eventually causing the formation of aβ plaques. cholesterol hypothesis the cholesterol hypothesis is a combination of the amyloid hypothesis, tau hypothesis, and potentially the inflammatory hypothesis. cholesterol was shown to be upstream of both amyloid and tau production. the cholesterol is produced in the astrocytes and shipped to neurons where it activates amyloid production through a process called substrate presentation. the process required apoe. cholesterol's regulation of tau production is less well understood, but knocking out the cholesterol synthesis enzyme srebp2 decreased tau phosphorylation. innate immunity triggers cholesterol synthesis and cells take up the cholesterol. presumably a cell in the brain dies with old age and this triggers innate immunity. more studies are needed to directly tie the inflammatory hypothesis to cholesterol synthesis in the brain. reelin hypothesis a relatively recent hypothesis based mainly on rodent experiments links the onset of alzheimer's disease to the hypofunction of the large extracellular protein reelin. a decrease of reelin in the human entorhinal cortex where the disease typically initiates is evident while compensatory increase of reelin levels in other brain structures of the patients is also reported. of key importance, overexpression of reelin rescues the cognitive capacities of alzheimer's disease model mice and τ-protein overexpressing mice. a recent circuit level model proposed a mechanism of how reelin depletion leads to the early deterioration of episodic memory thereby laying the theoretical foundation of the reelin hypothesis. isoprenoid changes a 1994 study showed that the isoprenoid changes in alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of premature aging. during aging the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. in alzheimer's disease, the situation is reversed with decreased levels of dolichol and increased levels of ubiquinone. the concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. the increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance induced by lipid peroxidation. ropren, identified previously in russia, is neuroprotective in a rat model of alzheimer's disease. glucose consumption the human brain is one of the most metabolically active organs in the body and metabolizes a large amount of glucose to produce cellular energy in the form of adenosine triphosphate (atp). despite its high energy demands, the brain is relatively inflexible in its ability to utilize substrates for energy production and relies almost entirely on circulating glucose for its energy needs. this dependence on glucose puts the brain at risk if the supply of glucose is interrupted, or if its ability to metabolize glucose becomes defective. if the brain is not able to produce atp, synapses cannot be maintained and cells cannot function, ultimately leading to impaired cognition. imaging studies have shown decreased utilization of glucose in the brains of alzheimer's disease patients early in the disease, before clinical signs of cognitive impairment occur. this decrease in glucose metabolism worsens as clinical symptoms develop and the disease progresses. studies have found a 17%-24% decline in cerebral glucose metabolism in patients with alzheimer's disease, compared with age-matched controls. numerous imaging studies have since confirmed this observation. abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the alzheimer's disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices. these brain regions are believed to control multiple aspects of memory and cognition. this metabolic pattern is reproducible and has even been proposed as a diagnostic tool for alzheimer's disease. moreover, diminished cerebral glucose metabolism (dcgm) correlates with plaque density and cognitive deficits in patients with more advanced disease. diminished cerebral glucose metabolism (dcgm) may not be solely an artifact of brain cell loss since it occurs in asymptomatic patients at risk for alzheimer's disease, such as patients homozygous for the epsilon 4 variant of the apolipoprotein e gene (apoe4, a genetic risk factor for alzheimer's disease), as well as in inherited forms of alzheimer's disease. given that dcgm occurs before other clinical and pathological changes occur, it is unlikely to be due to the gross cell loss observed in alzheimer's disease. in imaging studies involving young adult apoe4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (dcgm) was detected in the same areas of the brain as older subjects with alzheimer's disease. however, dcgm is not exclusive to apoe4 carriers. by the time alzheimer's has been diagnosed, dcgm occurs in genotypes apoe3/e4, apoe3/e3, and apoe4/e4. thus, dcgm is a metabolic biomarker for the disease state. insulin signaling a connection has been established between alzheimer's disease and diabetes during the past decade, as insulin resistance, which is a characteristic hallmark of diabetes, has also been observed in brains of subjects with alzheimer's disease. neurotoxic oligomeric amyloid-β species decrease the expression of insulin receptors on the neuronal cell surface and abolish neuronal insulin signaling. it has been suggested that neuronal gangliosides, which take part in the formation of membrane lipid microdomains, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface. in alzheimer's disease, oligomeric amyloid-β species trigger tnf-α signaling. c-jun n-terminal kinase activation by tnf-α in turn activates stress-related kinases and results in irs-1 serine phosphorylation, which subsequently blocks downstream insulin signaling. the resulting insulin resistance contributes to cognitive impairment. consequently, increasing neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat alzheimer's disease. oxidative stress oxidative stress is emerging as a key factor in the pathogenesis of ad. reactive oxygen species (ros) over-production is thought to play a critical role in the accumulation and deposition of amyloid beta in ad. brains of ad patients have elevated levels of oxidative dna damage in both nuclear and mitochondrial dna, but the mitochondrial dna has approximately 10-fold higher levels than nuclear dna. aged mitochondria may be the critical factor in the origin of neurodegeneration in ad. even individuals with mild cognitive impairment, the phase between normal aging and early dementia, have increased oxidative damage in their nuclear and mitochondrial brain dna (see aging brain). large gene instability hypothesis a bioinformatics analysis in 2017 revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture. these genes are also highly enriched in cell adhesion gene ontology (go) terms and often map to chromosomal fragile sites. the majority of known alzheimer's disease risk gene products including the amyloid precursor protein (app) and gamma-secretase, as well as the apoe receptors and gwas risk loci take part in similar cell adhesion mechanisms. it was concluded that dysfunction of cell and synaptic adhesion is central to alzheimer's disease pathogenesis, and mutational instability of large synaptic adhesion genes may be the etiological trigger of neurotransmission disruption and synaptic loss in brain aging. as a typical example, this hypothesis explains the apoe risk locus of ad in context of signaling of its giant lipoprotein receptor, lrp1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site. the large gene instability hypothesis puts the dna damage mechanism at the center of alzheimer's disease pathophysiology. dna damage naturally occurring dna double-strand breaks (dsbs) arise in human cells largely from single-strand breaks induced by various processes including the activity of reactive oxygen species, topoisomerases, and hydrolysis due to thermal fluctuations. in neurons dsbs are induced by a type ii topoisomerase as part of the physiologic process of memory formation. dsbs are present in both neurons and astrocytes in the postmortem human hippocampus of ad patients at a higher level than in non-ad individuals. ad is associated with an accumulation of dsbs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward. dsbs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for aβ in dsb accumulation or vice versa. the predominant mechanism for repairing dna double-strand breaks is non-homologous end joining (nhej), a mechanism that utilizes the dna-dependent protein kinase (dna-pk) complex. the end joining activity and protein levels of dna-pk catalytic subunit are significantly lower in ad brains than in normal brains.