in the human brain  and discuss the relationship among these spms and ad mar1 is produced from dha by 15-lox and 5-lox.,[26650044 28004822 29757195]
302,the development of an nfl assay in plasma follows a greater trend in the ad community focused on developing plasma biomarkers to measure βamyloid aβ   and tau pathologies    plasma biomarkers have the potential to transform the tracking of biological effects of drugs in clinical trials by significantly reducing common barriers for sample collection such as high measurement cost timeconsuming procedures eg mri or aversion to lumbar puncture,[29420472 32123385 32123386 32333900 30171200],comparing progression biomarkers in clinical trials of early alzheimer’s disease neurofilament light nfl is a cytoskeletal protein which is released from injured neurons in several neurodegenerative diseases including in alzheimers disease ad  nfl concentration measured in cerebrospinal fluid csf nfl has served as a biomarker for axonal injury and neurodegeneration in research and to some degree clinical practice for decades and recently a highly sensitive assay has been developed to reliably measure nfl in plasma pnfl recent work has shown that pnfl levels increase over time in mild cognitive impairment and ad and are associated with brain atrophy in adassociated brain regions,[]
303,the vgfderived peptide tlqp62 regulates neuronal activity neural progenitor proliferation memory formation and depressionlike behavior via mechanisms largely dependent on bdnftrkb signaling and was never previously shown to be causal to ad,[26180209 28594546 29158577 26180209 24747217 30022437],the vgf vgf gene we identified and validated is ngf and bdnf inducible and expressed in neurons in many different brain regions encoding a 615aminoacid 617 in mouse precursor polypeptide that is processed into several bioactive peptides regulating neuronal activity and survival neurogenesis energy balance and lipolysis and behavior vgf is robustly regulated in the hippocampus by voluntary exercise and by bdnftrkb signaling and in our studies vgf overexpression rescued cognitive deficits and neurogenesis in 5xfad mice figs  and,[26180209 24747217 15233376 25675362 30022437 18059283  7551568]
304,tyr682 phosphorylation regulates app binding to specific adaptors and thus controls app endocytosis and distribution in neurons,[26658856 11544248 11606195 11279131 21266574],as bace1 is optimally active in acidic environments such as in the late endosome and lysosome  it is reasonable that increased aβ peptide production might be due to a preferential app trafficking towards such organelles we and others previously reported that the tyrosine 682 tyr682 residue in the 682yenpty687 motif of app is crucial for app trafficking in neurons,[20687525 10531052 31039414 14736502 26658856 25287911 19602287]
305,the paradoxical disconnect of classic ad pathologic changes without clinical dementia and the converse progressive dementia without pathologic ad changes could be explained by the presence or absence of disruption to normal bbb and glymphatic clearance,[14656067  1961359 16801647 24585367 21516511],"this ultimately leads to development, accumulation, and spread of toxic misfolded proteins (aβ and hp tau) and neurodegeneration, all required for pathologic diagnosis. the latter occurrence leads to dysfunction and death of neurons and supporting glia with loss of cognitive function",[26848654 24005412 25492702 26635213]
306,in fact researchers have found evidence pointing to the presence of pathogens such as viruses bacteria and fungi in ad brains,[22899188 30250480 25932012 25182736 30338482],the cytokines interleukin 1 and interleukin 6 are especially elevated one source of the neuroinflammation in ad patients could be the response to invading microorganisms and viruses.,[20182045]
307,furthermore a number of studies have shown that trem2 is related with microglial phenotype switching in neurological disorders including ad,[29621548 26802771 28930663 31379859 28602351],furthermore knockdown of trem2 in microglia suppresses phagocytic activity and activates gene transcription of tnfα whereas overexpression of trem2 in microglia not only promotes phagocytosis but also diminishes proinflammatory responses particularly it was shown that upregulated trem2 expression in the 5xfad mice reduced aβ plaque and neurite dystrophy and improved cognitive function and promoted microglial phagocytosis,[15728241 29518357]
308,for example in one study genechip and microfluidic fluorescent arraybased andor lednorthern dot blot mirna analysis that interrogates the entire 2650 mirnas yet characterized in human brain tissues revealed a selective upregulation of mirna146a in 3636 short postmortem interval pmi human superior temporal lobe neocortical tissue specimens analyzed compared to 30 age gender and pmimatched controls all pmis  31 h     mirna146a levels were found to range from 17 to 36fold greater in ad than in age gender and pmimatched controls in the same anatomical regions,[28838542 23217212 20937840 30083102 22138609 23217212 20937840 30083102],this wellcharacterized subset of rapidly activateable mirnas defines a subfamily of mirna all containing onetoseveral nfkb p50p65 recognition features in the immediate 5 upstream sequence of their proximal promoter regulatory regions one of these mirnas is mirna146a normally only moderately abundant in the human brain neocortex and hippocampus but inducible to many times its basal level by pathogenic agents associated with stress proinflammatory glycolipids such as lps local levels of reactive oxygen species ros and the abundance of aβ42 peptides and prion amyloids whose accumulation are characteristic respectively of the human disorders alzheimers disease ad and prion disease prd,[30734227 23217212 22138609 23217212 20937840 28193766]
309,interleukin1β il1β is an important proinflammatory cytokine in the brain it is generated by the cytosolic nucleotidebinding domain leucinerichcontaining family pyrin domaincontaining3 nlrp3 inflammasomes where nucleotidebinding oligomerizationdomainlike receptors nlrs are engaged resulting in increased il1β release evidence is growing that il1β plays a central role in ad progression the nlrp3il1β is synthesized and released from activated microglia and astrocytes,[ 3487617  1784142 25625584  2529544  2091832],the pathophysiology of ad is characterized by abnormal extracellular accumulation of amyloidβ peptide aβ in amyloid plaques and abnormal intracellular accumulation of tau protein in neurofibrillary tangles nfts several theories are published regarding the ad pathogenesis the amyloid cascade theory proposes that the accumulation of aβ plaques in the brain is the primary pathogenic event the tau hypothesis proposes that tau hyperphosphorylation is the underlying etiology the cholinergic theory suggests ad is associated with a reduction in the choline acetyltransferase activity and acetylcholine levels in specific areas of the brain such as the cerebral cortex these proposed disease mechanisms result in a loss of synaptic function mitochondrial damage activation of microglia and neuronal death neuroinflammation is mediated primarily by microglia cells and neuroinflammation contributes to ad pathogenesis microglia activation has a dual effect on ad progression it leads to a a reduction of aβ accumulation by increasing phagocytosis clearance and degradation and b the release of proinflammatory cytokines and triggers the inflammatory cascade that contributes to neuronal damage and death,"[27547756  7997077  2424016  2423512  3083509  2424015    66473 26207229
  2874657  3670729  3263583 26207229]"
310,in the second phase of their study daniels and colleagues showed that the fenamate drug class also prevented aβinduced memory deficits in rats and it decreased adrelated neuroinflammation in three adtransgenic tg mice that expressed the presenilin mutation ps1m146v the mutant amyloid precursor protein appswe and a transgene of the human mutant p301 tau gene taup301l transgene these animals develop a progressive neuropathological phenotype with increasing age that includes aβ plaques and neurofibrillary tangles fenamate treatment was associated with decreased il1β expression and microglial activation in ad mice equivalent to levels in wildtype mice,[27509875  8878479 11520987 15509565 28601278 27509875],in 2016 daniels and colleagues also detected a protective effect of the fenamate class of nsaids against ad and they hypothesized that it was due to inhibition of il1β release from the nlrp3 inflammasome in immortalized mouse bonemarrowderived macrophages in the initial in vitro phase of their study the fenamates flufenamic acid mefenamic acid and meclofenamic acid were more effective at inhibiting il1β release than celecoxib or ibuprofen which had no effect on il1β release in contrast diclofenac was associated with a modest but significant reduction in il1β release,[27509875 27509875]
311,for example familial ad fad mutations have been identified in app and presenilin ps the catalytic subunit of gs,[ 1671712  7638622  7596406 10801983 21115843],"aβ aggregates are thought to trigger a cascade of reactions involving neurofibrillary tangle (nft) formation, neuronal death, neuroinflammation and, ultimately, cognitive decline. this hypothesis has significant genetic support.",[]
312,a review of the literature indicates that measures of neuroticism and conscientiousness show the largest and most reliable change before and after the onset of dementia in sporadic ad these same factors typically also show large differences between cognitively healthy older adults and those with either mild or very mild dementia  furthermore evidence suggests that high levels of neuroticism andor low levels of conscientiousness confer the greatest risk for developing dementia in healthy older adults    given the predictive power of personality recent guidelines have even suggested incorporating these measures into clinical diagnoses of dementia,[22552913 23364170 20973606 19153372 21514250],"personality traits refer to enduring characteristics including attitudes, values, social behaviors, and habits that manifest predictably across situations. it is generally agreed upon that personality can be adequately captured by five major factors collectively known as the big five neuroticism extraversion openness agreeableness and conscientiousness some common adjectives that describe each of these traits are anxious and worrying neuroticism energetic and outgoing extraversion curious and insightful openness generous and forgiving agreeableness and efficient and organized conscientiousness these traits have been shown to change with age and are related to a variety of life outcomes including physical health depressive symptoms and even mortality importantly personality traits also change with the onset of clinical symptoms of ad",[16435954 26014798 23911610]
313,t1weighted magnetic resonance imaging mri was performed to define regions of interest rois and to perform pvc using the mullergartner approach pet scans were performed on the highresolution research tomograph 207 slices resolution 3 mm full with at half maximum fwhm with eventbyevent motion correction dynamic 11cpib scans were acquired for 90 minutes following administration of a bolus of up to 555 mbq of tracer dynamic 11cucbj scans were acquired for 60 minutes after administration of a bolus of up to 740 mbq dynamic pet images were motion corrected fslflirt registered to the participants mri,[30014145 17301468 24089924 29111487 28792356],all participants received a pet scan with 11cpittsburgh compound b 11cpib to determine the presence of brain amyloid β aβ accumulation as described previously 11cpib pet scans were required to be negative for cn participants and positive for mcidementia due to ad participants supplementary methods all participants provided written informed consent as approved by the yale university human investigation committee prior to participating in the study.,[30014145]
314,cyclooxygenase2 cox2 a major factor in inflammatory reactions catalyzes the conversion of its substrates such as arachidonic acid aa eicosapentaenoic acid epa and docosahexaenoic acid dha to proinflammatory lipid mediators including prostaglandins pgs 11hydroxyeicosatetraenoic acid hete 11hydroxyeicosapentaenoic acid or 15hydroxyeicosapentaenoic acid hepe and 13hydroxydocosahexaenoic acid hdha,[24684963 23786234 11034610 12391014 20194532],n-as-triggered spms are direct regulators of microglia in a model of alzheimer’s disease,[]
315,the catecholamines norepinephrine and dopamine are synthesized by neurons in brainstem that project to forebrain with dense projections to subcortical structures such as the thalamus and striatum respectively and a more delicate projection to the cortex including the pfc methylphenidate blocks dopamine transporters and increases extracellular dopamine concentrations in the striatum and in the medial pfc a comprehensive examination of catecholamine changes  made the surprising discovery that methylphenidate produces an even greater increase in norepinephrine than dopamine in rat medial pfc the low clinically relevant doses used had greater effects on pfc than those seen subcortically in nucleus accumbens or septum thus methylphenidate effects on pfc catecholamine actions may be particularly important to understanding the clinical benefits of this compound as described below,[ 1709528  3950077  9109529 28154152 16806100 16806100],"researchers have wondered whether they could lessen symptoms of apathy by administering methylphenidate a treatment for attention deficit hyperactivity disorder adhd that is known to improve motivation in nonad patients methylphenidate is thought to have many of its beneficial catecholamine actions in adhd by strengthening pfc function and it may boost remaining pfc circuits in ad patients as well methylphenidate may also enhance motivation by enhancing dopamine actions in striatum, a region more resilient in ad.",[23164814 23164814]
316,the amygdala volume has been strongly implicated in ad  but studies concerning the rate of decline relative to the hippocampus have been inconsistent with the amygdala showing lower levels of atrophy   equal levels of atrophy  and greater levels of atrophy as shown in this study,[21920712 16367898 11706109 17030660 16524704],"these findings are supported by the braak model which suggests that mature neocortical neurons are not affected by pathology until later in the disease process interestingly, we report that the amygdala declined 11.6% faster than the hippocampus (95%ci 9.9, 13.0%) in ad patients in this study.",[16906426]
317,although no diseasemodifying therapy has been approved yet promising signals have been observed in a number of antiamyloid clinical trials in which small to modest reductions in brain amyloid levels were achieved in treatment groups albeit not accompanied by effects on cognitive decline     these trials have maintained hope in the search for a successful therapy but also identified challenges in trial design,[27176461 29365294 24450891 29719179 27582220],"currently ad dementia is conceptualized as the endpoint of a cascade of events leading to cognitive impairment with the accumulation of amyloid beta aβ plaques being considered the first detectable change in the braina process that continues for decades prior to the onset of cognitive decline although no causal link between aβ plaque deposition and subsequent dementia has been established it remains a pathological hallmark in the pathway toward ad dementia as such, its measurement has been part of many observational studies in aging and dementia, and it has also been used in clinical trials both as inclusion criteria and as part of the outcome measures in the case of anti‐amyloid interventions.",[23332364]
318,tnfα exerts a key role in this early proinflammatory process observed in preclinical ad as emerges from preclinical studies in animal models of ad  as well as from human longitudinal studies,[22096345 29516540 24567119 27697064 26996175],cumulative evidence suggests that microglial inflammation-induced oxidative stress in ad is amplified. in contrast microglialmediated clearance mechanisms are not functional,[28862638 30593839]
319,several studies reference in curcumin analogues that have been labeled with fluorine18 4 and gallium68 113114 for future application in pet imaging and proton3 112 and iodine125  for future application in spect and in mri imaging respectively,[31858697 27608011 24766626 27461789 28841047],"furthermore, bmaoi14 is specifically bound to aβ plaques. Further research is in progress to optimizethe BMAOI 14(Table 3).",[]
320,their attitudes to influence learning and cognition in animal models of disease and also in humans have been exhibited by dietary supplementation experiments involving flavonoidrich food or plant extracts,[11976192 15236762 16547523 23810791 30914316],as a whole when compared to nondemented older adults tau is at least 3to 4times more hyperphosphorylated in the brain of ad patients growing evidence confirms that flavonoids display promising neuroprotective potential due to their ability to lessen the progression of agerelated neurodegenerative disorders or avert the onset of neurodegeneration,[ 8226987 30733944]
321,the previous structural mri fmri and 18ffdg pet studies have reported reduced volume disrupted intrinsic activity and hypometabolism of hippocampus and hippocampal subregions in both ad and mci patients,[30420801 28653793 29629524 29592955 16473024],in addition to fmri the fluorine 18 18f fluorodeoxyglucose 18ffdg pet showed that the glucose metabolism of the left hippocampal body ca23 and ca4dg subregions was significantly lower in the early ad group than in the control group in mci patients we found that the left hippocampal ca2 functional connectivity measured by restingstate fmri was associated with decreased dorsal raphe nuclei binding potential measured by 11cdasb pet,[29629524 28379618]
322,the mri data were centrally processed at lund university using previously reported procedures in brief cortical reconstruction and volumetric segmentation were performed with the freesurfer software version 60 image analysis pipelines the magnetization preparedrapid gradient echo mprage images underwent correction for intensity homogeneity removal of nonbrain tissue and segmentation into gray matter and white matter with intensity gradient and connectivity among voxels cortical thickness was measured as the distance from the gray matterwhite matter boundary to the corresponding pial surface reconstructed data sets were visually inspected for accuracy and segmentation errors were corrected,[30326496 21514249 21514250 27323247 26962052],"the pet images were acquired using a biograph micro-ct pet/ct scanner (siemens medical solutions) in the memory disorder clinic of gangnam severance hospital, discovery 690 pet scanner (ge medical systems) in the biofinder study, and a biograph 6 truepoint pet/ct scanner (siemens medical solutions) for ucsf patients. the pet data were locally reconstructed into 4  5minute frames for the 80 to 100minute interval after injection the mris were acquired on a 30t discovery mr750 scanner ge medical systems in the memory disorder clinic of gangnam severance hospital 30t tim trio or skyra scanner siemens medical solutions in the biofinder study and a 30t tim trio or prisma scanner siemens medical solutions at ucsf",[29050382 27323247 26962052]
323,noninvasive highresolution retinal imaging technologies such as fundus imaging optical coherence tomography oct as well as recently developed oct angiography 42 62 72 retinal amyloid imaging 4648 and retinal hyperspectral imaging  incentivize the use of feasible and inexpensive retinal imaging in the clinical setting to improve ad screening and monitoring,[23918361 30352114 27830174 31530809 27333181],among key findings were severe optic nerve and retinal ganglion cell rgc degeneration thinning of the retinal nerve fiber layer rnfl glial stress altered electroretinography responses and vascular abnormalities notably the pathological hallmarks of adaβ plaques and tauopathywere further identified in the retina of ad patients including earlystage cases,"[29312125 23443359 27645291 28814675  2774510 30593285 20550967 28814675
 26505992]"
324,some of their postsynaptic counterparts influence formation of functional dendritic protrusions sept6 62 sept7 63 64 and sept11 41 and sept7 is reported to effectively suppress the lateral movement of membrane proteins by forming a barrier at the base of the dendritic spine,[21544625 17935993 17935997 19380581 25494357],septins are fundamentally engaged in substantial synaptic functions. presynaptic septins tightly regulate synaptic vesicle trafficking and exocytosis moreover neurite growth and maintenance reviewed in,[25888325]
325,erk regulates adam9 10 and 17 at multiple levels and regulates transcription factor sox9,[22002568 17704059 20087163 10655493 21512138],however rivastigmine nanoformulation can produce significant inhibition in mrna levels of bace1 rivastigmine stimulates the activation of both erk and akt,[]
326,"furthermore the current understanding
of crf in persons with ad is limited to a few studies that have investigated
vo
2peak
obtained via cpet using treadmill protocols in patients with
relatively mild ad only with ranges of
194216 mlkgmin most commonly reported",[22133248 21574893 18625967 22020383 23559521],"likewise there is
an increasing interest in exercise and fitness in alzheimers disease ad
given the accumulating evidence supporting the potential therapeutic effects of
aerobic exercise and fitness and the maintenance of cognitive health however, little data exist on the objective
measurement of crf in older adults with ad.",[]
327,for example the top 20 clonotypes account for 60 of all γδ t cells in the pb of adults  γδ t cells are also found in peripheral and barrier tissues where they mediate antiviral and antimicrobial defense support wound healing and promote immune tolerance  γδ t cells can also be involved in pathological processes such as oncogenesis  autoimmunity  and even stroke,[28218745 28920588 29963061 29203226 27019327],"upon somatic v(d)j recombination starting at γ- and δ- chains and then progressing to α- and β-chains, t cells are generated to express unique γδ- or αβ-tcr pairs on the cell membrane, respectively termed γδ and αβ t cells. unlike αβ t cells γδ t lymphocytes represent a less abundant population of peripheral blood pb cells  and have on the one hand diverse tcr repertoire  but on the other hand it is considered to be oligoclonal",[23085947 29720665]
328,finally other mechanisms that lead to secondary toxicity include inflammation oxidative stress glial activation among others molecular targets in this respect besides the aβ peptide include bace tau protein markers of inflammation and even the 5ht2a receptor,[21176189 30501965 31334330 27955995 30134967],"in cytoskeletal degeneration, i.e., tau pathology, nfts would be the primary target. however, upstream alterations responsible for nft formation would be better targets at earlier stages.",[]
329,in addition to aβ and nft neuroinflammation is exhibited in the brains of ad patients,[29107864 23930978 25792098 27179961 28185874],"to date, a considerable gap regarding the onset and progression of ad neuropathology and clinical symptoms still exists. over the last few decades, a third core neuropathological feature of ad has emerged.",[]
330,interestingly recent studies have reported that hsamir1013p is differentially expressed in ad serum  and precursor as well as mature forms of mir101 regulate the expression of amyloidβ precursor protein in human hela cells and rat hippocampal neurons  mir101 is also associated with the innate immune response in macrophages  and hepatocellular carcinoma,[25349172 20395292 21172309 21068409 28559963],"as braak nft stage progressed, the expression of hsa-mir-101-3p was increased specifically in the ec. furthermore, overexpression of hsa-mir-101-3p in the human neuronal cell line sh-sy5y caused rac1 downregulation.",[]
331,while reports of increased activity in early stages of ad have mainly implicated the hippocampus this phenomenon has been documented in the prefrontal cortex as well  for instance ad patients who had higher activity in prefrontal areas were better able to perform tasks of semantic and episodic memory nevertheless while previous studies have identified hyperactivation of adrelated regions under fmri    the high temporal resolution of our eeg data suggests two processes to be involved one is a decrease in orientationrelated activity along the ad continuum while the other is a parallel increase of a distinct activity,[16315273 12574428 12574428 16087905 21194156 10944562 16315273],nonetheless these results are in congruence with a growing body of evidence reporting a paradoxical increase in activity relative to baseline in patients at high risk for ad rather than a loss of activity   for example mci patients performing an associative memory encoding task under fmri showed greater hippocampal activation compared to control similarly asymptomatic genetically atrisk individuals such as carriers of familial earlyonset ad fad and apoeε4 carriers demonstrated greater mean entorhinal or hippocampal  taskrelated activation compared to noncarriers patients who had progressed to the ad stage exhibited decreased taskrelated hippocampal activity bilaterally correlating with deteriorating memory performance notably increased activity was found not only on the neurocognitive level but also in the molecular and cellular level it remains unclear whether these increased activations play a compensatory role to maintain performance in the early stages of ad or a causal role acting as a harbinger of imminent neuronal failure,"[16087905 18206188 29986165 16087905 21194156 10944562 16087905 21194156
 10944562 16315273 20463288 29986165]"
332,"this concept has evolved over time with various taxonomies nomenclatures and definitions which are summarised in  and described in an historical context below
table 1various definitions of cognitive impairment that is not dementiatermbsfcdrqdaamiaacdcindpetersen mciwinblad mciniaaamncdcognitive complaintself or carer complaint about memoryself or carer complaint about cognitionselfcomplaint about memoryself or carer complaint about cognitionself or carer complaint about cognitionself or carer complaint about cognitionpsychometric impairment1 sd below healthy young adults1 sd below agematched samplebattery of neuropsychological tests15 sd below age and edu matched sampleno cutoff specifiedtypically 115 sd below age and edumatched samplemodest impairment typically 12 sd below age and edu matched sampleadlslight or mild changenormalminimal impairment in complex instrumental adlmild change but still independently functioningindependent but possibly with greater effort or strategiesdementianonononononononononotesmild dementia may have cdr  05at least 6 months durationdoes not exclude nondementia causesaka mayo criteriaaka revised mayo criteria or revised petersen criteriabiomarker criteria not presented hereaacd agingassociated cognitive decline aami agingassociated memory impairment adl activities of daily living aka also known as bsf benign senescent forgetfulness cdr clinical dementia rating scale cind cognitive impairment not dementia edu education mci mild cognitive impairment mncd mild neurocognitive disorder niaaa national institute on aging and the alzheimers association qd questionable dementia",[ 7104545  9269213 10190820 15324367 21514249],alzheimers disease is a progressive neurodegenerative condition that is the most common cause of dementia accounting for approximately 5070 of cases its clinical hallmark is impairment of memory and new learning with rapid forgetting of newly learned information diagnostic criteria emphasise impairment of memory with insidious onset and gradual progression as well as impairment of at least one other cognitive domain which are severe enough to impair functional abilities significantly the most recent iteration of the dsm has adopted the term major neurocognitive disorder due to alzheimers disease while retaining the essential diagnostic criteria mci is an intermediate state between cognitively intact persons and those with dementia.,[17975326 10854354 21514250 21514250  9343469]
333,in particular while the overexpression of mutant app and apppsen1 yields amyloidosis neuroinflammation and degeneration of monoaminergic and cholinergic neurons it is generally not considered sufficient to cause aggregation of endogenous murine tau into neurofibrillary structures,[25774009 25680265 19091971 17662610 19560104],transgenic mouse models that reproduce the amyloid aggregation and glial activation due to aβ overexpression have been generated based on mutations in the amyloid precursor protein app and presenilin 1 psen1 and 2 psen2 genes which are known to cause familial ad despite playing important roles in evaluating app processing aβ toxicity and amyloidtargeting therapeutic strategies transgenic mice are not being regarded as models that can replicate the full spectrum of ad histopathology,[28304309 28768718]
334,by contrast nfts in ad first develop in the brainstem and entorhinal cortex braak stage iii then in the medial temporal lobe braak stage iiiiv and finally in the neocortex braak stage vvi where nfts are evenly distributed in layers iii and v,[23208308 11484824  1759558  1285493 22002422],"histologically nft is one of the most common pathological findings in cte and has been observed focally and perivascularly in the cerebral cortex with a predilection for deep sulci in the superficial neocortical layers layers ii and iii in the later stages of cte, nfts typically spread irregularly to the neocortex, medial temporal lobe, diencephalon, basal ganglia, and brainstem.",[20720505 21358359  8866777 25943889]
335,previous studies also showed an association of osa and adrelated biomarkers including brain amyloid β load and cerebrospinal fluid levels of tau,[28550245 27129429 24439479 30794315 28329084],in comparison the association between lateonset ad load and genetic variants is much more complex with at least 56 loadassociated genes  reported in the literature these genes may involve lipid metabolism and regulate the production and clearance of amyloid β thereby inducing ad,"[24336208 21460840 17324514 26611832 29181857 23296339 26828303 20460622
 24162737 24022074 21460841 19734902 19734903 20413852 22829467 27097852
 23666170 20971101  7968373 22261503 23150934 11455132 21840299 16608404
 20420935]"
336,consistently tnfrelated apoptosis inducing ligand tnfsf10 a potent proapoptotic member of the tnf superfamily also produced by injured neurons 13 and activated glia 14 is known to modulate cellmediated immune response 15 for example by inducing an increase of the treg cell subset of t lymphocytes 16 and it is in fact regarded as a critical regulator of autoimmune t cells,[12655302 17067687 19476510 20921531 11994437],on the other hand in the past two decades laboratory research has shed more light on various adrelated candidate pathogenetic factors including superoxides 6 7 excitotoxicity 8 9 as well as inflammation in this line peripheral immune cells have more recently been indicated as factors disrupting the immune equilibrium of the brain potentially contributing to neurodegeneration,[18826565 20394761  8649576 23668663 26284939]
337,the clinical effects of azd0530 treatment were assessed by the alzheimers disease assessment scalecognitive subscale adascog11 score range 070 with the highest score indicating worst mmse adcsactivities of daily living scale adcsadl score range 078 with the highest score indicating best clinical dementia ratingsum of boxes cdrsb score range 018 with the highest score indicating worst and neuropsychiatric inventory npi score range 0144 with the highest score indicating worst the adascog11 was administered at baseline and weeks 13 26 39 and 52 and the mmse was administered at screening and weeks 13 26 39 and 52,[9236948 6496779 9236950 7991117 9153155],"a 30-minute dynamic emission scan consisting of six 5-minute frames, either preceded by a ct scan (for pet/ct scanners) or followed by a transmission scan (for pet-only scanners), was acquired starting 30 minutes after intravenous injection of 18f-fdg (5 mci) as the patient lay quietly in a dimly lit room. data were corrected for radiation attenuation and scatter using transmission scans or x-ray ct and reconstructed using standardized algorithms.",[]
338,examination of soluble aβ species in ad brain extracts by several investigators has indicated that the neurotoxic activity resides primarily in the low molecular weight lmw fraction of aβo dimers trimers tetramers dodecamers while high molecular weight hmw aggregates are largely inert though they reportedly can dissociate into lmw species,[15608634 18568035 21421841 28053038 26051935],"the selectivity of hupmn310 for soluble toxic oligomers with no binding to plaque or aβ monomers is a therapeutic advantage as it is expected to prevent the loss of antibody to unproductive interactions and, more importantly, avert triggering dose-limiting induction of aria-e and aria-h. it is recognized that synthetic aβo, while a useful tool, do not exactly replicate the structural plasticity, conformational heterogeneity, co-aggregation species and polydispersion of native aβo found in ad brains.",[]
339,further ad is a multifactorial disease where the toxic context could be the result of different insults to the body and quercetin has been shown to have beneficial effects in many diseases such as hypertension diabetes and atherosclerosis as well as against oxidative stress and inflammation,[18827577 20637779 21606866 27713250 21856292],"therefore, studies controlling those variables, specifying doses per type of comorbidity, and clinical trials including middle cognitive impairment patients should be developed. nevertheless, with our present study, we are close to discovering a preventive intervention that could be successful in decreasing the probability of βa or tau accumulation in the brain, and in this way, prevent the toxic environment that initiates the neurodegeneration cascade.",[]
340,there is also evidence that blood lps levels in ad patients are 3 times those in controls 14 37 suggesting an association between lps with ad e coli bacteria that bear lps can trigger host inflammatory responses and induce the formation of extracellular amyloid plaques 14 38 39 that are very similar to the aβ aggregates in the brains of ad patients,[29403371 19013651 29403371 25653617 22197327 29403371 14597556],cows milk fermented with lactobacillus has attenuated lpsinduced memory deficit by increasing antioxidant enzymes sod gsh and gpx and by decreasing mda ache and proinflammatory cytokines in mice 35 lactobacillus helveticus could improve behavioral and cognitive impairments  and decreases in populations of these bacteria are correlated with ad pathology lps have also been found in large amounts in brain lysates from the hippocampus and superior temporal lobe neocortex of ad brains,[29154736 26408987 29302204]
341,cooccurring lrp may relate to visual hallucinations 63 extrapyramidal symptoms 51 53 72 and a shorter more aggressive disease course,[15068176  2153271  8453435 19752301  9710002],these results were later confirmed in a larger cohort of autopsyconfirmed ad cases upon closer examination it indeed has turned out that a substantial proportion of ad patients examined at autopsy exhibited lrp in the neocortex 52 57 limbic system 2224 6163 65 and to a lesser extent in the substantia nigra,[ 8546207  8229084  8782917 15751230 10885656 15751230]
342,recently several studies that used oct found that the thickness of the retinal nerve fiber layer rnfl     and also the ganglion cell layer   was reduced in patients with ad when compared with healthy subjects,[27394689 21454010 26888864 23920375 25428254],during 19861987 hinton and sadun   provided evidence that visual dysfunction and opticnerve degeneration occurred during the early stage of ad spectral domain optical coherence tomography (sd-oct) is a newly developed sophisticated imaging technique that can be used to rapidly obtain objective and reliable measurements of the retinal layers with an axial resolution of ≤5 μm.,[3736630 3618708]
343,in ad lipid biochemistry is dysregulated causing profound effects on signaling and aβ plaque accumulation,[19303044 17986152 23306153 22835784 30207230],memory impairment is more pronounced in ad than dlb whereas spect and pet scans have demonstrated hypometabolism and hypoperfusion in the primary visual cortex in dlb but not in ad lipids are involved in critical neurobiological functions such as membrane formation cellular binding and recognition transport energy and signaling,[19585950 17882252 28887769]
344,recent technological advances have improved assay sensitivity delivering ultrasensitive assays capable of measuring specific amyloid markers in plasma,[29458036 29758941 26480202 27241045 29420472],"these methods are not suitable either for high-volume screening of presymptomatic individuals, required to identify early disease, or frequent monitoring required in assessing response to interventions. biomarkers informative in csf are currently difficult to measure in plasma in the routine context",[26480202]
345,in particular smri and the study of brain networks can reveal the underlying pathology and its spread      thus possibly helping to understand the emergence of these subtypes through different brain networks,[22951070 27239533 29070667 29136123 23531697],"however, the underlying biological mechanisms that determine this differential nft expression are still completely unknown. the finding of misfolded tau proteins first developing intraneuronally and then spreading from neuron to neuron through brain networks opens a promising door",[20029438 22445347]
346,among these delivery systems systems involving cellbased drugdelivery into the brain received considerable attention due to the ability of the cells to locally release efficacious doses of the protein of interest 561213 andor their ability to replace damaged neural cells and modulate inflammation,[20531393 29615705 29649621 18579298 29649621 27924726],the development and optimization of platforms for targeted drug delivery to and within the central nerve system cns is one of the key challenges in the treatment of neurodegenerative disorders primarily due to the need to cross the bloodbrain barrier during the past decades several strategies for protein delivery to the cns were developed using cells 13 4 5 6 viral vectors 78 nanoparticles 9 liposomes 10 and specific transporters that facilitate the entry of proteins into the brain,"[21348773 15036633 24601738 20531393 29615705 16299771 29535375 22100125
 27212923 29600349]"
347,however the plausibility of the glymphatic hypothesis has been questioned on theoretical grounds 2 21 24 and from the fact that clearance of βamyloid aggregates occurs primarily via the periarterial and not the perivenular spaces,[27929105 28847942 27836940 29754206 18208483],one explanation has been offered a glymphatic hypothesis proposing that mislocalization of aqp4 causes failure of a transendfoot convective fluid flow which impairs clearance of toxic protein aggregates from the brain parenchyma into the perivenular spaces during sleep in support of this hypothesis an increase in βamyloid deposition has been observed in appps1 mice that lack aqp4 55 and human aqp4 polymorphisms have been reported as a genetic risk factor for ad,[22896675 24136970 26526066 29067342 29479071]
348,this is comparable to the spreading we and others have described after seeding with brain extracts of tau transgenic mice or tauopathy patients,[24531916 25534024 23690619 19503072 26150341],"inoculation of csf collected from ad and mci patients resulted in a significant increase of markers of tau pathology in the hippocampus of p301s tau host mice. advanced tau pathology was also notable in the contralateral hippocampus, and in anterior and posterior directions.",[]
349,furthermore those measuring baseline hdlc levels at middle age all found significant associations with alzheimers disease risk 677172 whereas those with baseline measures in subjects at least 70 years old did not,[24685634 27113638 17298957 18559637 11890840],baseline age and followup length may explain these inconsistencies indeed the above studies with followup times greater than 10 years found significant associations between hdlc levels and alzheimers disease risk 7274 whereas others with less than 10 years of followup did not,[17298957 16217057 16217057 11890840]
350,some studies report significant crosssectional associations of blood lead with minimental status examination scores or word recall and perception comparison tests whereas other crosssectional analyses using blood lead did not show an association of blood lead with cognitive function tests in another analysis of nhanes data van wijngaarden et al found that blood lead was positively associated with a lower score on the digit symbol substitution test but that association was not statistically significant,[14569188  9511166 15583371 16971698 21093481],"however, there is an extensive literature evaluating the relation of environmental lead exposure with cognition, a key symptom of ad, discussed more below. results from cross-sectional analyses of lead and cognition are not consistent.",[]
351,moreover other studies also pointed out various pharmacological properties of semisynthetic derivatives of some amaryllidaceae alkaloids such as those related to haemanthamine 26 lycorine 2728 narciclasine  and others figure 1,[22910226 20627737 26443922 26263960 27542176],notably some species of amaryllidaceae produce the alkaloid galanthamine which was isolated for the first time from galanthus woronowii in the 1950s and at the beginning of this century was approved for the treatment of mild to moderate stages of ad being a competitive ache inhibitor with modulatory properties towards nicotinic ach receptors other alkaloids isolated from amaryllidaceae plants like narciclasine haemanthamine pancratistatine and lycorine figure 1 have demonstrated interesting antitumor andor apoptotic effects,[11172080 28756149 26263960]
352,the observed pattern of retinal thinning in ad whereby thinning was greatest for the inner layers of the retina followed by the outer layers may likely be attributed to aβ deposition and consequent neurotoxicity as suggested by previous studies notably however the ipl was less severely thinned relative to the inl and onl,[26505992 20550967 28814675 27598262 27377656],"intriguingly, the magnitude of thickness reduction for the inl and onl was notably less than that of the rnfl and rgcl. these thickness findings may be explained by the distribution of the retinal aβ deposits which were more concentrated in the rgcl and to a lesser extent in the inl and onl similarly koronyohamaoui et al observed neuronal reduction in the inl and onl accompanied by retinal aβ pathology",[26505992 20550967]
353,this kind of crossdataset research approach was frequently used in the radiomic studies to avoid the overfitting problem as well as to test the generalization ability of the whole research framework,[26579733 24892406 26441442 27347764 27064691],"this study utilized statistical analysis and svm to investigate whether a radiomic method based on 18f-fdg pet images could be used for ad and mci computer-aided diagnosis. to prove the stability and generalization of the proposed radiomic method, we selected different samples by different pet scanners with different imaging properties, including samples from the adni database and huashan hospital.",[]
354,aβ oligomers can induce neuronal and synaptic damage through different mechanisms such as inhibition of hippocampal longterm potentiation inhibition of exocytosis by impairing snare complex formation deregulation of nmdamediated calcium influx triggering synaptic collapse or the formation of membrane pores causing permeabilization and inducing neuronal death,[11932745 26279571 28327181 22837695 27621459],several in vitro and in vivo studies have shown that under certain conditions aβ peptides are able to form small soluble oligomers that grow into protofibrils and finally into dense insoluble structures that accumulate in the brain in form of extracellular βamyloid plaques there is growing evidence that soluble aβ species are more toxic than fibrillar aβ in causing neuronal loss and synaptic dysfunction,[17286590 25604547 17251419 27211547]
355,it is known that oligomeric aβ accumulation induces neuronal cell loss astrocytic dysfunction and synaptic toxicity and it is possible that higher levels of nonfibrillar aβ are a characteristic of adad and may be the reflection of abnormal app processing,[21487307 28607171 27258414 22637583 23224319],"however, we were able to detect non-fibrillar aβ structures 2 times smaller using at-sted in human tissue. in addition, we show preliminary evidence that non-fibrillar aβ structures were increased in an adad case compared to a sad case in human brain tissue.",[]
356,it is of interest to note that the receptormediated effects of apoe4 are associated with increased internalization and subsequent degradation of numerous receptors including nmda insulin and vegf receptors 33 69 147 as well as the amyloid precursor protein and apoer2,[20547867 27372644 28957663 24251389 17428983],the binding of apoe to these receptors is affected by the degree of lipidation of apoe such that nonlipidated apoe binds preferentially to lrp1 and vldlr whereas lipidated apoe binds more effectively to ldlr in addition lrp1 and apoer2 are differentially affected by apoe4 and apoe3,[24559670 19339974 15863833 28292942 25015123]
357,the search included 13 articles from the temporal cortex 6476 6 from the hippocampus 65 7781 8 from the frontal cortex 77 78 8287 1 from the entorhinal region 81 and 1 the parietal lobe,[18801740 24014289 18525125 20507594 20126538],"this highlights the need for detailed standardised procedures. twenty-seven articles were found looking at deregulated mirna in the brain, corresponding to 250 mirnas.",[]
358,shank3 postsynaptic scaffolding proteins thereby play essential roles in synapse formation and organization synaptic cell adhesion dendritic spine maturation and synaptic vesicle release,[29739861 29939863 30292394 25309321 28469556],"shank proteins are essential to post-synaptic structure and function in connecting, linking, networking and anchoring neurotransmitter receptors, ion channels, and other integral membrane proteins to the actin cytoskeleton and in the normal “homeostatic” operation of g-protein-coupled signaling pathways. research evidence indicates that the massive shank3 protein at 185 kda forms an extensive postsynaptic cytoskeletal scaffolding network involving the linkage of multiple shank3 proteins at the psd to which the smaller psd95 at 95kda protein is tethered usually via the sapap protein 100 kda interestingly both shank3 and psd95 proteins highly interactive components of the psd complex are reduced in abundance in the temporal lobe of adaffected brain",[30292394 25264360 29321508]
359,in fact the spatial reorientation task requires translating between egocentric viewer dependent information about the landmarks and allocentric maplike representations of space,[24741034 28910623 17500630  8180489 29170377],"the task used here requires the mouse to use features of the environment to determine the new starting location, which would be a critical feature of navigating, particularly if an individual was navigating new environments. interestingly most human and animal studies have focused on allocentric maplike aspects of spatial navigation however a recent report showed that a distinguishing feature of human ad is the presence of both egocentric viewerdependent and allocentric navigational impairments",[28697554]
360,reversal of calcium dysregulation and related ad pathology with ryr negative allosteric modulators has been demonstrated in two ps1app lines appsweps1m146v 59 c57bl6sjlf1appc57bl6d2f1ps1 113 tg2576 114 and ps1m146vki mice 17 and the restoration of normal ca2 signaling results in reduced amyloid and tau pathology normalized synaptic transmission and plasticity and improved cognitive function,[16687509  2564640 23029404 27814403 25100603],the pathogenic er ca2 dyshomeostasis component of ad has been consistently demonstrated over many years across numerous ad mouse models including the ps1m146vki 17 111 ps1app appsweps1m146v 112 ps1app c57bl6sjlf1appc57bl6d2f1ps1 113 and tg2576 114 among others Furthermore human cells obtained from AD patients demonstrate similar Ca2 signaling abnormalities 20 and RyR dyshomeostasis is identified in nonhuman primates with ADlike pathology ,[16687509 24902695 17901262]
361,lipid rafts are cholesteroland sphingolipidenriched microdomains of the plasma membrane described as signaling platforms 129 130 rafts are strongly associated with aβ production and both βand γsecretases are enriched in these structures 129 131 132 lipid rafts also seem to influence aβ aggregation,[20590841 29632069 20590841 21660213 23723072 27295499],the role of ceramide/s1p was analyzed in the context of these damage pathways as well as the process of amyloidogenesis. structural roles of sphingolipids in cellular membranes including lipid rafts constitute an important aspect of their engagement in aβppaβ metabolism,[28566300]
362,our agitation prevalence estimates fall within the 18 to 87 range described by a recent systematic review of previous studies on nps in dementia point prevalence rates for agitationwandering and mechanicalmotor abnormalities have previously been reported in the range of 18 to 57  and 10 to 61  respectively    the variation in reported rates may be attributable to methodological differences due to earlier studies defining nps using the neuropsychiatric inventory npi an assessment tool commonly used in clinical studies to screen for behavioral symptoms among patients with dementia first while we identified agitation on the basis of ehr notes from direct physician encounters and available diagnosis codes the npi is conducted via an interview with the patients primary caregiver whose assessment of agitation may differ from that of a physician,[27491532 22323347 12834515 22323347 22323347 27623026 24059840],"in this large‐scale analysis, the prevalence of agitation during the 2‐year observation period was substantial: 44.6% in the full study sample and 61.3% in a subset of patients with staged ad/dementia severity. this constitutes not only a considerable strain on patient and caregiver health but also a considerable economic burden as agitation has been shown to engender high additional costs compared with cognitive impairment alone  in a recent uk study the presence of agitation was associated with significantly increased health care costs among homedwelling patients with ad accounting for mean excess costs of 2 billion per year",[]
363,confounds arising from toxicity prevent calibration and absolute quantitation in living organisms however evaluating relative changes of in vivo nadh fluorescence intensity still provides a useful indication of pathologyinduced variations of mitochondrial function and intracellular oxygen requirements the in vivo measurement techniques utility was greatly extended by coupling nadh fluorescence with 2photon microscopy 2pm a powerful tool for investigating multiple facets of brain function with high spatial and temporal resolution using deeper penetrating nearinfrared excitation while fluorescence intensity imaging of nadh offers a nondestructive labelfree and simple method to evaluate mitochondrial function fluorescence lifetime imaging microscopy flim shares these benefits and is also insensitive to fluorophore concentration or excitation and emission intensity,[19703658 15232110 16388306 16772166 18270513],"for several decades, measurements of reduced nicotinamide adenine dinucleotide (nadh) have been utilized as a nondestructive tool to characterize mitochondrial respiratory chain activities. nadh is an electron carrier molecule residing in almost all eukaryotic cells both in cytosol and mitochondria and it performs vital roles in both anaerobic glycolysis and aerobic oxidative metabolism extensive studies have utilized single photon uv excitation of nadh fluorescence in isolated mitochondria or cell suspensions as a sensitive quantitative measure of oxygendependent mitochondrial respiratory chain activity under these in vitro conditions oxygen levels can be adjusted and metabolic substrates can be added such that the samples nadh can reversibly be adjusted between its fully oxidized and fully reduced states therefore providing calibration for the minimal and maximal detectable nadh fluorescence signal",[]
364,control apoe4 mice and showed increases in amyloid beta aβ42 and tau staining and a decrease in vglut levels compared to apoe3 mice 16 apoe4 ki mice have decreased spine densities and synaptic integrity at several ages compared to apoe3 ki mice,[23684315 19955384 20951774 28542068 20079752],"these studies place an emphasis on the increased risk of ad experienced by apoe4 carriers, with women being more affected than men. studies of apoe knock-in (ki) mice have complemented the studies in humans.",[]
365,consequently these interventions improve hippocampaldependent learning 159 160 and pattern separation ability in mice 32 and humans alike,[22138509 23110171 20133882 28698596 27997992],moreover ee and physical exercise have an impact on diverse hippocampal neurotransmission systems 36 61 91 141 142 including the expression and properties of glutamate receptor subunits 143147 synaptic adaptor proteins 148151 and other molecules related to plasticity thus through a shift in the environment in which newborn neurons are born  physical exercise and ee positively modulate the neurogenic permissiveness of the subgranular zone sgz and facilitate the incorporation of highly plastic newly generated maturing granule neurons into the trisynaptic circuit,[22798066 27789840 28883658 20393057 14960340 27267685 26545456 16648603]
366,this annotation project recognised that ageing go0007568 is a normal physiological process and consequently teased out data that described the association of dementia with ageing and the involvement of amyloidbeta in ad pathology,[11140684 11140685 11880515 23640054 19660551],"when annotating gene products relevant to a specific disease, this presents a major challenge, as it is necessary to determine what is ‘normal’. For the annotation of AD-relevant gene products, this was a significant hurdle, particularly when capturing the roles of amyloid-beta species, including monomers, dimers, and oligomers (Table S2).",[]
367,in addition scientific findings have demonstrated that the effects of amyloidbeta are agerelated  ageing go0007568 is a normal physiological process involving the loss of functions such as resistance to disease homeostasis and fertility as well as wear and tear ie aspects that are directly translatable to impairments in cellular processes underlying dementia,[11140684 11140685 11880515 23640054 19660551],a literature search revealed that in normal physiological conditions amyloidbeta levels are regulated by neuronal activity 99100101 and that amyloidbeta in turn modulates synaptic plasticity in neural circuits amyloidbeta has also been shown to positively affect neuronal growth,[12670422 16364896 23064434 19118188 22910355 15190117  2218531]
368,smi precipitates worry about ad 37 38 depressive symptoms 39 40 and withdrawal from cognitively protective activities eg physical or social activities,[28804427 18389396 18074258 22354117 26321944],"however, no research to date has: 1) elucidated mediators underlying linkages among smi and memory decline; 2) characterized smi subgroups at highest risk by identifying moderators of these mediational relationships; or 3) compared the differential predictive effects of specific smi assessment items. this study addresses each of these critical knowledge gaps through the testing of our conceptual model using multilevel modeling in constructlevel replication analyses  across four longitudinal datasets",[19485624 19485626]
369,the elevated level of 8oxo2dg was observed in nuclear dna from frontal temporal and parietal lobes and cerebellum of ad patients 91 as well as in peripheral tissues,[ 9798928 17691219 27538622 21845541 19630534],the gsh content decreases in severe dementia and the compensatory mechanisms associated with oxidative stress become disturbed. it seems that reduction of gsh in ad may be associated with increased oxidative stress and may promote accumulation of dna oxidation adducts such as 8oxo2dg,[28566155]
370,studies in cellular or mouse models of ad report changes in specific astrocyte functions including metabolic support 2 72 neurotransmitter recycling 51 antioxidant defense 2 83 and synaptic transmission,[20203192 25099753  8957017 20203192 26200696 25533482],but astrocyte reactivity involves significant transcriptional changes that go well beyond these two morphological alterations and the functional consequences of reactivity are unclear in alzheimers disease ad the most frequent neurodegenerative disease nd characterized by amyloid and tau deposition in the brain as well as memory loss and synaptic alterations the role of reactive astrocytes is still debated,[26283915 24462092 28636962 26671410 29225140 26797041]
371,moreover other publications provide a broader review of the whole dementia spectrum and not only ad,[25093211 23900731 21778116 23432716 27430350],"however, none of these have treated exclusively the specific topic of eeg-based ad diagnosis. for instance some reviews do not study eeg as the main technique for diagnosis 9 47 6974 while others are exclusively focused on the synchronization of eeg signals",[27506128 21629749 25941486 25660305]
372,five papers using source localization methods  used mediumto highdensity electrode montages ranging from 64 to 214 electrodes the 12 remaining used 19 electrodes,[22736322 24240722 22902196 23786792 27255822],fifteen of these articles utilized the lowresolution electromagnetic tomography loreta method or its derivatives eloreta and sloreta the remaining two articles used the local autoregressive average laura source localization method,"[24214287 21396882 22736322 24240722 26941594 27668356 26444753 28184183
 23786792 26603651 24577480 26940242 26541308 26960946 28454845 22902196
 27255822]"
373,probable ad was diagnosed based on the criteria of the national institute on aging and alzheimers association and classified as mild according to final score one on the clinical dementia rating cdr the diagnosis of mci was defined using the criteria of petersen the control group comprised elderly without cognitive complaints recruited from the community that scored2 on the functional activities questionnaire faq and greater than the educationadjusted median on the mmse illiterate20 points 14 years of education25 points 58 years26 points 911 years28 points 11 years29 points and 7 on the memory recall of the brief cognitive screening battery bcsb only participants aged 60 years were eligible for inclusion,[21514250 15324362  7069156 14595482  7611936],the mini-addenbrooke’s cognitive examination (m-ace) as a brief cognitive screening instrument in mild cognitive impairment and mild alzheimer’s disease twenty-three subjects with ad and 36 with mci were recruited from the neurology clinic and from the referral center for cognitive disorders of university (ceredic) of são paulo.,[]
374,using a similar approach the aβ4240 ratio has successfully been shown to increase diagnostic accuracy 22 34 56 and have diagnostic value in clinical settings 21 as well as circumventing the issue of highand lowproducers,[17374949 25079805 20043812 26034513 17254013],"the elisa presented here most likely quantifies both full-length and peptide ng, and the separation between the groups is not as good compared to peptide-to-total full-length ng ratio. in theory, it might be possible to develop two assays that quantify peptide and full-length ng, respectively.",[]
375,the majority of research demonstrated a higher plasma complement c3 level correlated with more brain amyloid burden 26 27 and less hippocampal volume 28 in sporadic ad 29 and mutation carriers of autosomal dominant form of ad,[20930274 23028511 20603455  2452738 27381087],complement c3b adherence is a key step in the removal from the bloodstream of pathogens and proteins recognized as foreign. previous studies have shown inconsistent associations between plasma complement c3 and ad.,[]
376,the impact of sex differences on ad risk between women and men however has been variably interpreted,[ 8450993  9921852 17975326 11445258 20442496],sex and age interact to determine clinicopathologic differences in alzheimer’s disease the strongest risk factor for alzheimers disease ad is increasing age,[]
377,first animal experiments demonstrated that exercise can promote neural plasticity and induce increases in neurogenesis in the hippocampus and aerobic fitness promotes blood flow glucose utilization and oxygen extraction and improves functional and structural brain reserves second exercise can promote the secretion of brainderived neurotrophic factor bdnf which is related to learning and memory,[21460835 12654355 12086747 21569847 15858047],"in order to achieve this positive result, it is necessary to start the exercise intervention in the early stage and to persevere in the long run as a daily habit. there are three mechanisms for exercise to improve cognition.",[]
378,studies from our group and others have described that the protective factors for better cognitive response to chei were lower cognitive status 14 17 male sex 17 18 older age 17 19 and absence of the apolipoprotein e apoe ε4 allele,[16906631 21774798 21774798  9777427 21774798  1775604 21774798  8618881],in randomized clinical trials cheis have exhibited shortterm response in both cognitive abilities and activities of daily living adl 13 however the response differed between the ad patients after 6 months of therapy 4963 of the individuals had improved or were unchanged as measured by cognitive scales 15 while the corresponding percentages were 49 for instrumental adl and 74 for basic adl,[16437532 16906631 25213579 23126532]
379,the battery includes the selective reminding test  the benton visual retention test recognition and matching trials  the rosen drawing test  the boston naming test  the controlled oral word association test  the category fluency test  the color trails test  the similarities subtest from the wechsler adult intelligence scale  and the orientation items from the minimental state examination,[23571587 20460622 26101835 27016693 21911656],"in brief, efiga participants have been recruited since january 1998 from clinics in the dominican republic and puerto rico, as well as the alzheimer disease research center memory disorders clinic at columbia university in new york city. participants are followed up every 18 months at each visit participants completed a standardized assessment that included ascertainment of medical history physical and neurological examination and an extensive neuropsychological battery  for evaluation of cognitive impairment which measures cognitive function in key domains affected by aging and dementia including memory visuospatial ability psychomotor speed and executive function",[1580806]
380,many studies have shown that patients with mci who subsequently declined to ad were first impaired in delayed recall memory in the early phase of mci executive functions were preserved as a compensation for hippocampal dysfunction however with the progression of the disease the frontal executive networks were also involved and caused encoding memory deficit that did not improve with cueing the memory index score of mocabc mocabcmis was calculated by adding the number of words remembered in free delayed recall categorycued recall and multiple choicecued recall multiplied by 3 2 and 1 respectively with a score ranging from 0 to 15,[26620850 23236445 29019061 26027810 22193353 26027810 26027810],"however, no relevant research has been conducted concerning moca-bc in staging dementia severity. the present study aimed to find out whether moca-bc or its subtests could be applied as a preliminary screening method to distinguish among outpatients with mci, mild and moderate ad as a substitute for mmse.",[]
381,based on these protocols several mri volumetric studies have shown consistent pattern of hippocampus and cholinergic basal forebrain atrophy in ad dementia   and prodromal atrisk stages of ad dementia such as amnestic mild cognitive impairment mci   or individuals with amyloid positive mci,[16014654 20672311 19889714 19375072 24176625],the hippocampus represents a key input area of cholinergic projections from the basal forebrain in recent years mri based protocols for an automated measurement of cholinergic basal forebrain volumes have been established that make use of stereotactic information derived from combined post mortem mri and histology,[23852922 16014654 24503619]
382,recent studies have shown that micrornas mirnas are involved in the pathogenesis of ad 6 and that mirnas might play important roles in neurogenesis neuronal maturation and brain development 78 and might regulate several neurodegenerative diseases including ad,[27524239 20380818 17711588 27264337 21728971],"currently, there are no diagnostic biomarkers for the early detection of ad, and there are no effective drug treatments that delay or prevent the progression of ad. therefore, further studies are required to identify ad-related genes and to develop screening methods for these genes to improve the diagnosis and the therapy for ad.",[]
383,most of these risk genes are either expressed by microglia or associated with their reactivity including cd33 bin1 cr1 trem2 and clu,[23623698 24316888 23454195 23150934 10918055],"the sustained activation of microglia results in a chronic neuroinflammatory response and increased production of proinflammatory cytokines such as tnfα and il1β of relevance, recent genome-wide association studies have uncovered several risk-associated genes in the development of sporadic ad.",[23254930]
384,butterbur petasites japonicus siebold  zucc maxim has been known for various biological activities including antiallergic antiinflammatory and antioxidant effects 91011 p japonicus leaf pl extract and petaslignolide a an active compound of pl have been reported to have neuroprotective effects on oxidative stress induced by kainic acid in mice,[20828319 23711828 26674157 16248548 16117608],"accumulating evidence suggests that increased ros by aβ is one of the most important mechanisms involved in the neuronal degeneration synaptic loss and memory impairment of ad thus, inhibition of aβ-induced neurotoxicity may provide neuroprotective benefits in ad.",[25511446]
385,ppar agonists remain attractive because these small molecules cross the bloodbrain barrier are effective for remediating neurodegeneration in ngml concentrations 2836 and they modulate gene expression by targeting nuclear receptors  bypassing abnormalities at the cell surface,[16988486 27802237 10548883  8695669  8725145],however as ad progresses the fundamental abnormality that could eventually limit therapeutic efficacy of trophic factor administration is progressive brain insulin and igf resistance or reduced ability to respond to trophic factor stimulation one potential strategy shown to circumvent this barrier in experimental animals 2836 and to some extent in humans  is to use insulin sensitizer drugs such as ppar agonists,[16340083 16988486 27802237 20930300 18645613]
386,the cause of microglial priming is unclear and likely results from multiple factors including but not limited to 1 a loss of inhibitory ligandreceptor communication with aging neurons  2 interactions with agerelated misfolded proteins such as aβ which promote proinflammatory cytokine production  3 agerelated exposure to increasing transforming growth factorβ which could compromise microglial transitioning from a pro to antiinflammatory phenotype  4 agerelated alterations in production of il4 and ccl11 in the choroid plexus  and 5 unique microenvironment effects in white and gray matter,[24638131 17378753 25385836 21886162 23597431],while the agerelated proinflammatory response to immune challenge is decreased in macrophages  aged microglia displayed an exaggerated proinflammatory response referred to as microglial priming first described in a model of prion disease a primed microglia profile includes 1 increased basal expression of inflammatory markers and mediators 2 decreased activation threshold to express and release proinflammatory molecules and 3 exaggerated inflammatory response to immune challenge,[24157572 16207887 25445485]
387,liraglutide lowers phosphorylated tau levels in cultured neurons and in mice and reduces hippocampal neuronal loss in transgenic ad mice,[27131827 25869785 23948890 28382596 28337257],"for example, the glp‐1 receptor agonists exendin‐4 and liraglutide, a long‐lasting glp‐1r agonist, exert many protective effects in ad pathology. exendin4 or liraglutide reduces cortical and hippocampal plaque load and alleviates brain insulin resistance and glial activation in transgenic ad mice",[22476196 22938097 21525299 23973293 12749025]
388,hippocampal volume atrophy has long been associated with disease progression in ad 24 25 and it has been suggested that hippocampal atrophy could be used as a surrogate marker for efficacy in an ad ct 22 26whole brain atrophy has also been strongly associated with cognitive decline  with rates of atrophy typically being higher the further down the ad disease trajectory a patient lies,[10953178 10227624 18302232 12552040 18574133],"as such, adni database contains several mri measurements including hippocampal and whole brain volume that are thought to be useful for the classification of cognitively impaired individuals into an ad or mci subset. for details of how the mri volumes are calculated see",[18302232 26194310]
389,thus many studies suggest that the progression and the severity of the disease directly correlates with neuronal loss 33 34 and synaptic dysfunction especially the decrease in the presynaptic marker synaptophysin and with the increase in the number of nft in the hippocampus entorhinal cortex and association cortices,[ 9005861 12743238  2360787  1789684 15037694],the hippocampus is the major area that undergoes severe neuronal loss with atrophy reaching up to 10% per year. more than 50% of the neurons in the hippocampus are lost and the loss increases with the severity of the disease.,[]
390,alzheimers disease ad is a complex disorder in which genomic epigenomic cerebrovascular metabolic and environmental factors are potentially involved,[12943467 17957277 19732004 15265264 27324946],pharmacogenetics of vascular risk factors in alzheimer’s disease,[]
391,recent literature suggests that ageing may induce posttranslational modifications in particular spontaneous aβ amino acid modifications defined as agerelated modifications which enhance its pathogenic properties 9 21  27 44 leading to the protein ageing hypothesis of ad,[24283798 20298218 10834947 27318146 27272258 10834947],"ageing is considered the main risk factor for ad, but the pathway through which ageing contributes to aβ misfolding remains unclear. in particular, we still do not know whether ageing induces molecular changes in aβ, driving its accumulation in the brain.",[]
392,all three promoters are active in the embryonic brain    and in the adult may be expressed in multiple neuronal subtypes,[12112467  1986868  9539132 16366735 11086982],several common promoter constructs have been used over the years including prion protein prnp ie tg2576  tgcrnd8  appps1 line 85  jnpl3  and ps19  plateletderived growth factor b chain pdgfb ie pdapp  and j20  and thymus cell surface antigen 1 thy1 ie app23  5xfad  and 3xtgad while these three promoters induce strong and persistent transgene expression in neurons pdgfb and prnp are also active to a lesser extent in nonneuronal cells of the cns  and all three promoters elicit expression in multiple organs outside of the nervous system including heart and liver,"[ 8810256 11279122 14645205 10932182 17270732  7845465 10818140  9371838
 17021169 12895417 11709540 12112467  1986868]"
393,all trials reported a positive safety profile   and treatment was well tolerated in combination with alzheimers disease medications an analysis of these trials indicated that fortasyn connect can achieve clinically detectable effects in patients with mild alzheimers disease dementia but did not slow cognitive decline in mildtomoderate alzheimers disease dementia given the hypothesis that earlier intervention might be more beneficial the lipididiet trial was designed to investigate the effects of fortasyn connect on cognition and related measures in prodromal alzheimers disease,[20129316 22766770 25322923 24280255 27767993 24280255],the aim was to provide neuroprotection by targeting disease processes in early alzheimers diseaseie by supplying ratelimiting compounds for brain phospholipid synthesis and addressing multiple alzheimers diseaserelated pathological processes in vivo       results from animal studies showed that this multinutrient combination improved neuronal membrane composition increased the formation of synapses cholinergic neurotransmission and cerebral blood flow and perfusion preserved neuronal integrity restored hippocampal neurogenesis reduced βamyloid pathology and improved cognition       concentrations of these nutrients in plasma and csf or the brain were also found to be lower in patients with alzheimers disease for clinical use fortasyn connect was adapted to address nutritional requirements in the presence of alzheimers disease pathology two previous randomised clinical trials in patients with mild alzheimers disease dementia reported that daily intake of fortasyn connect for 3 or 6 months improved memory performance  increased neurophysiological measures of synaptic activity and enhanced functional connectivity in the brain  a third randomised controlled trial in patients with mildtomoderate alzheimers disease dementia did not report benefits therefore heterogeneity in the benefits of fortasyn connect exists in previous trials,"[14519522 16631143 21811020 22146060 22914588 24445040 24210253 22914588
 24445040 24210253 18606862 24086523 25146455 26502816 20129316 22766770
 22766770 24475144 24280255]"
394,synthetic aβoligomers impaired longterm memory after icv injection into mice 4041424344 aβ peptides after icv injections reach brain cells by csf cerebrospinal fluid influx via the perivascular and glymphatic pathways,[20133875 19464276 17192927 21703413 26195256],"other less expensive, pharmacological animal models have also been introduced during the last 20 years. ad is considered to be a synaptic failure 37 and aβ oligomers induce synaptic dysfunction  thus aβ peptides have been used in model experiments",[12399581 18359102 19930651]
395,mwm is one of the most commonly used experimental models for rodents to measure spatial learning and memory,[23073928  6471907  2869411 17406317 28052060],biological effectiveness of these different aggregates was further studied in consecutive biological experiments. the morris water maze (mwm) task was used to assess spatial learning and memory.,[]
396,memory deficits are characteristic of typical ad but similar deficits of immediate and delayed episodic memory    and autobiographical memory   have been reported in frontotemporal dementia ftd,[23457466 23670951 21239854 21658396 25396740],meanwhile the diagnostic utility of structural neuroimaging in early ad is controversial as atrophy may be subtle or nonspecific before the development of amyloid biomarkers efforts to improve ad diagnosis emphasized improving neuropsychological tests of memory,[16328732 20711906]
397,this method was previously shown to be successful in the differential diagnosis of parkinsonian disorders in predicting disease onset in prodromal individuals with parkinsons disease and in evaluating disease progression and treatment effects,[20061183 26449840 24453082 20089913 17470495],"for quantification, normalized scans are projected onto a previously identified disease pattern to calculate a subject score. the subject score reflects the degree to which the pattern is present in a subject’s scan.",[]
398,among them p38 mapk has been suggested to phosphorylate tau at specific amino acid residues figure 4,[11578769 15632108 16987243 25131590 21215781],numerous kinases including more than 20 serinethreonine kinases were suggested to phosphorylate of tau several kinases that are candidates for diseaserelated tau phosphorylation include glycogen synthase kinase3 cyclindependent kinase5 and the mapk family all of which have been known to be implicated in ad pathogenesis,[16712493 23798682 19903024 19903024]
399,another gene identified through this study ctnna1 encodes a catenin expressed at elevated levels in the nervous system 50 galr3 is a receptor for the neuropeptide galanin which has been shown to modulate a variety of processes including cognition and memory functions disrupted in ad 5152 mief1 was nominally associated with lateonset ad in a metaanalysis of two family datasets from the adgc thereby suggesting that it may play a wider role in ad that extends beyond a single multiplex ad family mief1 may play a role in dysfunctional mitochondria and their potential to damage neurons,[21708131  9832121 11259657 19491039 23840916],neuroinflammation has been shown to occur in ad patients possibly through misregulation of microglia and triggered by amyloid beta plaques additionally established ad risk genes such as abca7 cd33 and trem2 have also been linked to the immune system,[26509334  8346443]
400,hydrogen sulfide h2s is an endogenous antiinflammatory and neuroprotective agent with antioxidant and antiapoptotic effects in neuronal and glial cells furthermore the levels of sadenosylmethionine an activator of cystathionine βsynthase main h2sproducing enzyme in the brain have been found to be lower in ad brains compared with healthy brains xuan et al wanted to investigate whether h2sreleasing drugs nahs through their antiinflammatory action may inhibit tnfα and thus be beneficial in ad pathology,[15155563 19631409 19540852  8752143 22898621],"this suggests that minocycline may indirectly decrease tnf-α concentration through decreasing microglial activation and increasing il-10. despite tnf-α levels not reaching statistical significance, cognitive benefits were still observed, with minocycline-treated mice performing at par to healthy mice.",[]
401,the margin of noninferiority for bai cesd and ies scores was 5 points as used in prior reveal study trials indicative of medium to large effect sizes cohens d  103 064 and 066 respectively this criterion was a more conservative margin than 5 to 10point definitions of clinically meaningful differences used in other studies that are based on the intervals between cutoffs for minimal mild moderate and severe anxiety and depression for igtad scores where prior studies have not identified a meaningful difference we set margins following the strategy used in a related noninferiority analysis three points representing a shift from sometimes to never on a single item and indicative of medium effect sizes cohens d  043 and 048 for distress and positive subscales respectively,[25499536 19605829 19718255 17469892 24449235],"consistent with analyses of prior reveal study trials outcomes at 12 months were considered primary while outcomes at 6 months and 6 weeks were considered secondary data for ad+cad and ad-only disclosure arms were pooled in analyses because interactions between ad-only/ad+cad randomization status and in-person/telephone disclosure randomization status were not observed (p-values for two-way tests of interaction between the two treatment arms and three-way interactions between the treatment arms and time were all greater than 0.05 except for analyses of igt-ad distress scores, as noted earlier).",[25499536 26810768]
402,the presence of neuropathological hallmarks ie βamyloid plaques    αsynuclein   and huntingtin  in the retina of these neurodegenerative disorders demonstrates that the retina is specifically affected by neurodegeneration and affords access to potential biomarkers of the disease,[27645291 27551275 28093567 24816946 24785101],we also underscore the differences in the patterns of optic nerve degeneration described in these disorders which predominantly affect the magnocellular rgcs of the retina in ad   and the parvocellular rgcs in pd    and hd  possibly explained by the predominant mitochondrial dysfunction documented in pd and hd similarities and differences are also discussed in regards to the circadian rhythm imbalance documented in ad and pd.,[ 2314849 26252902 24465663 22436028 24339212 26233693]
403,"in rikn prnp mice kim et al in our group have observed pathological alterations and some physiological dysfunctions in the olfactory bulb ob recently le pichon et al have proposed that electrophysiological alterations at the dendrodendritic synapse in the ob could underlie the behavior phenotypes in detail the cookie finding phenotype was manifested in three prnp lines zrch i prnp mice ngsk prnp mice npu prnp mice on alternate genetic backgrounds indicating strong evidence of its dependence on prpc rather than other genetic factors prnp mice also displayed altered behavior in the habituationdishabituation task suggesting the phenotype is most likely to be olfactoryspecific
prnp mice exhibited wide spread alterations of oscillatory activity in the ob as well as altered pairedpulse plasticity at the dendrodendritic synapse",[17611634 19098904  1373228  8606772  7999308 17611634 19098904],"taken together, prpc is functionally involved in copper metabolism, signal transduction, neuroprotection, and cell maturation. despite these putative roles mice null for prpc display no consistent phenotype apart from complete resistance to tse infection further searches for prpcinteraction molecules using prnp mice and various types of prnp cell lines under various conditions may elucidate the prpc functions",[1373228 8100741]
404,"if were found in 270 of the participants which is similar to studies involving older participants and higher than the prevalence typically reported in most previous studies with comparable populations nevertheless some other papers report much higher prevalence rates these discrepancies can be mostly accounted for by the criteria for defining what constitutes an if technical features type and quality of mri sequences and the training of the scan reader
 and the characteristics of participants included presence of comorbidities screening selection and ethnicity
 for instance in a retrospective study that included 1000 asymptomatic volunteers only 18 of them presented with if in comparison to our study the age range of their population 383 years old was wider including very young participants who are less prone to the present parenchyma atrophy or vascular pathology",[23967214 27337027 17978290 10404909 10404909 16207376 23967214],"in this study, we aimed at describing the prevalence of if from brain mri in healthy participants aged between 45 and 75 of a population-based study, most of them first-degree descendants of patients with ad. the if found were classified on the basis of their mri characteristics alone and were not confirmed by further studies.",[]
405,this is not surprising given that csf aβ levels and aβ accumulation as determined by pibpet are validated ad biomarkers,[26635716 17502554 25442939 24012374 23477989],this becomes particularly pertinent given that there was no overlap between the findings of these two reports. several studies have examined the predictive ability of plasma aβ levels.,[]
406,these risks have been described more fully elsewhere as they relate to preclinical ad trials,[23578568 26374677 27220838 21443378 25969699],"thus registries that use fluid or neuroimaging biomarker information such as amyloid positron emission tomography pet and cerebrospinal fluid analysis  which require inperson visits for data collection should implement written informed consent the need for written consent is underscored, given that the collection and storage of biomarker information carries ethical and legal risks that must be addressed in these consent documents to ensure autonomous decision making—including the decision not to enroll for some.",[21514248]
407,intravascular netosis can be triggered by different stimuli including microbes proinflammatory cytokines activated platelets and antibodyantigen complexes,[23435331 15001782 17384648 23110185 25024378],our recent results also demonstrate that transgenic ad mouse models treated with a neutrophildepleting antibody show a reduction in both microglial cell density and their activation state suggesting that neutrophils promote the activation of glial cells fueling an inflammatory loop that may promote neuronal injury and memory decline the release of intravascular nets by adherent neutrophils has been observed in several diseases including sepsis atherosclerosis autoimmune pathologies such as autoimmune smallvessel vasculitis experimental deep vein thrombosis transfusionrelated acute lung injury and cancer,[26214837 23435331 19448636 17384648 22980329]
408,"our findings are consistent with previous reports of an association between pericyte
loss and bbb breakdown in ad and provide further evidence that pericyte loss is related to aβ level and
influenced by apoe genotype at least within the cerebral
cortex there is also a close relationship between pdgfrb content fibrinogen and
blood flow in keeping with in vivo evidence that loss of bbb integrity is related
to pericyte degeneration cerebral hypoperfusion and cognitive impairment uncertainty persists as to the precise timing of the various vascular
abnormalities in ad and the details of the complex causal interrelationships",[25611508 25757756 23126372 27459939 27243267],"in neither cortex nor white matter could loss of pdgfrb be
attributed to a reduced level of pdgf-bb, which was elevated in ad. however, as
discussed below, the differential distribution of fibrillar aβ may have influenced
the availability of this trophic factor.",[]
409,mt12 isoforms have been shown to be upregulated in ad 5678 whereas the results for mt3 are less consistent,[ 2780570  9710146 10069577 11470309 18313142],transition metals such as cu or fe together with zn contribute to oxidative stress as well as to the aggregation and precipitation of amyloidβ peptides in the ad brain a number of studies suggest that the metallothionein (mt) family of proteins may be important for the understanding of ad.,[ 8073293 12689772]
410,a range of mechanisms have been proposed for the link between elevated hcy and ad and preclinical studies show that hyperhomocysteinemia induced by genetic manipulation or by bvitamin deficiency causes known hallmarks of ad such as accumulation of amyloidβ peptide 133134135136 and intensified tau protein hyperphosphorylation in the brain,[18243734 11799129 19939226 16516482 17360897],according to the authors of a recent review low folate and vitamin b12 status contribute to the development of cognitive impairment directly and via elevated hcy levels these mechanisms will be discussed in the following sections.,[27431367]
411,fulllength fl app coprecipitated with cmyc antibody was quantified and normalized to the amount of immunoprecipated sorl1 as previously described,[17220890 25382023 21280075 16531402 10993067],coimmunoprecipitation was performed after cell lysis in 1 chapso buffer using g plus beads with 2 μg mouse monoclonal anticmyc antibody for the immunoprecipitation of sorl1myc immunoblotted with anticterminal app antibody ab365 and anticterminal sorl1 s9200 western blot band intensities were measured with imagej software.,[17220890]
412,however the exact agerelated percentages differ between studies with some reporting prevalence rates of 50  or more in people with ds in their 50 s 6 see fig 1 with other genetic and possible environmental factors influencing risk 911fig 1agespecific prevalence of dementia in adults with downs syndrome 9 line with filled diamond data from lai and williams 6 dot with triangle data from visser et al 7 line with filled square data from lai et al 11 line with filled dot data from holland et al,[11983636  2527024  9017086 10430422  9828989],consequently there has been an increase in the prevalence of age-related morbidities such as dementia. The overall prevalence of dementia in adults with DS is estimated at 1 68  with an increase with age from 89  in individuals up to 49 years to 321  in individuals from  to 9 years old ,[]
413,agespecific prevalence of dementia in adults with downs syndrome 9 line with filled diamond data from lai and williams 6 dot with triangle data from visser et al 7 line with filled square data from lai et al 11 line with filled dot data from holland et al,[11983636  2527024  9017086 10430422  9828989],The overall prevalence of dementia in adults with DS is estimated at 1 68  with an increase with age from 89  in individuals up to 49 years to 321  in individuals from  to 9 years old  however the exact agerelated percentages differ between studies with some reporting prevalence rates of 50  or more in people with ds in their 50 s 6 see fig 1 with other genetic and possible environmental factors influencing risk 911fig 1agespecific prevalence of dementia in adults with downs syndrome 9 line with filled diamond data from lai and williams 6 dot with triangle data from visser et al 7 line with filled square data from lai et al 11 line with filled dot data from holland et al,[11983636  2527024  9017086 10430422  9828989]
414,subsequently 5 groups independently reported the molecular cloning of the βsecretase enzyme which they variously named bace asp2 and memapsin 2     it is important to note that all the groups agreed on the same polypeptide sequence even though they used different experimental approaches to identify the βsecretase lending strong support for the conclusion that the authentic βsecretase had been cloned,[10531052 10591213 10591214 10656250 10677483],"thus, their molecular identities were vigorously pursued. the properties of aβ generation and secretase activities in cells and tissues led to the development of cell-free and cell-based assays that could be exploited for the identification of the secretases.",[]
415,five studies used a transgenic model 16 29 30 34 35 3 studies used a dgalactoseinduced model 3133 2 studies used a cholinergic damage model 37 38 2 studies used an ageadvanced model 11 42 5 studies used an amyloidβ142injected model 12 36 39 41 42 1 study used an aluminium chlorideexposed model 14 and 1 study used a hypercholesterolemia model,[16901557 17935895 22032649 23181273 22032649 19927176],a total of 10 studies used mice 3 balbc mice 31 32 36 2 kunming mice 33 38 3 pdappv717i transgenic mice 16 29 30 and 2 senescence accelerated prone mice8 34 35 7 studies used spraguedawley rats 11 12 14 37 39 41 42 and 1 study used wistar rats female animals were used in 3 studies 31 32 36 male animals were used in 11 studies 11 12 14 34 35 3742 and both males and females were used in 4 studies,"[16901557 17935895 23181273 19927176 22032649 17935895 23181273 19927176
 16901557]"
416,it has been reported that ad pathogenesis and memory impairment can be mitigated by transplanting mesenchymal stem cells into an ad animal model,[22015609 22570192 18550916 19070649 24336078],these findings indicate that restoring not only damaged neurons but also dysfunctional glial cells may be crucial for the development of an ad therapeutic strategy in line with these observations pluripotent stem cells are a promising regenerative medicine because they can be differentiated to various cell types in the central nervous system,[23112326 21943254 21609820]
417,these approaches include transcranial magnetic stimulation tms 10 11 transcranial direct current stimulation tdcs 12 and deep brain stimulation dbs  via chronicallyimplanted electrodes,[21246222 23076723 21840288 20687206 24798585],"given the many years of unsuccessful drug intervention studies against ad, investigating new and innovative “non-pharmacologic” interventions against ad are now clearly warranted. neuromodulatory approaches have consequently emerged and are currently being clinically tested against ad.",[]
418,there is a marked temporary increase in ttau with normal ptau levels in traumatic brain injury and stroke that correlates with the severity of neuronal damage it is the same for creutzfeldtjakob disease which shows a large increase in ttau reflecting rapid neurodegeneration but normal ptau since there are no neurofibrillary tangles in this condition the csf level of ptau correlates with severity of tau pathology postmortem and high ptau has not been found in disorders other than ad,[11137759 17101890 24566866 16298235 19273758],biomarkers of βamyloidosis are specific for ad pathology however amyloid pet tracers do bind to aβ deposits in vessel walls and increased tracer binding can be found following acute traumatic brain injury csf aβ42 is decreased ie abnormal in some nonad conditions such as hiv encephalitis and multiple system atrophy typical ad shows an increase in both ttau and ptau and a tight correlation between these biomarkers neither csf ttau nor ptau shows any change in primary tauopathies such as frontotemporal dementia progressive supranuclear palsy or corticobasal degeneration however findings on csf ttau and ptau diverge in conditions with acute brain damage,"[12601108 19273758 18339640 24217171 23052602 12539213  8748926 15563479
 22925882]"
419,uchl1 13 and ubiquitin  are found in aβ plaques and neurofibrillary tangles in the ad brain supporting evidence for ups dysfunction in ad,[2166150 3033674 3029875 8391280 1706517],ubiquitin carboxylterminal hydrolase l1 uchl1 also called neuron cytoplasmic protein 95 and pgp 95 is a highly abundant neuronspecific cytoplasmic enzyme it modifies the activity of the ups by acting as a deubiquitinating hydrolase 10 ubiquitin ligase 11 and a monoubiquitin stabilizer,[ 6343558  2964855  2530630  2530630 12408865 12913066]
420,several plantderived compounds are known to be protective in models of alzhiemers disease including flavonoids resveratrol green tea polyphenols curcumin and ferulic acid,[21605052 19863373 16153607 26184304 27118174],The berries of H arbutifolia are eaten fresh and cooked as foods by California Indians and other people  the current study examined the chemistry and safety of the plant medicine.,[]
421,"among the studies analyzed participants were diagnosed with alzheimers disease
according to the diagnostic and statistical manual of mental disorders iv
dsmiv

 and by the national institute of neurological and communicative disorders and
stroke and the alzheimers disease and related disorders association
nincdsadrda

 only one study investigated for the presence of diffuse brain atrophy on
magnetic resonance imaging mri and decreased blood flow in the parietal lobe and
posterior cingulate gyrus on single emission computed tomography spect",[25504466 23429813 16777648 17132973 21518170],"table 1characteristics and results of studies included in final selection.
gds: geriatric depression scale; npi: neuropsychiatric inventory; hdrs-21:
hamilton rating scale for depression; raid: rating anxiety in dementia;
csdd: the cornell scale for depression in dementia; aes: apathy evaluation
scale; ham-a: hamilton anxiety rating scale; rmbpc: revised memory and
behavior problems checklist. gds: geriatric depression scale; npi: neuropsychiatric inventory; hdrs-21:
hamilton rating scale for depression; raid: rating anxiety in dementia;
csdd: the cornell scale for depression in dementia; aes: apathy evaluation
scale; ham-a: hamilton anxiety rating scale; rmbpc: revised memory and
behavior problems checklist.",[]
422,there is some concern that the efficacy of longterm treatment of ad patients with intranasal insulin application could be attenuated by longterm brain insulin receptor desensitisation or decreased efficacy of peripheral mechanisms ie the sink hypothesis for aβ lowering strategies that contribute to insulininduced aβ clearance from the brain,[15750215 22430016 22476197 21330304 21864751],intranasal insulin treatment for early ad or mild cognitive impairment mci improved memory and attention abilities in four phase 2 clinical trials without significant adverse effects or changes in blood levels of insulin or glucose intranasal insulin administration elicited changes in peripheral glucose metabolism but no significant change in blood insulin levels were detected,"[18430999 17942819 18230654 15964100 21911655 17942819 22205300 22162476
 25288674 25576060 18442862]"
423,aβ has been found in the retina in all layers apart from the retinal pigment epithelium,[19271231 23750151 24439169 18691390 20550967],−absent. app has been found in the ganglion cell layer through the inner nuclear layer in ad animal models,[19271231 23714377 19834067]
424,neuroimaging studies have shown that medial temporal lobe and hippocampal atrophy are associated with vad 14 54 and svd 119 167 albeit not to the same extent as in ad,[17962598 21518997 17963999 21613775 19022858],"greater putamen haemosiderin was significantly associated with indices of small vessel ischaemia, including microinfarcts, arteriolosclerosis and perivascular spacing and with lacunes in any brain region but not large vessel disease, or whole brain measures of neurodegenerative pathology. higher levels of putamen haemosiderin were correlated with more microbleeds upon mr imaging, but it is possible that brain iron homoeostasis and small vessel ischaemic change are responsible for these rather than only as a marker for minor episodes of cerebrovascular extravasation.",[]
425,many reasons to the failure have been proposed including duration of treatment 127 apoe ε4 allele 128 129 ages 127 disease stages 130 and disease progressing speeds,[25022541 18003940 19448381 25022541 21784351 22687143],although it supported the use of nsaids for prevention of ad there were no positive results from the randomized control trials rcts moreover in a followup evaluation study of the randomized ad antiinflammatory prevention trial adapt and its followup study adaptfs that treatment for 1 to 3 years with naproxen a nonselective cyclooxygenase cox inhibitor or celecoxib a selective cox2 inhibitor the results show no prevention for the onset of dementia or no attenuation for the cognitive functions in older adults with a family history of ad,[25024454 25227314 25022541]
426,nutrition and ppar alphasirt 1 expression related to hepatic fgf21 production has become important to nafld and the metabolic syndrome,[17601491 26451842 24184811 18840786 23663741],fibroblast growth factor 21 fgf21 is an important activator of sirt 1mediated release of adiponectin fgf21 binds to fgf receptor and beta koltho receptor complex 4748495051 and activates adipose tissue sirt 1 by increases in nad and activation of peroxisome proliferatoractivated receptor gamma coactivator 1alpha pgc1alpha and ampactivated protein kinase ampk,[20616029 18187602 22248288 18762812 24013744 20616029 25932355]
427,for example cystatin c cst3 has been suggested to be related to white matter lesions 13 grey matter density 14 and the global neurophysiological phenotype 15 of ad patients and amci individuals and sortilinrelated receptor sorl1 gene variants are associated with hippocampal atrophy and white matter hyperintensities in ad patients,[18511756 20468060 16213753 24938503 21220680],in a recent study we demonstrated that the opposing trajectories of the influence of the apoe ϵ2 and ϵ4 alleles in the default mode network with age may reflect their antagonistic pleiotropic properties and their association with different ad risk factors other genetic polymorphisms associated with the cholesterol metabolism pathway have also been proposed as risk factors that influence the ad brain.,[25336599]
428,mitochondria are the major source of cellular ros and hence stress signaling that induces cellular senescence and apoptosis 118 164 165 166,[20430626 23102266 16738333 15734681 21982713],"importantly it was found that exercise training also increases brain mitochondrial biogenesis mtdna and pgc1α sirt1 and citrate synthase and this may have important implications not only with regard to fatigue but also with respect to various central nervous system diseases and agerelated dementia that are often characterized by mitochondrial dysfunction therefore, exercise could be considered as a therapeutic option to reduce the negative effects of aging and decrease the risk of ad.",[21817111]
429,in order to achieve degradation of aggregated proteins in the autophagylysosome system there must be a successful fusion of the autophagosomes with the lysosomes,[ 2351689  2161853 22966490  1324248  9639028],the major lysosomal degradative pathway in eukaryotic cells macroautophagy hereafter referred to as autophagy is responsible for degrading longlived or aggregated proteins and is the principal mechanism for turning over cellular material too large to be degraded by the ups autophagy is a highly regulated process that involves the sequestration of cytoplasmic cargo such as aggregated proteins and damaged organelles within doublemembrane vesicles called autophagosomes which are typically labelled by the microtubuleassociated protein 1a1blight chain 3 lc3,[22966490 20811353 20034776 19653858 22966490 11099404 17909521 20034776]
430,the establishment of dna methylation is essential for normal cell development and differentiation 19 and impacts many key cellular processes including gene regulation 20 x chromosome inactivation 21 22 and genomic imprinting,[23925113 21251332 21862626 24186870 17467259],these changes can arise within cells of an individual and be maintained through mitosis 17 as well as passed from parent to offspring meiotically one of the best-studied epigenetic modifications involves changes in dna methylation at cpg dinucleotides.,[19234478 21933173]
431,widespread ad pathology can manifest itself without obvious symptoms and clinically atypical presentations are relatively frequent in addition presence of vascular involvement is very common and has been reported in 80 of over 4500 brains from patients with neuropathologically verified ad one of the core pathophysiologic processes in ad is assumed to be mismetabolism of aβ initiating a series of processes that eventually lead to neuronal degeneration with brain atrophy and cognitive decline as has been outlined in the so called amyloid cascade hypothesis increased basic knowledge about aβrelated issues has resulted in various pharmaceutical attempts to counteract the aβrelated disease process using enzymatic inhibition of the secretases involved in aβ generation and different variants of aβ immune therapy however yet without much success,[21514250 23842566 16472206 24556009 24476230],"alzheimers disease is the most commonly diagnosed disorder causing cognitive dysfunction among adults ad is characterized by deposition of plaques containing aβ aggregates neurofibrillary tangles composed of tau fibrils loss of synapses and degeneration of neurons leading to memory impairment and other cognitive impairments however, it has gradually become clear that the clinical–pathologic correspondence is inconsistent.",[21514250]
432,repeated treatment with solanezumab did not show a significant benefit in data obtained from patients with mild or moderate ad dementia but a slowing of cognitive decline was found in approximately 34 of mild ad patients diagnosed as adascog14 ad assessment scale cognitive subscale 606263 supporting the suggestion that amyloidtargeted therapy could be more effective when applied at earlier stages of ad or before visible symptoms appear,[22672770 24450890 26238576 24412277 23411394],"in order to prevent the side effects induced by active immunization, passive immunization was utilized. there were no significant clinical improvements in phase 1 and 2 studies using a single dose of solanezumab an igg1 antiamyloid monoclonal antibody that binds to soluble monomers and lowermolecularweight aβ oligomer species but not to fibrillary aβ species or highermolecularweight aβ oligomer species",[22672770 25045405]
433,cerebral small vessel disease csvd is considered as an important pathological process of subcortical structures such as lacunar infarcts white matter lesions and microbleeds csvd is responsible for the pathogenesis of ischemic strokes cerebral hemorrhages and encephalopathy which are associated with advanced age and deteriorated by hypertension and diabetes mellitus csvd mainly contains lacunar infarct or lacunar stroke leukoaraiosis binswangers disease and cerebral microbleeds with the development of imaging examination and its clinical usage it has been well identified that cerebral vascular diseases especially csvd contribute to the occurrence of ad,[ 9368569 22006983 23569023 23887837 20957378],ad is clinically characterized by cognitive impairment at first and dementia eventually which gradually worsen over a number of years increasing research indicates that ad results from the destruction and death of nerve cells triggered by amyloid plaques and neurofibrillary tangles both of which are thought to contribute to the neurodegenerative death of the neurons in the brain and the subsequent symptoms of ad the main risk factor for ad is advanced age while the incidence of ad increases with the progress of aging substantial clinical research implicates the involvement of vascular risk factors in ad such as hypertension coronary artery disease diabetes and hyperlipidemia these vascular factors increase the risk of ad occurrence,"[25387055 25387055 24493463 24626484 23209064 23243502 17110895 25034716
 23887837 23209064 23569023]"
434,increasing imaging results have evidenced that csvd has a close association with cerebral atrophy a prospective followup research conducted by nitkunan et al showed that brain volume is decreased in the patients with csvd with respect to normal aging subjects and this decrease was correlated with cognition decline during 1year prospective followup the leukoaraiosis and disability study further proved that brain atrophy facilitates cognitive decline and brain atrophy is independently related to longitudinal cognitive decline in csvd according to mri measurement the severity of brain atrophy was correlated with the number of lacunar infarcts and the size of subcortical and periventricular white matter lesions while shorter telomere length is associated with brain atrophy and wmh,[23114884 20594616 21148440 22592361 23114884 23933740],"generalized cerebral atrophy will be linked with a range of clinical problems because of the involvement of the whole brain. cerebral atrophy can usually be identified in medical imaging such as computed tomography (ct) and/or mri, which can demonstrate structural changes in the brain.",[]
435,alzheimers disease can also be considered a metabolic disease in which brain glucose utilization and energy production are impaired,[ 9720972 11956956 15094078 16340083 15750215],"modulation of gamma secretase activity by nonsteroidal antiinflammatory drug nsaidlike agents has been postulated to reduce brain aβ42 concentrations and to prevent cognitive deficits in animal models of ad however several nsaid enantiomers such as rflurbiprofen have failed to demonstrate clear efficacy in reducing levels of aβ in clinical trials beta-secretase, otherwise known as the beta-site amyloid protein precursor cleaving enzyme (bace 1), is thought to initiate the amyloidogenic pathway by cleaving the amyloid precursor protein.",[]
436,agingassociating diseases of different mechanisms such as cardiomyopathy  degenerative valvular disease  atherosclerosis  and osteoarthritis  and cataract  present mechanical factors interacting with their pathogenesis,[25081406 11925731 24781409 24845389 18221767],cells are continuously subjected to mechanical forces that influence cell division gene expression cell migration morphogenesis cell adhesion fluid homeostasis ion channel gating and vesicular transport the seminal work of darcy thompson demonstrated that physical forces play a key role in plant and animal morphogenesis,[11274342 21763607]
437,the function of antiaβ antibodies is not understood but they have been implied to interfere with aβ toxicity and the oligomerization and fibrillization of aβ,[22805374 21490226 22826245 22355408 12821522],a vast part of anti-aβ antibodies are believed to be produced in response to aβ in the periphery and central nervous system. It has been proposed that antiAβ antibodies predominantly show affinity toward the toxic aggregated forms of Aβ including oligomers and protofibrils which may be considered nonselfantigens and not to monomers ,[]
438,in addition the location of the largest decrease in patients compared to controls varied over the studies main differences between groups were found in the anterior and central regions 18 28 29 as well as the posterior regions 21 and in one study both regional increases and decreases were found,[17574912 24726900  9623998 12488788 22902196],"lower functional connectivity in ad has previously been reported in studies using different modalities, but the pattern of this functional connectivity and the methodology varied considerably between studies. in studies with high temporal resolution time series eeg and magnetoencephalography meg functional connectivity in ad was found to be decreased in the higher frequency bands alpha and beta 9 2126 as well as the lower frequency bands theta 22 23 and involving mainly brain regions that are connected by long corticocortical fibers",[18952674  7511505 10727911 16076512  1422803]
439,however possible bias and heterogeneity for plasma tau were observed  between the different studies with some studies reporting an increase decrease and no change in ad patients,[25054847 24129926 24682919 23383382 24318929],"for plasma aβ measurement, most studies utilised elisa-based methods with sensitivity in the range of 10–70 pg/ml and specificity <0.1%. the funnel plot  also indicated that there is minimal bias between the studies used in the analysis",[]
440,to gain more insight into cebpd functions in the cns we focused next on the expression of candidate genes previously suggested to be regulated by the transcription factor cebpd in the periphery,[19270711 23028973 18673548 21112127 10594926],"no differences between the c/ebpd(-/-) and c/ebpd(+/+) animals were detectable concerning the expression of neprilysin (membrane metallo-endopeptidase; mme), apolipoprotein e (apoe), low density lipoprotein receptor-related protein 1 (lrp1), cathepsin b (ctsb), endothelin-converting enzyme 1 (ece1), angiotensin i-converting enzyme (ace), insulin-degrading enzyme (ide), and advanced glycosylation end product-specific receptor (ager; formerly termed rage). Hence, the increased Abeta deposition in C/EBPD(-/-) mice was not caused by alterations in expression levels of genes involved in turnover or transport of Abeta (S5 Fig).",[]
441,the goodness of usual antiad drugs is just a temporary relief of clinical symptoms and signs of dementia but the efficacy of these cholinesterase inhibitors in ad treatment is not supported by any highquality and longlasting clinical trials9 these medications cannot cure alzheimers dementia or stop the disease progression3132 because ad is a multifactorial disease using multifunctions and multitargeted agents have been considered extensively3334 enormous medical combination therapies have been proposed to cure alzheimers disease35 herbal medicines as a result of multifunction multitarget characteristics have potential of optimum pharmaceuticals and nutraceuticals effects on ad patients10 preclinical and epidemiological studies suggest that herbal drugs might be effective at reversing neurodegenerative pathology and agerelated declines in neurocognitive performance36 herbal drugs may act to protect the brain in a number of ways including by protection of vulnerable neurons promotion of peripheral and cerebral vascular system enhancement of existing neuronal function or by stimulating neuronal regeneration and inhibition of neuroinflammation moreover medicinal herbsderived drugs are natural and hence safer than synthetic drugs and that a complex mixture of herbs can effectively treat complex diseases,[15326237 17018549 22316321 15113710 11295356],"all together these data show that r. damascena extract in medium (600 mg/kg) and high dose (1200 mg/kg) improved long-term memory in a dose-dependent manner. effects of the amyloid-β and rosa damascena extract on long-term memory during the first (b, white color) and second (b, black color) probe trials, respectively, as measured by mean time step-through latency. **p < 0.01; ***p < 0.001 different from the control and sham groups. ##p < 0.01, ###p < 0.001 different from the aβ-injected group (alz + ns), @p < 0.05, @@@p < 0.001 different from the aβ-injected group (alz + 300)",[]
442,a mixedeffect beta regression model was selected after testing 10 basic models available in the literature,[19592311 21659625 23211395 12047920 21694449],"disease progression models were established using nonmem (version 7.1.0 with a gnu fortran compiler; icon development solutions, ellicott city, md, usa). data exploration and visualization were performed using r (http://www.r-project.org; version 2.14.0) and xpose package 4.0 (http://xpose.sourceforge.net).",[]
443,concentrations of csf tau and ptau are increased in ad and have been shown to positively correlate albeit to differing degrees with tangle load at autopsy    and regional brain atrophy as defined by magnetic resonance imaging mri,[19273758 14676043 17012293 21489655 20147537],csf levels of aβ42 tau and phosphotau181 ptau markers of amyloid neuronal injury and tangles respectively have stood the test of time in exhibiting both diagnostic and prognostic utility individuals diagnosed with very mild or mild ad dementia have low levels of csf aβ42  that inversely correlate with the presence of amyloid as visualized by positron emission tomography pet,[20157306 19822868 12601108 17210801 19268916]
444,given that general memories are semanticized due to the loss of episodic detail in ad 12 13 33 34 we were expecting a similar pattern of performances than that obtained for ps that is relatively spared in the early stages of ad and temporally graded,[19497331 12821510 15530208 20153463 15884035],"the aims of the present study were (i) to compare the distribution of specific versus general abms across the lifespan in ad patients compared with healthy elderly controls and (ii) to study the relationship between the specific and general components of abm and regional volumes of the hippocampus and the lateral temporal neocortex. tracking the anatomical substrates of general versus specific memories among two regions of the temporal lobe classically associated with episodic and semantic memory, respectively, we wished to explore whether the abstracted forms of abms are rather associated with the semantic or episodic components of memory.",[]
445,it has been proposed that the use of cholesterol and apolipoproteins as biomarkers may facilitate prognostication and guide therapeutic decision making in a broad spectrum of psychiatric illnesses including autistic spectrum disorders major depressive disorder schizophrenia and ad as reviewed by woods et al a reduction in neuronal cholesterol content promotes colocalization of betasecretase 1 and amyloid precursor protein disrupting plasmin generation and contributing to neurotoxic aβ production and associated neurodegeneration however elevated cholesterol levels also promote aβ production and aggregation as well as tau hyperphosphorylation neuritic plaque formation and cerebrovascular ischemia this apparent contradiction highlights the uncertainty regarding the molecular mechanisms implicated in cholesterolmediated ad neuropathology,[22304330 15583033 19199871  9329686 19321181],"the relationship between cholesterol and ad remains incompletely understood. cholesterol plays a key role in neurodevelopment, maintains the structural integrity of neuronal cell membranes, and ensures physiological extra-cellular messenger activity as well as neuronal repair.",[]
446,a single mirna capable of downregulating hundreds of target mrnas concurrently fine tunes diverse cellular functions involved in development differentiation proliferation apoptosis and metabolism overall the whole human mirnome regulates greater than 60 of all proteincoding genes importantly aberrant regulation of the mirnome plays a central role in pathological events underlying cancers and neurodegenerative diseases recently we identified 852 experimentally validated target genes for more than 100 mirnas downregulated in ad brains the molecular network analysis of 852 genes revealed that aberrant expression of cell cycle regulators contributes to neurodegeneration in ad,[18668040 18955434 21892151 25027972 21945006],development of diseasemodifying drugs for ad mainly targeting aβ has been unsuccessful suggesting that both early diagnosis and early treatment are highly important to achieve maximal response to diseasemodifying treatments however an accurate diagnosis of ad is often difficult solely based on neuropsychological examinations because the possibility of numerous dementing diseases such as frontotemporal dementia ftd dementia with lewy bodies dlb vascular dementia hivassociated dementia had and prion diseases should be carefully excluded although decreased aβ42 and increased ptau levels in the cerebrospinal fluid csf serve as a biomarker for the diagnosis of ad the collection of csf is too invasive to apply to routine clinical works therefore establishment of most reliable noninvasive ultrasensitive highthroughput and inexpensive biomarkers that promote the early diagnosis of ad would meet a growing demand from the public micrornas mirnas a class of endogenous small noncoding rnas ncrnas mediate posttranscriptional regulation of proteincoding genes by binding to the 3 untranslated region utr of target mrnas leading to translational inhibition or mrna destabilization or degradation currently 1881 precursor and 2588 mature human mirnas are registered in mirbase release 21 in june 2014,[21765871  9153154 21514250 24427524 20703300]
447,autophagy the molecular machinery for selfdigestion is an essential catabolic process in response to a multitude of physiological and pathological situations it is well known that autophagy is an intracellular degradation system that delivers cytoplasmic components to lysosome and degrades cellular components through autophagylysosomal pathway to alternatively remove unnecessary cellular constituents in the normal physiological function of cell metabolism autophagy upholds the balance between the synthesis degradation and subsequent recycling of cellular products playing an important role in maintaining cellular homeostasis cell survival differentiation and development although numerous studies have revealed the nature and role of autophagy since the 1960s many questions about the actual processes and mechanisms still remain,[15615779 16247502 16247502 19279132 22862962 20811354],increasing evidence highlights that the activation of mtor is an enhancer of aβ generation and deposition  mtor an inhibitor of autophagy decreases the aβ clearance of the autophagylysosome system which accounts for the clearance of abnormal proteins mtor also modulates the metabolism of app by regulating β and γsecretase in addition mtor may interact with several key signaling pathways and regulate aβ generation or aβ clearance including pi3kakt gsk3 ampk and insulinigf1 a variety of research studies have proved that the activation of mtor leads to the failure of aβ removal from the brain since the dysfunction of autophagy triggered by mtor facilitates the process of aβ generation and weakens its clearance,"[22344941 19301428 22344941 19210753 20376313 22829447 18023354 19291319
 23265840 22367557 19210753 15953364 22829447 23305067]"
448,antioxidants such as vitamin e could reduce βamyloidinduced neurotoxicity in cultured hippocampal neurons7 and can slow the progression of ad significantly8 similarly ginkgo biloba extract improves cognitive function in ad patients9 walnut extracts have been reported to offer benefits to aβ induced cytotoxicity in pc12 cells10 and pomegranate could improve memory in ad transgenic mice,[ 9987013  9110909  9823823 21706234 17010630],at present the number of patients suffering from ad is rising continually worldwide and represents one of the biggest challenges for most societies throughout the world1 although the etiology of ad remains unclear increased oxidative stress have been reported to be an important underlying cause of neurodegeneration in ad2 brain structures supporting memory are uniquely sensitive to oxidative stress due to their high demand for oxygen chronic oxidative stress increases with age and ageing is one of the major risk factor for ad Numerous studies have suggested that a diet rich in fruits and vegetables may represent an important alternative therapeutic options by improving agerelated memory decline and cognitive dysfunction observed in AD These beneficial antiageing effects are associated with their high antioxidant capacity,[10071091  9989456 22614926]
449,moreover it was seen that altered platelet function such as increased activation 14 or altered membrane fluidity 15 16 as well as an altered app ratio  are associated with the development of ad,[ 9561982  3438464 23228953  8912490  9740113],platelets share some properties with neurons because they store release and take up the neurotransmitter serotonin being a therapeutic target Most importantly platelets store and process also the amyloid precursor protein APP  which is cleaved into the toxic βA peptides and accumulates βA in the brain and vessels in AD,[25041722]
450,on the other hand whether a gradient of posterioranterior changes or anteriorposterior changes predominates or even a combination of these patterns occurring simultaneously is still under intense debate,[20371138 20368633 19643188 18455835 19100839],"taken together, the majority of tbss-based investigations have attempted to establish a pattern of dti changes that would characterize ad evolution. the sum of evidence regarding a gradient pattern for ad so far remains inconclusive and no firm conclusions can be drawn.",[]
451,indeed the phenotypes of beclin 1and vps34deficient mice are more severe e7585 lethal 173 176 than that of other autophagyrelated genes such as atg3 136 atg5 67 and atg16l  p1 neonatal lethal,[14657337 21283715 18768753 15525940 18849965],these mechanisms may be of great importance in ad as decreased pi3p vps34 and beclin 1 levels have all been reported importantly as genetic ablation of beclin 1 or vps34 results in reduced levels of both atg14l and uvrag 53  these changes in addition to compromising autophagy as well may affect endolysosomal trafficking,[20559548 23907271 18497889 18843052 20643123 20643123]
452,mci participants at baseline met the petersen criteria or revised petersen criteria furthermore core clinical criteria for mci proposed by the niaaa workgroup were also acceptable these criteria include subjective complaints a decline in memory objectively verified by neuropsychological testing in combination with a history from the patient a decline in other cognitive domains no or minimal impairment of activities of daily living and not meeting the criteria for dementia,[15324362 10190820 15324367 20008648 21514249],the definition of 11c-pib positivity was that 11c-pib ligand uptake exceeded a certain threshold in the pet imaging protocol and vice versa. the study was a longitudinal cohort study in which amyloid imaging results were obtained at baseline the reference standard clinical outcomes result of mci was identified at followup and the study included at least 10 mci participants,[24782322]
453,notably some studies in both subgroups generated their own optimal thresholds prespecified or did not prespecify what constituted a positive or negative test and some reports used visual 11cpibpet interpretation,[20205671 19587325 19475670 23799136 19587325 22441582 19475670],furthermore the mci subtype was diagnostically unstable in our review large variations and unavailable data of mci subtypes were observed in the included studies grimmer et al 2013 and wolk et al 2009 found no clear association between a particular clinical subtype of mci and 11cpibpet positivity however subjects with multidomain amnestic symptomatology more frequently exhibited a significant clinical decline compared with individuals with isolated memory impairment in grimmer et als study 2013 which is consistent with a previous study none of the included studies analyzed the underlying correlation between 11cpibpet imaging conversion rate and mci subtypes therefore to clarify the correlation between mci subtypes and brain aβ burden further prospective 11cpibpet studies with mci subtypes should be performed,[23102125 23036071 19475670 23036071 23102125]
454,a reduction of serotonin 5ht has been reported in several studies across several brain regions as have altered 5ht6 receptor function and a reduction in cell counts in the dorsal raphe nucleus in a recent study a significant reduction in serotonergic tone comprising lower 5hydroxyindoleacetic acid concentrations in the hippocampus and lower 5ht concentrations in the superior temporal gyrus and cerebral cortex correlated with dementia severity it may be that the association observed in previous studies between psychosis in ad and reduced 5ht may be related to regional disease severity in psychotic ad and not an independent risk factor for the emergence of the syndrome,[ 1710105 15707619 18525126  7953058 24685637],an early postmortem study of neurotransmission in psychotic ad did not identify any abnormalities in markers of dopamine signaling one small postmortem study suggested a selective increase in d3 receptor availability further using 11craclopride pet a modest increase in tracer binding in the striatum was observed in a cohort of delusional patients suggesting some increase in d3 availability yet a recent comprehensive postmortem study of monoaminergic correlates of behavioral symptoms in ad did not observe any relationship between alterations in dopamine or dopamine metabolite concentrations in nine behaviorally and neurochemically relevant brain regions and psychotic symptoms in ad perturbations in serotonergic systems have been reported in postmortem studies of psychotic ad.,[ 1710105 11255451 19204262 24685637]
455,furthermore prpc was shown to be related to signaling platforms including several intracellular effectors such as fyn lyn pi3kakt pka erk12 gsk3β and tace among others,[10988071 24810941 20615969 14597699 19457070],"therefore, for development of clinical disease, prpsc has to be close to neuronal prpc in a contiguous compartment. here, it is likely that lipid raft localization of prp isoforms in particular plays a key role.",[]
456,a logical compromise solution would be to illuminate the occupied room with a white light source with a high proportion of shortwavelength radiation delivering lower corneal photopic light levels than those previously employed although studies have shown that shortwavelength light or blueenriched light sources can be effective at correcting circadian sleep disorders other studies failed to show differences between lamps of different correlated color temperatures ccts,[ 9110101 18544724 17714459 21276222 18564297],recent research has shown that the human circadian system is maximally sensitive to shortwavelength blue light with peak wavelength close to 460 nanometers nm this finding opens the door for the potential application of lower more targeted light levels in therapeutic settings using this knowledge two pilot studies showed that evening exposure to 2 hours of shortwavelength light 30 lux at the cornea from lightemitting diodes leds peaking at 470 nm consolidated restactivity rhythms and increased the sleep efficiency of persons with adrd however delivering light to adrd patients via light boxes or light goggles is a challenge and would likely have low compliance rates,[11507175 11487664]
457,"some emerge rather early braak iiiiv and are sustained some appear early and subside and some are apparent only at a later phase table i
 earlyonset changes are most compatible with the notion of causation",[18525125 23962497 24014289 24027266 21946562],nonetheless there are some fairly consistent changes such as i increases in mir146a in temporal cortex and hippocampus and in an opposite direction decreases in mir132 in several brain regions ii reductions of mir107 in temporal cortex and iii diminished mir181c in frontal cortex and temporal cortex the latter change is interesting since it is mimicked by similar decreases in animal models for ad further aβ42 exerts comparable effects on mir181c in a cellular procedure see further below another interesting point comes from studies that have looked at the timecourse of changes,"[20937840 19406203 24014289 21807765 21062284 18234899 21994399 21994399
 21720722 20552018]"
458,thus downregulation in ad of mir124a and 132 which target ptpb will favour aberrant splicing of tau into neurotoxic isoforms third downregulation of mir15a 103107 and 27a3p enhances excess phosphorylation of tau by extracellular regulated kinase erk1 cyclindependent kinase cdk5 and glycogen synthase kinase gskp respectively on the other hand an increase in mir26b would act oppositely to repress gsk3β,[23684085 21807765 20660113 21625387 24027266],"first the synthesis of tau itself would be accelerated by reductions in the levels of mir27a3p and 34a both of which target it directly second the tau precursor can be alternatively spliced by the abovementioned appprocessing enzyme ptpb its actions will modify the ratio of “4r” to slightly-shorter “3r” isoforms, the former being more prominent in ad.",[24212398 24032460]
459,disruption in step function has also been implicated in seizures  ethanol abuse  amphetamamineinduced stereotypies  and huntingtons disease  although the basis for these changes remain to be determined,[21204826 21464302 19026408 21632937 22523092],"in contrast step levels or activity are lower in several other disorders including stressrelated conditions  excessive etoh consumption  and cerebral ischemia thus, the current model is that step activity must be within an optimal range and that either high or low levels of step disrupt synaptic plasticity.",[22649233 24012328 24588427 24198371]
460,mci is currently regarded as a complex condition that still needs further investigation to better define it and to develop a rigorous understanding about its clinical utility the recent subclassification of mci according to its cognitive features seems to be an effort to set some boundaries regarding the heterogeneity around this concept petersen suggested that mci be subdivided into two variants amnestic mci with clinically significant memory impairment and nonamnestic mci with significant impairment in functions other than memory such as attention executive processing language or visuospatial skills,[18473654 19035823 11735772 22143004 15324362],"also, we will synthesize which eye movement pattern changes might be associated with these deficits in mci/ad patients, and which might need further investigation. researchers have been trying to better understand the changes involved in the process of aging specifically focusing on the cognitive differences between normal and pathological aging mci is generally associated with aging processes and it is thought to be an intermediate state between normal aging and dementia thus increasing the risk of progression to ad however not all aging processes lead to cognitive declines and the pattern of cognitive decline may vary across individuals",[19822781 10190820 11735772 15324362]
461,the characteristics of the adni1 subjects have been published extensively briefly the mild ad subjects with csf information 102 subjects with 383 cdrsb observations were between ages of 57 to 89 years mean  standard deviation sd 758 years and the lmci subjects with csf biomarker data n199 1219 cdrsb observations were between 55 to 89 years 748 years,[20810324 22990808 21659625 22534009 20042704],the conditional probability was calculated based on the baseline hazards estimated in the dropout model and the simulated cdr–sb scores at the previous visit. a percentile vpc with confidence intervals was used to assess the extent to which the median prediction and extremes of the 90 prediction interval reflected the median and the fifth and 95th percentiles of the observed data,[19387434]
462,in general compared to nonconverters mci to ad converters show greater reductions in naa or naacr in different cerebral locations between baseline and followup 9196 naa or naacr especially those of the hippocampus often correlate with memory test scores 83 92 97 98 and so can be related to memory function and to predict ad with relatively high accuracy,[19427767 19398707 22129910 22390859 18692749 19398707 22390859],"longitudinal mrs investigations of at-risk people (e.g., mci) that involve multiple time-point mrs scans are especially important in understanding disease progression. In the few such studies available, subjects with MCI have been followed for 1-3 years, to characterize metabolite profiles of those who converted to dementia (Table 1).",[]
463,sleep deficits are known to impair cognitive function in healthy populations   to accelerate cognitive decline   and to predict incident mci and dementia,[16126646 21532950 20946702 17287134 19426575],in addition mood disturbance can contribute not only to impairment of memory but also to sleep disturbance hpa axis dysregulation and autonomic dysfunction and related proinflammatory changes thus helping to promote a vicious cycle of adverse physiologic neuroendocrine and psychosocial changes that foster the development and progression of ad cvd and related chronic conditions sleep disruption also common in cognitively impaired adults  likewise has negative effects on health functioning and quality of life and is a major reason for institutionalization,[17658122 17705097 17615391 22415141 19426575 20946702 17287134 18346674]
464,the therapeutic potential of cannabinoids 150 in ad becomes apparent in several mechanisms noncompetitive ache inhibition 151 antiaggregation of aβ peptides mediated by ache pas inhibition or by phagocytosis of aβ peptides mediated by cb2 receptors 152 antiglutamatergic effect 153 antioxidant activity 147 antineuroinflammatory properties,[22448595 10191316 17140265 14657172 11831553],"among the substances with the ability to reduce or mitigate neurodegenerative symptoms the group of cannabinoids has to be taken into consideration The connection between the endocannabinoid system and AD has been reported consistently [119, 147-149].",[18781980 20875047]
465,additionally studies using conventional timedomain oct technology lacking eyetracking capabilities found only a subtle rnflt decrease in ad patients,[17543991 21454010 17460292 11595144 20609426],"the rnflt has been examined in several studies using histopathologic techniques, with inconsistent findings. some stated that there is no decrease  while others found abnormal rnflt",[3736630 8725900 8498808 7542917]
466,the rate of change in the left hippocampus correlates with decline of performance in the boston naming test minimental status examination and the trailmaking test b such analyses help with the definition of special ad subtypes like posterior cortical atrophy or the logopenic variant of ad on the molecular level we find a downregulation of synaptic genes across multiple brain regions and widespread proteomic signs of synaptic stress or decay in the cerebrospinal fluid csf or blood changes in the molecular fine structure of ad brains also arise independently of atrophy as resonance spectroscopic investigations in ad imply,[22940716 22940716 21325651 23273601 23160951 19451528],highly myelinated neurons are only affected in the final phases of the disease low myelinization increases the overall energy expenditure of neurons in addition subcortical neuron loss occurs in the nucleus basalis of meynert and the locus ceruleus impairing the cholinergic and noradrenergic transmitter systems in the neocortex the parietal lobe along with certain areas of the prefrontal lobe is one of the last areas of the human brain to myelinate and many of its neurons remain poorly myelinated for the entire lifespan which may explain their vulnerability to factors capable of triggering ad the atrophy runs slowly but while in healthy aging only 02 to 041 of the brain volume vanishes per year the rates in ad may be ten times that and in especially vulnerable regions like the hippocampal formation atrophy rates might be even more devastatingly high and surpass 10 per year see also  in terms of neuropsychological tests regional atrophy and glucose metabolism correlate well with test results left hippocampal gray matter volume for example significantly correlates with performance in memory tasks and left temporal graymatter volume is related to performance in language tasks,[11193802  7198741  6707659 21130554 22920268  8676724 23554933 22940716]
467,functional impairments in ad place the greatest burden on both caregivers and the economy and results from several studies have suggested that neuropsychologic test performance is predictive of activities of daily living performance in patients with ad results from observational studies and clinical trials indicate that deterioration in the ability to carry out activities of daily living can be detected among patients with ad over followup periods comparable with that in the present study,[ 8059882 12614995 15814872  8505464 19929593],"caregiver assessments also indicate that memory and ability to carry out activities of daily living remained stable or improved during therapy with ct. in an assessment of overall memory, 40% of the caregivers reported somewhat better or much better memory after initiation of ct.",[]
468,also no correlation was found between the serum aβ42 levels and the aβ42 levels in csf of ad patients and healthy individuals   the accumulation of aβ peptides in ad brain  or the progression of cognitive deterioration in ad,[11335065 16909004 16372280 10634455 18268197],reports on potential serumbiomarkers for ad diagnosis have provided contradictory results and it is unclear whether changes in the periphery reflect pathologies within the brain thus studies of aβ42 levels in serum of ad patients showed both reduced   and increased values   compared to control subjects while other reports indicated no differences between groups,[19698775 15717023 20478847 18534566 10211483 10482274 12873852  8880695]
469,consistent with the early disruption of circadian and sleep physiology observed clinically neuropathological evidence in ad clearly implicates ascending brainstem pathways that govern the sleepwake cycle at or near the outset of the disease including cholinergic dopaminergic melatoninergic and neurosteroid systems,[21170538 21145918 22395806 20631712 16416333],our understanding of ad neurobiology has been transformed by a substantial body of neuroimaging data which demonstrates that the neurodegenerative process has a predictable and regionally specific evolution in the brain the very earliest disease targets in ad remain somewhat contentious but are likely to include entorhinal cortex and brainstem sites including locus coeruleus dorsal raphe nuclei or nucleus tractus solitarius,[ 1759558 21170538 21778116 22219130]
470,sorl1 through its codependent interaction with vps26 regulates the intracellular transport and processing of app resulting in reduction of amyloid beta aß peptide production    sorl1 knockout mice carrying both pathogenic mutations in the psen1 exon 9 deletion and app swedish k595mn596l exhibited increased production and accumulation of aß  sorl1 variants might influence the csf aß42 level in ad patients,[21220680 16174740 22279231 19036982 18541377],s5 sorl1 also known as sorla and lr11 and app proteins are colocalized in the endosomal and golgi compartments,[16174740]
471,s100b is a multifunctional ca2 binding protein that can act as an intracellular regulator or extracellular signal molecule that interacts with a wide variety of proteins including the receptor for advanced glycationend products rage s100b can be neuroprotective at lowphysiological levels or toxic at higher concentrations although not connected to a pd diagnosis increased levels of s100b in the serum of pd patients positively correlated with the progression of disease although controversial this suggests s100b may also serve as a general marker of brain injury or neurodegeneration due to its abundant presence in oligodendrocytes and astrocytes in this context it has been reported that increased levels of s100b result in glycogen synthase kinase 3β gsk3β and hyperphosphorylation of tau our analyses revealed that s100b was significantly and positively correlated with ptau181,[19110011 12645009 19110011 21303299 15619461 12645009 21303299 18494933],"however, a moderately significant and positive correlation was apparent between aβ42 and apoe carrier status when the pd and nc cohorts were combined. intriguingly, within the nc group only, apoe ɛ4-positive subjects had significantly higher apoe levels and ttr levels.",[]
472,our results are consistent with the wellestablished role of the apoe4 allele as a risk factor for sporadic ad p00001    7,[17596691 19734902 19734903  8350998 17541051],"in the second step, a binomial logistic regression model was used to compare the interactions between apoe*4 and each of the three snps in the entire sample. the statistical analysis was conducted using r software version 2.12.2.",[]
473,the aβrebound observed in cells experimental animals and humans is an expected pharmacodynamic feature for all biphasic inhibitors,[16548522 18574238 22323718 15647487 22381714],"in summary the biphasic inhibitors could facilitate potentially pathogenic processes that could explain why clinical trials showed dose dependent cognitive decline with avagacestat   and irreversible cognitive decline with semagacestat on the optimistic side, studies of the biphasic inhibitors could give valuable insights in the molecular pathogenesis and lead to novel drug development strategies.",[22381714]
474,several studies have suggested that greater cognitive impairment predicts an increased risk of the onset of psychosis in patients with alzheimers disease several neuroimaging studies have implicated the frontal lobe parietal lobe striatal regions and insula in the manifestation of delusions in patients with the disease in a previous study examining structural brain abnormalities significant findings indicated an association between low volumes of regional gray matter in several areas and delusions in patients with alzheimers disease,[16582044 18239195  9813789 20375510 18669506],however among a wide variety of neuropsychiatric symptoms in patients with alzheimers disease psychotic symptoms such as delusions are particularly associated with increased caregiver burden a decreased quality of life for both the patient and the caregiver and a relatively poor prognosis for the course of the disease a 2year prospective longitudinal study of patients with alzheimers disease reported that the cumulative incidence of psychotic symptoms delusions hallucinations was 369 the examination of possible predictors of the development of psychotic symptoms in patients with alzheimer’s disease is clinically relevant.,[17299264 16401890 16216946 12566599]
475,all variances are on the observed 01 scale were estimated using restricted maximum likelihood  and were transformed to those on the liability scale as shown previously  assuming a disease prevalence lifetime risk of 8 for ed  2 for ad  and 01 for ms,[16451790 21376301 21151130  9736873 21833088],"where  is the additive genetic variance tagged by the snps,  is the error variance, a is the genomic similarity relationship matrix estimated from snp data and i is an identity matrix. the genomic similarity relationship for each pair of individuals is calculated as the sum of the products of snp coefficients between two individuals scaled by the snp heterozygosity",[20562875]
476,clusterin also known as apolipoprotein j is a multifunctional lipoprotein involved in amyloidβ aβ fibrillisation and clearance   complement inhibition   and neuronal apoptosis,[ 7980587 19651157  9200695  9247197 21762182],biomarkers are therefore urgently needed to correctly identify subjects affected by ad before they have developed dementia and to track disease progression in ad recently several independent genomewide association studies have identified the clu gene encoding clusterin as a genetic locus associated with ad    raising hope for clusterin as a potential marker of ad,[19734902 19734903 20460622]
477,autopsyproven studies demonstrated a range of prevalence of cerebrovascular lesions in ad from 39 to 68  and that variability mostly depended on differences in the kind of studied vascular lesions macroscopic infarcts microscopic infarcts etc,[11213093 15792814 20173339 17568013 14504965],"this was a naturalistic study conducted in two neurology clinics where patients were referred by their family physicians and, in all cases, a chei was initiated by the attending neurologist. in that context, which seems quite representative of incident ad, one third of the patients (32.5%) qualified for the advc group.",[]
478,in addition nmdarenhancing treatment can reduce depressive symptoms 213 214 218 and improve cognitive function in patients with schizophrenia,[15023571 16275807  9892253 15023571 16275807 11806864 15780844],"alternatively, nmdar enhancers may improve the cognitive, mood and psychotic symptom in ad like in schizophrenia and major depression. Previous studies revealed that NMDAR enhancing agent can alleviate psychotic symptoms of patients with schizophrenia [213-217].",[]
479,by adding charged sequences polyethylene glycerol peg 44 nmethylation 45 using denantiomeric residues replacing residues with tyrosine and introducing nterminal acetylation and cterminal amidation 26 27 iaβ5 derivatives with enhanced properties ie higher proteolysis resistance stability activity solubility and bbb permeability could be established,[19250644 12578830 15098004 11967228 10363910],additionally the charged residue aspartate d was added at the end of the peptide to increase hydrophobicity and bbb permeability despite its significant activity to inhibit aβ fibrillogenesis iaβ5 was unstable and easily degraded by proteases which hampered its therapeutic usage in vivo,[ 9662374 11967228]
480,apart from the antiamyloid properties  and antitau hyperphosphorylation properties  against the two major pathological changes in ad curcumin is also able to regulate the secondary changes that occur during the disease like oxidative stress   inflammatory stress   and cholesterol regulation   which are very beneficial while considering ad therapy,"[15974909 19966973 18573304 18573304 11606625 19966973 11755008 15974909
 19966973]","curcumin can modulate multiple transcription factors, cytokines, growth factors, kinases and other enzymes. while the intravenously or intraperitoneally administered curcumin is metabolized to tetrahydrocurcumin hexahydrocurcumin dihydroferulic acid and ferulic acid the orally administered curcumin is excreted mainly through feces in unchanged form",[17900536]
481,recent studies have identified morphological differences in the sulci of some professional groups including musicians  patients with psychiatric and neurological conditions like schizophrenia  and bipolar disorder  and individuals with cerebral small vessel disease,[19433652 17988891 19270763 18577545 21518996],indeed cortical folding patterns have been used to predict cytoarchitecture in addition to being a macroscopic probe for hidden architectural organization folding geometry may also provide information on developmental events,[18079129 20489617]
482,white matter abnormalities have been widely reported in ad     and observed in the 3xtgad mouse brain as well,[14675724 12633151 18926601 18474742 18661556],"in parallel to the reduction of aβ and phospho-tau, apα treatment significantly reduced microglial activation as indicated by reduced expression of ox42. while the reduction in microglia activation by apα is likely a consequence of apα-induced reduction of ad pathology, suppression of microglial activation would relieve the inflammatory burden associated with ad pathology.",[]
483,gains tend to be modest and may be best documented as a slight improvement in certain cognitive domains compared with the mmse the skt may be more sensitive to subtle changes because it is a more comprehensive cognitive assessment battery and takes into account processing speed and response accuracy in addition the availability of five parallel versions of the test makes it less prone to learning effects upon retesting which is an important issue in longitudinal studies,[17166312 18430980 19640874 19142405 16255841],"studies involving combined pharmacological and nonpharmacological treatment with multimodal stimulation programs reported slight improvements in mmse scores most studies that have evaluated the effect of nonpharmacological interventions in ad observed stabilization or at most modest improvement of cognitive functions conversely untreated patients may show cognitive decline our results are in agreement with the findings of previous studies, which have suggested that robust changes in cognition are unlikely to occur as a consequence of cognitive training in patients with ad.",[16323385 17297213]
484,of reviews supporting the use of memantine in bpsd most relate to patients with moderate to severe 15165051 or moderately severe to severe ad,[19194105 18058838 15852444 17496417 18294023],"the current review demonstrates that the evidence, within their respective licensed indications, is in fact stronger for donepezil. it is of interest to examine the licensed-indication results in the context of previous systematic reviews and meta-analyses.",[]
485,researchers have been estimating and interpreting different patient profiles in iiv with respect to reaction times and accuracy ie rightwrong response summary for at least a decade see,[11055261 16820224 20025396 16997285 17484601],while total scores provide an estimate of overall performance on cognitive measures iiv measures can complement these scores and may improve prediction of global decline  functional decline  and incident dementia it has been suggested that estimates of iiv provide a quantitative measure of neurobiological integrity in cognitive aging and neurodegenerative disease   as greater mean iiv levels have been reported in samples with mild cognitive impairment  and mild dementia  and has been found to associate with decreased frontal gray matter  white matter alterations  and altered dopaminergic and acetylcholinergic neurotransmission,"[14654726 15832049 18714062 15242692 15910117 11055261 12876148  1710967
 16820224 20025396 11765745]"
486,"sorl1 has been associated with lateonset ad through using snps and picalm clu and cr1 have recently been identified by gwas as novel risk factor loci grb2associated binding protein 2gab2 bridging integrator 1 bin1 exocyst component 3like 2 exoc3l2 and methylenetetrahydrofolate dehydrogenase napd dependent 1like mthfd1l have been identified as associated with the development of ad but have been replicated with mixed results other possible ad genes can be found online wwwmolgenuaacbeadmutations
and
wwwalzgeneorg",[20388643 17220890 19734902 19734903 20460622],"however, as already mentioned, some alleles have been identified to increase the risk of developing late-onset ad. apoe ε4 is a wellestablished risk factor for ad and is associated with a fourfold risk of developing the disease since 2007 a number of gwas have been performed confirming that apoe ε4 is the most significant gene associated with lateonset ad other identified genes have only a small effect on the risk of developing ad",[10844923 20388643 20955934 17474819 19734903]
487,this is a novel biomarker that may interest several ad researchers as the selective targeting of several neurotrophin receptors has been proposed as a viable mechanism of intervention for neuroprotection  with much of the attention being on the p75ntr the common neurotrophin receptor,[19874265 17049785 19710315 19334058  9410912],as rantes upregulation in ad has been put forward as a mechanism for neuroprotection  the concurrent lack of upregulation of blc may point to a protective response that is not properly functioning in early ad worth investigating nt3 neurotrophin 3 nerve growth factor 2  also appears in a meta feature with mip1delta ccl15 chemokine cc motif ligand 15,[18440671  8114936  9116211]
488,building upon previous findings that low csf aβ42 can identify cognitively normal individuals with plaques preclinical ad   and that tauaβ42 and ykl40aβ42 ratios can predict risk of developing cognitive impairment    this minimal panel of six csf biomarkers ykl40 nrcam chromogranin a carnosinase i tau and aβ42 begins to segregate individuals into six clinicopathological categories normal cognition without amyloid plaques normal cognition with amyloid plaques preclinical ad normal cognition at increased risk to develop dementia converters very mild dementia cdr 05 very mild dementia at increased risk for progression and mild dementia cdr 1,[16372280 20049742 17210801 17698783 21035623],"currently, however, this panel of six biomarkers appears likely to show much greater promise in its application to csf. indeed by providing proof of concept this study outlines a scheme to categorize the early stages of ad using csf protein biomarkers that reflect established features of the pathophysiological evolution of the disease",[]
489,moreover omega3 essential fatty acidrich diets are associated with a trend in reduced risk for mci and with mci conversion to ad whereas dha has been shown to be beneficial in transgenic ad models,[15788759 11724467 19262590 17442823 16040805],"we note that the adam10 cleavage product sappα further induces the conversion of free dha into npd1, thus constituting a positive, neurotrophic feedback loop. dha partially counteracts cognitive decline in the elderly",[19262590]
490,early identification of alzheimers disease ad is needed to facilitate timely treatment delivery and to improve quality of life for affected patients and their families cholinergic deficit is present early in the course of ad and is a likely contributor to the earliest clinical manifestations of this illness including declarative memory impairments and disturbances of preattentive information filtering ie impaired auditory sensory gating the latter of these impairments reflects cholinergic deficitrelated abnormal hippocampal physiology disturbances of which are amenable to identification using the functional magnetic resonance imaging fmri auditory sensory gating paradigm,[ 9581218 14747516 15174015 14747516 15174015  7568559  7527772],functional imaging of hippocampal dysfunction among persons with alzheimer’s disease: a proof-of-concept study,[]
491,this measure has been used to study some biological signals such as heart rate time series 42 43 eeg data 23 44 and meg recordings 18 sampen has two input parameters a run length m and a tolerance window r sampen is the negative natural logarithm of the conditional probability that two sequences similar for m points remain similar at the next point,[15886445 12185014 15366100 19130227 10843903],"additionally the algorithm used to compute the sampen is simpler than the apen one despite its advantages over apen, the use of sampen is not widespread.",[10843903]
492,glycogen synthase kinase3 is increasingly thought to play a pivotal role in the pathogenesis of alzheimers disease both as a regulator of the accumulation of aβ peptide    and through its wellestablished role as a tau kinase,[12761548 17314294 15170327  1336152 11226152],"p<0.01, and p<0.0001 when comparing uas-arcaβ42/uas-gfp;elavgs/+ to uas-arcaβ42/+;elavgs/uas-sggs9e flies on +ru486 sy medium, and uas-arcaβ42/uas-gfp;elavgs/+ +ru to uas-arcaβ42/uas-gfp;elavgs/+ +ru +li respectively. (b) rna levels of uas-arcaβ42/uas-gfp;elavgs/+, uas-arcaβ42/+;elavgs/uas-sggs9e +ru486 sy medium and uas-arcaβ42/uas-gfp;elavgs/+ +ru + lithium flies were measured at day 5. no significant difference was seen in the levels of rna expression, number of independent tests (n) = 3.",[]
493,therefore the findings of our study in the iranian population is supported by certain studies in the world    and is in contrast with the results of other studies carried out in this subject in other parts of the world,[18585350 20061624 20164592 19655363 20164602],in another study carried out in spain the difference between this polymorphism with ad was significant in study carried out in the usa 2009 with sample size including 510 cases and 524 controls no significant difference was shown,[20164592]
494,however these traditional roles of cox isoform expression are not observed in the brain as cox2 mrna and protein are detectable in neurons in absence of inflammatory stimulus 131415 and cox1 has been reported to contribute to elevations of pge2 in experimental models of neuroinflammation,[ 7608344  8637870  8352945 19825412 15850932],"when considering genetic sequences cox2 has a unique promoter region that allows upregulation of expression by growth factors tumor promoters hormones bacterial endotoxin cytokines anoxia neurotoxins electrical stimulation and proinflammatory stimuli therefore, it has been accepted that cox-1 is constitutively expressed whereas cox-2 is expressed as part of the inflammatory response in most tissues.",[10933512]
495,in particular aspirin acetylsalicylic acid or its metabolite salicylic acid has been extensively investigated and has repeatedly conferred protection from the neuronal damage induced by mptp and 6ohda via reduction of ros,[ 9751197 16712818 16318861 12618347 11180504],"animal models generally support the notion that nsaids protect against the dopaminergic neural degeneration that is induced by certain neurotoxins for review see however, the nsaid-associated neuroprotection appears to be dependent on duration, dose, and onset relative to neurotoxin exposure, as well as the specific nsaid utilized.",[17433296]
496,some authors revealed changes in the commissural tracts as well,[16614789 16520023 12023417 19043518 18180656],"so far, the vast majority of dti examinations carried out in patients with ad, demonstrated the presence of microstructural changes in white matter, manifested by the decrease in fa value, with inhomogeneous damage of the white matter and of the cerebral cortex. most changes were found in the selected association tracts",[18180656]
497,the study group was a relatively small sample  35 patients with ad and 15 controls but the vast majority of dti studies in ad was also carried out within similar or smaller groups of patients,[16614789 16520023 12023417 17905894 18180656],"predilection of changes for the association tracts and preservation of pyramidal tracts and medial cerebellar peduncles, as determined in our study, corresponds to the distribution of cerebral gray matter damage. it possibly proves that the white matter tract damage and wallerian-type degeneration of axons are secondary to neuronal damage in association areas of the cerebral cortex and the limbic system.",[]
498,the dynaminlike gtpase drp1 influences mitochondrial density in axons and dendrites   and reductions in drp1 levels or increases in drp1 activity by snitrosylation are induced by aβ and detected in ad brains,[16055061 15607982 19605646 19050078 19342591],the motility of mitochondria is thought to be interrelated with the fissionfusion machinery and an imbalance between mitochondrial fission and fusion induced by aβ42 may result in reduced mitochondria in the axons and dendrites in ad mitochondrial size is increased and mitochondrial numbers are decreased in neurons  suggesting that the normally strict regulation of mitochondrial morphology is impaired,[16055061 15607982 19605646 11312286]
499,the homozygous arte10 is among those lines displaying a relatively early plaque onset and a high maximal plaque burden,[16906128 11279122 14645205 15261108 17029828],"an in vivo pet study of aβ in arte10 mice using [11c]-labeled pib is reported separately (manook et al, submitted). the onset development and maximal amount of amyloid plaque deposition vary considerably between established mouse lines co expressing app and presenilin mutants",[16567017]
500,further studies in mutant mice have shown that elevated aβ levels result in spine loss 17 99101 reduction in the number of excitatory synapses 102 and depressed glutamatergic synaptic transmission 103 104 accompanied by glutamate receptor endocytosis,[17360908 19228947 12670422 17145504 17145504 16025111],the observation that amyloid plaques in vivo are surrounded by hyperactive cells 90 came as a surprise because of the wealth of data showing that ad is associated with synaptic dismantling and synaptic failure Already early histological studies of brain tissue from AD patients were able to reveal neuronal loss shrinkage of dendritic trees and a decrease in the density of synapses ,[18802001 12399581]
501,despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor,[18473829 18396368 18299246 15491780 15632341],in experimental animal models epo may reduce apoptotic pathways during periods of hyperoxia in the developing brain furthermore clinical disorders may have periods of hyperoxia followed by cerebral hypoperfusion and hypoxia that can lead to cerebral injury with associated oxidative stress in these circumstances epo also may be protective since it can promote neurite outgrowth and also may regulate hemoglobin levels that have recently been associated with cognitive decline in other work elevated epo concentrations during infant maturation have been correlated with increased mental development index scores and epo may prevent toxic effects of agents used to control cognitive function such as haloperidol in addition knowledge that epo and its receptor are present in the neurovascular systems has generated great enthusiasm for the potential clinical applications of epo for ad and related cardiac insufficiency and cardiac transplantation in the nervous system primary sites of epo production and secretion are in the hippocampus internal capsule cortex midbrain cerebral endothelial cells ecs and astrocytes further work has revealed several other organs as secretory tissues for epo that include peripheral ecs myoblasts insulinproducing cells and cardiac tissue the epor also is expressed in primary cerebral ecs as well as in human umbilical veins bovine adrenal capillaries and rat brain capillaries,"[19067366 18973793 18502414 18672044 19001795 17805306 17483696 17161060
 16309765 17896976 15491780 15632341 15210945 15272145  8171022 10995753
 12717230 15632341 17631185 12621307 12769640  8171022  8706759]"
502,in contrast to epo cytoprotection foxo transcription factors usually lead to apoptosis during oxidative stress for example forkhead transcription factors such as foxo1 and foxo3a must be present for oxidative stress to result in apoptotic cell injury foxo3a in conjunction with jnk also has been shown to modulate an apoptotic ligand activating a fasmediated death pathway in cultured motoneurons to lead to apoptosis through tumornecrosisfactorrelated apoptosisinducing ligand trail and bh3only proteins noxa and bim in neuroblastoma cells and to promote proapoptotic activity of p53 in addition loss of foxo expression during oxidative stress is protective to cells,[18473829 18035477 15569384 16888645 16757565],with epo it can prevent cell injury during ad and aβ cell injury hypoxia excitotoxicity parasitic disease endotoxin shock free radical exposure cardiac disease amyloid toxicity and pulmonary disease epo also represents a potential option for the prevention of retinal degeneration or neovascularization as well as glaucoma  in the cns systemic application of epo also can improve functional outcome and reduce cell loss during spinal cord injury traumatic cerebral edema cortical trauma and epileptic activity epo also can reduce cytokine gene expression in endothelial cells exposed to tumor necrosis factor prevent ulcer progression in cases of scleroderma reduce inflammation in murine arthritis models and block primary microglial activation and proliferation during oxidative stress to prevent phagocytosis of injured cells through pathways that involve cellular membrane ps exposure protein kinase b and the regulation of caspases epo can directly inhibit several proinflammatory cytokines such as il6 tnfα and monocyte chemoattractant protein 1 and reduce leukocyte inflammation epo also may foster the preservation of microglial cells for neuronal and vascular restructuring by preventing apoptotic injury in microglia,"[17289346 16375720 19268480 18512763 12684267 12460881 16417583 16054296
 17157835 18711747 18359468 16518761 19237893 18983707 12584724 12621307
 15979589 18651544 18586265 16375720 18512763 18069756 19061883 18952918
 18788995 17873720 17614942 17236773 17264861 17470644 17241225 17166730
 17166730 15784966 17397351 15751086 15149850 12920191 16181114 12684267
 16375720 15149850 12684267 12621307 17508273 15632341 15627815 16918383
 12270034]"
503,the genetic background of ps1 fad mutations has been proposed to correlate with increased vulnerability to oxidative stress and apoptosis    possibly due to aberrant ps1 function in maintaining er calcium homeostasis,[11520901 16042546 12419469 16959576 16156741 16042546],the ps2 mutant cells resembled ps1 mutants in regard to p38 and normal cells in regard to erk while trisomy 21 cells exhibited both bkdependent p38 activation and erk activation that was equivalent to normal fibroblasts despite showing other avenues of signal transduction that are like presenilin ad fibroblasts the functional divergences observed between erk and p38 may relate to upstream steps in this overall pathway differentially linked to presenilin functions that remain to be defined.,[]
504,a number of studies used the criteria nincds possible or probable ad or other nonstandard clinical measures data not shown  while clinical diagnosis is often used to validate imaging findings and neuropathological diagnosis is the overall gold standard and despite the existence of modern standardized criteria the application of these standards should not be considered free of ambiguity,[9785148 9681644 2642615 4078573 3415196],"thus, for instance, to achieve a specificity greater than 80%, four out. of five studies had to settle for sensitivity lower than 70%. this correlation is depicted in",[]