clinical , case -control , and epidemiologic studies show an association between late - life depression and persistent cognitive deficits , and between history of depression and subsequent dementia , especially ad .
studies of late - life depression generally find significant cognitive impairment , concurrent with affective symptoms , ( eg , refs 2,3 ) that is mediated almost , entirely by slowed information processing or working memory deficits .
the cognitive deficits accompanying late - life depression often persist following treatment and remission of affective symptoms .
one year after good treatment response for a major depressive episode , significant impairment was found in 23% of subjects who had been deemed cognitively intact while depressed . 
  two recent meta - analyses found that a history of depression approximately doubles an individual 's risk of subsequent dementia in general and ad in particular . yet , many large individual studies have found no such relationship , giving rise to varying conclusions regarding the temporal and directional association between depression and mild cognitive impairment ( mci ) and/or dementia . that is , it is not clear whether prior depression is a true etiologic risk factor for dementia or rather represents a prodromal clinical manifestation of dementia neuropathology some evidence suggests that , risk for both m'ci and dementia is proportionate to cumulative depression burden in terms of symptom severity , lifetime duration of depression , or number of major depressive episodes ( m'drs ) . in the cardiovascular health study , severity of depressive symptoms independently predicted diagnosis of mci 6 years later .
a large danish case - registry study found the number of prior mdes predicted dementia diagnosis , with a hazard ratio increasing by 13% per mde . finally , several studies suggest the longer the interval between onset of first depressive episode and time of assessment for dementia , the greater the risk of dementia ( also see meta - analyses in refs 10,11 ) .
overall , the weight , of available evidence suggests that , depression , including related pathophysiologic processes , may act as a true risk factor for mci and dementia . however , there is no consensus as yet on this point .
other studies have found that the shorter the interval between depression onset , and assessment for dementia , the greater the risk , while others found no such relationship between depression and cognitive impairment or subsequent , dementia .
such findings suggest that when depressive and cognitive symptoms appear close in time they likely arise from common neuropathologic processes .
this is an important , competing hypothesis to the concept of depression as a risk factor for dementia .
overall , these findings emphasize the heterogeneity of late - life depression , its cognitive manifestations , and possible cognitive sequelae .
many authors emphasize the importance of determining whether depression is a true risk factor versus an early symptom occurring in the prodromal phase of dementia , particularly ad .
this report , does not resolve this issue ; rather , we review evidence for several specific pathways by which depression may be linked to subsequent , cognitive decline and dementia and present , two related models that accommodate and reconcile many of the seemingly disparate research findings .
one model is shown in figure 1 and presents three interacting links which affect brain and cognitive reserve thereby moderating the relationship between underlying ad neuropatholgy and its expression as clinical dementia . in the sections that follow
depression is associated with neuroendocrine changes similar to those observed in animal models of chronic stress , including abnormalities within the hypothalamicpituitary - adrenal ( hpa ) axis .
most notably , depressed subjects have been shown to exhibit , increased hpa central drive with elevated corticotrophin - releasing hormone ( crh ) and vasopressin production by cells of the hypothalamic paraventricular nucleus ( pvn ) ; impaired negative feedback regulation due to decreased expression of corticosteroid receptors in the hypothalamus and pituitary as well as upstream cns regulatory centers ; and adrenal hypertrophy ( reviewed in ref 25 ) .
the net effect of these changes in hpa function is chronic elevation of adrenal glucocorticoid production with impaired negative feedback and abnormal homeostatic regulation .
such hpa dysregulation is clinically detectable ( via dexamethasone nonsuppression or elevated 24-hour urinary cortisol ) in about , half of patients with major depression .
hpa dysregulation may be more common among older depressed individuals , as suggested by the finding of a significant correlation between age and post - dexamethasone cortisol levels in individuals with late - life depression . 
 
adrenal glucocorticoid / cortisol regulates hpa activity through both direct , negative feedback at the pituitary and hypothalamus and indirect , mechanisms involving higher central nervous system ( cns ) centers .
the human hippocampus , for example , contains large numbers of corticosteroid receptors and plays a critical role in downregulating crh release via a multisynaptic pathway terminating in y - aminobutyric acid ( gaba)-ergic output to the paraventricular nucleus ( reviewed in ref 28 ) . at . the same time
, hpa disturbances causing prolonged hypercortisolemia may promote hippocampal atrophy and functional decline , such that hpa regulation is further compromised . '
iliis interaction may underlie the observed association between hypercortisolemic disease states such as cushing 's syndrome and depression , and both hippocampal atrophy and impairment , in the verbal and spatial memory functions subserved by the hippocampus . 
 
animal studies suggest that high - stress conditions or exogenous glucocorticoids can cause hippocampal neuronal damage and memory impairment .
these changes have been observed concurrent with stress or exogenous glucocorticoid administration , and appear to progress over a lifetime of stress or glucocorticoid excess ( see review in ref 33 ) .
human studies in older adults likewise suggest that hippocampal size and function are diminished in the setting of elevated glucocorticoids , and in proplemiaortion to duration of prior hypercortisolemia . 
  on the basis of these findings ,
many have hypothesized that glucocorticoids may promote hippocampal cell injury and death when chronically elevated , as in the setting of hypercortisolemica associated with major depression .
glucocorticoid - induced cellular damage may be mediated through effects on several biochemical substrates . postulated mechanisms include decreased glucose uptake and atp generation , elevated intracellular calcium with increased free radical production and degradative enzyme activity , and impaired uptake of glutamate from hippocampal synapses resulting in excitotoxicity .
in addition , hypercortisolemia has been linked to a decrease in neurogenesis in the dentate gyrus .
while the combination of cell death and decreased neurogenesis may theoretically contribute to hippocampal cell loss over time , recent , evidence suggests at .
most a minor role for this mechanism in hypercortisolcmic human subjects in the absence of cooccurring insults .
animal and human studies support the idea that glucocorticoids contribute to hippocampal atrophy and functional deficits predominantly through more subtle alterations , including reduced synapse number , atrophy of pyramidal cell dendrites , derangement , of glial cells , and other changes .
neuroimaging studies have generally shown reduced hippocampal volumes in late - life depression subjects relative to age - matched controls ( see meta - analysis by videbech and ravnkilde ) , although this finding is not universal . furthermore , many studies find a significant association between hippocampal atrophy and greater lifetime duration of depression , as assessed by number of depressive episodes , total days depressed , total days of untreated depression , duration since first depressive episode , or early - onset as opposed to late - onset depression .
although these findings differ somewhat , most studies support , to some degree the notion that depression - related hypercortisolemia can compromise hippocampal structure and function , especially in the context of old age and comorbid disease .
the impact of glucocorticoids on brain structures can be expected to vary not only with age and disease status , but also with individual genetic and environmentallyimparted differences influencing hippocampal volume and connectivity , hpa reactivity , and other neurobiologie factors . besides the possibility of persistent synapse or neuron loss induced directly by prolonged hypercortisolemia , glucocorticoid - related derangement of hippocampal physiology , as described above , may increase vulnerability to damage through other pathophysiologic mechanisms .
this latter effect may become clinically relevant in older persons with co - occurring neuronal insults such as accumulating ad pathology or cerebrovascular disease , promoting synapse or neuron loss through a synergistic relationship with these factors .
the loss of hippocampal volume and memory function observed in some elders with late -life depression suggests the possibility that depression may be a predispositional risk factor for ad in particular .
indeed , lower hippocampal volumes independently predict subsequent ad in groups of mci and cognitively normal elderly subjects .
likewise , deficits in verbal learning and memory , similar to those described in cuthymic patients with history of major depression , also predict ad ( eg , ref 53 ) . while a primary causal role for depression in ad pathogenesis seems unlikely , depression - associated hypercortisolemia leading to decline in hippocampal size , connectivity and cognitive function may represent one of multiple links between depression and dementia as described below ( also see figure 1 ) .
the association between depression and dementia suggested by epidemiologic data may be partially explained by one or more direct , mechanistic links between late - life depression - related processes and adspecific neuropathology ( focal and diffuse cortical neuronal loss , p - amyloid plaques , and neurofibrillary tangles ) .
emerging evidence from neuroimaging studies , postmortem neuropathology analyses , and animal models provides support , for such links . some structural magnetic resonance imaging ( mri )
studies find that hippocampal atrophy is more strongly associated with late - onset than early - onset depression , suggesting that early ad - related pathophysiology could generate both hippocampal atrophy and depressive symptoms in some elderly persons .
in addition , one of these studies failed to find a significant correlation between hippocampal volume and cortisol level among elders with depression .
furthermore , the late - life depression subjects showed persistent memory and cognitive impairment at 6-month follow - up despite effective treatment of mood symptoms and normalization of cortisol levels .
all of these data are consistent with the idea that ad pathology is a major cause of hippocampal atrophy in some ( but not all ) individuals with late - life depression , and their depressive symptoms may represent prodromal ad . several recent , animal and human studies suggest , a possible direct pathophysiologic link between late - life depression and the neuropathologic hallmarks of ad .
postmortem studies report greater hippocampal amyloid plaque and neurofibrillary tangle pathology in ad patients with lifetime history of depression compared with those without , such history , and more severe cortical neurofibrillary tangle pathology in the brains of ad subjects who suffered from comorbid depression .
the hippocampal findings , combined with the observation of marked hippocampal neurofibrillary pathology early in the course of ad , provoke speculation that depression - associated hypercortisolemia may facilitate ad pathogenesis by rendering hippocampal neurons and glia vulnerable to toxic insults , as discussed in the previous section .
neurobiologie interaction or overlap between late - life depression and ad is further suggested by the discovery of glial changes consistent with a cns inflammatory process in both older depressed individuals ( eg , ref 60 ) and those with neurodegenerative diseases such as ad .
the prolonged hypercortisolemia associated with both diseases may partially account for these findings , as glucocorticoids can induce proinflammatory changes within the cns . 
 
overall , these findings provide associational evidence for a link between late - life depression and ad , yet offer little insight into whether depression history may act as a true etiologic risk factor for ad , or , conversely , whether late - life depression arises secondary to adrclatcd neuropathologic changes . however , two recent animal studies suggest the existence of a direct mechanistic link between hypercortisolemic depression and ad pathology .
green and colleagues found dexamethasonc administration increased ( i - amyloid production in a transgenic mouse model of ad , and traced this effect to increased expression of amyloid precursor protein and the p - secrctase enzyme .
this group also found increased tau aggregation within neuronal cell bodies and dendrites of dexamethasone - treated animals .
kang and colleagues demonstrated increased hippocampal interstitial p - amyloid levels in another mouse model of ad following acute restraint or chronic isolation stress .
this finding was reproduced through direct , infusion of crh into the hippocampus , and blocked by pretreatment with crh antagonists . in conclusion , diverse findings from structural mri and human or animal histopathologic studies suggest a direct , relationship between late - life depression and ad - specific pathology .
reports of a cross - sectional association between later age of depression onset and hippocampal atrophy support , the notion that early ad - related pathophysiology is causing depressive symptoms in these study groups and correlate with epidemiologic reports of elevated dementia risk in subjects with depression onset . in the recent , versus distant past , ( eg , refs 19,20 ) . conversely , postmortem ad studies suggest an association between more severe plaque and tangle pathology and lifetime depression history preceding ad diagnosis , offering support for the idea that , prior depression is a true , etiologic risk factor for ad , as suggested by other epidemiologic data ( eg , ref 11 ) .
furthermore , both stress and exogenous glucocorticoids increase p - amyloid production in rodent , models of ad , consistent , with a direct .
given the tremendous heterogeneity of late - life depression , various dementia pathologies , and the other clinical or subclinical disease inevitably present in older individuals , depressive symptoms should be expected to bear an inconsistent relationship with cognitive decline , dementia in general , and ad specifically .
such symptoms in a given elderly individual may potentially represent either prodromal ad , or an independent process interacting with ad - related pathophysiology . as discussed in this manuscript
, depression may furthermore contribute to cognitive decline and ad through glucocorticoid - relatcd hippocampal toxicity and interrelationships with other types of pathology such as vascular disease .
substantial data exist showing an association between latelife depression and cerebrovascular changes . in separate reports ,
alexopoulos and krishnan pointed to the thennascent evidence that a subgroup of individuals with latelife depression showed evidence of cerebrovascular changes .
alexopoulos coined the term  vascular depression ,  positing that , a subgroup of individuals experience disruption of prefrontal systems that mediate both mood and executive functions , by either single vascular lesions or accumulation of lesions . '
ihc concept of vascular depression has subsequently been supported and expanded by a growing literature .
depression increases risk for first - ever myocardial , infarction ( mi ) and stroke , and has been shown to predict worse outcomes in a wide range of concurrent vascular disease states ( reviewed in ref 67 ) .
notably , clinical diagnosis of major depression confers significant relative risk for mi , stroke , and post - mi cardiac mortality .
moreover , major depression confers greater relative risk than diagnosis of dysthymia or indices of self -reported depressive symptoms , suggesting a possible dose - response relationship between severity of depressive illness and excess cardiovascular risk . 
 
diverse mechanisms have been proposed to explain the link between prior depression and subsequent vascular disease .
depressed individuals exhibit poor treatment compliance and other behaviors such as smoking , substance abuse , and inactivity , which may cause or worsen comorbid disease .
elevated cortisol levels independently predict several features of the metabolic syndrome including abdominal obesity , low high - density lipoprotein ( hdl ) levels , and hypertriglyceridemia .
they disrupt normal endothelial function and may contribute over time to the development , of hypertension in some cases .
depressed subjects with coronary artery disease ( cad ) exhibit , autonomic dysfunction with decreased heart rate variability , a condition that likely predisposes to both cardiac arrhythmias and episodic hypoperfusion .
cad show greater baseline platelet activation than nondepressed control subjects , suggesting greater susceptibility to thromboembolic events .
finally , cross - sectional studies have linked depression to elevations in proinflammatory cytokines . while the causal relationship between such immunologic changes and depression is unknown , a similar proinflammatory cytokine shift
c - reactive - protein is directly atherogenic , and high levels of several proinflammatory cytokines have been found to predict cardiovascular events . 
  in a reciprocal fashion , many acute and chronic vascular disease states may promote depression .
mi and stroke substantially increase risk for depression during the immediate postacute period , with depressive symptoms reported in 25% to 50% of individuals
one study comparing cumulative 1 -year incidence of major and minor depression immediately following stroke or mi found no difference between these groups .
this finding suggests that the loss of specific neuronal populations is less important than more global postischemic vascular or inflammatory mechanisms in the pathogenesis of poststroke depression .
accordingly , depression is more frequent and severe in vascular dementia than ad , despite widespread neuronal loss in both dementia syndromes .
studies of individuals with chronic cardiovascular diseases show that diabetes mcllitus ( sec meta - analysis in ref 89 ) and cad , each approximately double risk for depression .
not all studies of older subjects indicate a longitudinal association between vascular disease / risk and subsequent depression .
several prospective studies in elderly subjects report that clusters of cardiovascular risk factors or pre - existing cad independently predict incident depression , while at least , one large prospective study found no relationship between an index of generalized atherosclerosis and incident depression . in old age , the observed association between vascular disease and depression
may be attenuated by the fact that persons with severe or long - standing disease of either type incur substantial morbidity and mortality .
surviving individuals with significant , vascular or depressive pathology might , actually be expected to possess protective biopsychosocial factors which interrupt the positive bidirectional relationship described above .
strong supporting evidence for the notion that vascular disease contributes to late - life depression comes from structural mri studies showing a robust association between ischemic brain lesions and depression diagnosis or selfreported symptoms in older persons .
large communitybased studies have demonstrated independent cross - sectional relationships between late - life depression and small basal ganglia lesions and white matter abnormalities visualized as hyperintense regions on t2-weighted m'ri ( wmhs ) in deep or subcortical areas .
longitudinal studies suggest white matter changes may both predate and independently predict late - life depression . 
 
the ischemic etiology of wmhs is suggested by several lines of evidence , including post - mortem histopathologic studies in patients with late - life depression and in the general population , correlating wmhs with both evidence of cerebrovascular disease and systemic hypotensive , or hypoxemic disease . 
 
ischemic damage to frontostriatal brain regions may explain the executive dysfunction , psychomotor slowing and resistance to treatment common in late - life depression .
the few studies examining wmhs and cognition in late - life depression have found associations with psychomotor slowing , memory , language , and executive functioning .
the relationship between wmhs and executive function may be particularly strong in individuals with late - onset depression . taken together , these studies suggest a relationship among late - onset depression , ischemic wmhs ( especially in the frontostriatal region ) and executive dysfunction , raising the possibility that ischemic structural changes in the brain are a common etiologic factor of both the depression and the associated cognitive dysfunction .
the cognitive impairment related to this ischemic damage may be severe enough to culminate in a clinical diagnosis of dementia .
high prevalence in the population ( up to 44% of all dementia ) . in accordance with the bidirectional relationship described here
, prior depression independently predicts subsequent vascular dementia ( or = 2.1 5 ) and individuals with late - life depression who develop clinical ad have high rates of cerebrovascular pathology upon postmortem examination .
indeed , prospective community - based studies report associations between baseline systemic vascular disease / risk and both higher rates of incident ad , and more rapid cognitive decline in established ad .
moreover , rapid progression of cerebrovascular disease as inferred from serial mri predicts subsequent dementia diagnosis . 
  in sum , mounting evidence suggests factors associated with late - life depression may predispose to persistent cognitive impairment and dementia .
plausible moderators of this relationship include glucocorticoid - related hippocampal damage , an interaction between depression and ad neuropathology , and increased vascular disease , but .
the potential importance of other factors ( eg , neurotransmitter and immunologic abnormalities ) can not , be excluded . moreover , in reality there appear to be abundant , interactions between the three distinct links described here and depicted in figure 1 .
hypertension , for instance , is associ ated with diminished regional cerebral blood flow in the hippocampus and related limbic and paralimbic structures of cognitivcly normal older adults .
together these findings suggest ischemic and inflammatory insults related to cerebrovascular disease may affect the same neuronal populations endangered by hypercortisolemia and ad .
it is conceivable that hippocampal insults related to vascular disease , hypercortisolemic depression or prodromal ad which are insufficient to cause significant , cellular damage or death by themselves may produce cell death through synergistic interaction with co - occurring insults . in the context of neurodegenerative disease , cerebral ischemia may contribute to cell death outside the hippocampus , as suggested by an independent association between wmh volume and cortical grey matter atrophy in ad .
notably , plasma levels of p - amyloid predict the extent , of ischemic white matter damage in mci and ad , suggesting a reciprocal interaction between cerebrovascular and ad pathophysiology .
together these examples suggest that , particular combinations of insults arising from different pathophysiologics may play a crucial role in promoting cognitive decline and progressive dementia subsequent to depression , an effect , related to extensive crosstalk between links and synergism of insults at . the cellular level .
clearly , many factors influence the impact , a particular risk or disease factor will have on expression of dementia . in the following section ,
we describe how the concepts of brain and cognitive reserve can be used to explain this multifactorial process and account for the highly variable clinical course , cognitive course and neuropathology associated with late - life depression .
depression is associated with neuroendocrine changes similar to those observed in animal models of chronic stress , including abnormalities within the hypothalamicpituitary - adrenal ( hpa ) axis .
most notably , depressed subjects have been shown to exhibit , increased hpa central drive with elevated corticotrophin - releasing hormone ( crh ) and vasopressin production by cells of the hypothalamic paraventricular nucleus ( pvn ) ; impaired negative feedback regulation due to decreased expression of corticosteroid receptors in the hypothalamus and pituitary as well as upstream cns regulatory centers ; and adrenal hypertrophy ( reviewed in ref 25 ) .
the net effect of these changes in hpa function is chronic elevation of adrenal glucocorticoid production with impaired negative feedback and abnormal homeostatic regulation .
such hpa dysregulation is clinically detectable ( via dexamethasone nonsuppression or elevated 24-hour urinary cortisol ) in about , half of patients with major depression .
hpa dysregulation may be more common among older depressed individuals , as suggested by the finding of a significant correlation between age and post - dexamethasone cortisol levels in individuals with late - life depression . 
 
adrenal glucocorticoid / cortisol regulates hpa activity through both direct , negative feedback at the pituitary and hypothalamus and indirect , mechanisms involving higher central nervous system ( cns ) centers .
the human hippocampus , for example , contains large numbers of corticosteroid receptors and plays a critical role in downregulating crh release via a multisynaptic pathway terminating in y - aminobutyric acid ( gaba)-ergic output to the paraventricular nucleus ( reviewed in ref 28 ) . at . the same time
, hpa disturbances causing prolonged hypercortisolemia may promote hippocampal atrophy and functional decline , such that hpa regulation is further compromised . '
iliis interaction may underlie the observed association between hypercortisolemic disease states such as cushing 's syndrome and depression , and both hippocampal atrophy and impairment , in the verbal and spatial memory functions subserved by the hippocampus . 
 
animal studies suggest that high - stress conditions or exogenous glucocorticoids can cause hippocampal neuronal damage and memory impairment .
these changes have been observed concurrent with stress or exogenous glucocorticoid administration , and appear to progress over a lifetime of stress or glucocorticoid excess ( see review in ref 33 ) .
human studies in older adults likewise suggest that hippocampal size and function are diminished in the setting of elevated glucocorticoids , and in proplemiaortion to duration of prior hypercortisolemia . 
  on the basis of these findings ,
many have hypothesized that glucocorticoids may promote hippocampal cell injury and death when chronically elevated , as in the setting of hypercortisolemica associated with major depression .
glucocorticoid - induced cellular damage may be mediated through effects on several biochemical substrates . postulated mechanisms include decreased glucose uptake and atp generation , elevated intracellular calcium with increased free radical production and degradative enzyme activity , and impaired uptake of glutamate from hippocampal synapses resulting in excitotoxicity .
in addition , hypercortisolemia has been linked to a decrease in neurogenesis in the dentate gyrus .
while the combination of cell death and decreased neurogenesis may theoretically contribute to hippocampal cell loss over time , recent , evidence suggests at .
most a minor role for this mechanism in hypercortisolcmic human subjects in the absence of cooccurring insults .
animal and human studies support the idea that glucocorticoids contribute to hippocampal atrophy and functional deficits predominantly through more subtle alterations , including reduced synapse number , atrophy of pyramidal cell dendrites , derangement , of glial cells , and other changes .
neuroimaging studies have generally shown reduced hippocampal volumes in late - life depression subjects relative to age - matched controls ( see meta - analysis by videbech and ravnkilde ) , although this finding is not universal . furthermore , many studies find a significant association between hippocampal atrophy and greater lifetime duration of depression , as assessed by number of depressive episodes , total days depressed , total days of untreated depression , duration since first depressive episode , or early - onset as opposed to late - onset depression .
although these findings differ somewhat , most studies support , to some degree the notion that depression - related hypercortisolemia can compromise hippocampal structure and function , especially in the context of old age and comorbid disease .
the impact of glucocorticoids on brain structures can be expected to vary not only with age and disease status , but also with individual genetic and environmentallyimparted differences influencing hippocampal volume and connectivity , hpa reactivity , and other neurobiologie factors . besides the possibility of persistent synapse or neuron loss induced directly by prolonged hypercortisolemia , glucocorticoid - related derangement of hippocampal physiology , as described above , may increase vulnerability to damage through other pathophysiologic mechanisms .
this latter effect may become clinically relevant in older persons with co - occurring neuronal insults such as accumulating ad pathology or cerebrovascular disease , promoting synapse or neuron loss through a synergistic relationship with these factors .
the loss of hippocampal volume and memory function observed in some elders with late -life depression suggests the possibility that depression may be a predispositional risk factor for ad in particular .
indeed , lower hippocampal volumes independently predict subsequent ad in groups of mci and cognitively normal elderly subjects .
likewise , deficits in verbal learning and memory , similar to those described in cuthymic patients with history of major depression , also predict ad ( eg , ref 53 ) . while a primary causal role for depression in ad pathogenesis seems unlikely , depression - associated hypercortisolemia leading to decline in hippocampal size , connectivity and cognitive function may represent one of multiple links between depression and dementia as described below ( also see figure 1 ) .
the association between depression and dementia suggested by epidemiologic data may be partially explained by one or more direct , mechanistic links between late - life depression - related processes and adspecific neuropathology ( focal and diffuse cortical neuronal loss , p - amyloid plaques , and neurofibrillary tangles ) .
emerging evidence from neuroimaging studies , postmortem neuropathology analyses , and animal models provides support , for such links . some structural magnetic resonance imaging ( mri )
studies find that hippocampal atrophy is more strongly associated with late - onset than early - onset depression , suggesting that early ad - related pathophysiology could generate both hippocampal atrophy and depressive symptoms in some elderly persons .
in addition , one of these studies failed to find a significant correlation between hippocampal volume and cortisol level among elders with depression .
furthermore , the late - life depression subjects showed persistent memory and cognitive impairment at 6-month follow - up despite effective treatment of mood symptoms and normalization of cortisol levels .
all of these data are consistent with the idea that ad pathology is a major cause of hippocampal atrophy in some ( but not all ) individuals with late - life depression , and their depressive symptoms may represent prodromal ad .
several recent , animal and human studies suggest , a possible direct pathophysiologic link between late - life depression and the neuropathologic hallmarks of ad .
postmortem studies report greater hippocampal amyloid plaque and neurofibrillary tangle pathology in ad patients with lifetime history of depression compared with those without , such history , and more severe cortical neurofibrillary tangle pathology in the brains of ad subjects who suffered from comorbid depression .
the hippocampal findings , combined with the observation of marked hippocampal neurofibrillary pathology early in the course of ad , provoke speculation that depression - associated hypercortisolemia may facilitate ad pathogenesis by rendering hippocampal neurons and glia vulnerable to toxic insults , as discussed in the previous section .
neurobiologie interaction or overlap between late - life depression and ad is further suggested by the discovery of glial changes consistent with a cns inflammatory process in both older depressed individuals ( eg , ref 60 ) and those with neurodegenerative diseases such as ad . the prolonged hypercortisolemia associated with both diseases may partially account for these findings , as glucocorticoids can induce proinflammatory changes within the cns . 
 
overall , these findings provide associational evidence for a link between late - life depression and ad , yet offer little insight into whether depression history may act as a true etiologic risk factor for ad , or , conversely , whether late - life depression arises secondary to adrclatcd neuropathologic changes . however , two recent animal studies suggest the existence of a direct mechanistic link between hypercortisolemic depression and ad pathology .
green and colleagues found dexamethasonc administration increased ( i - amyloid production in a transgenic mouse model of ad , and traced this effect to increased expression of amyloid precursor protein and the p - secrctase enzyme .
this group also found increased tau aggregation within neuronal cell bodies and dendrites of dexamethasone - treated animals .
kang and colleagues demonstrated increased hippocampal interstitial p - amyloid levels in another mouse model of ad following acute restraint or chronic isolation stress .
this finding was reproduced through direct , infusion of crh into the hippocampus , and blocked by pretreatment with crh antagonists . in conclusion ,
diverse findings from structural mri and human or animal histopathologic studies suggest a direct , relationship between late - life depression and ad - specific pathology .
reports of a cross - sectional association between later age of depression onset and hippocampal atrophy support , the notion that early ad - related pathophysiology is causing depressive symptoms in these study groups and correlate with epidemiologic reports of elevated dementia risk in subjects with depression onset . in the recent , versus distant past , ( eg , refs 19,20 ) . conversely , postmortem ad studies suggest an association between more severe plaque and tangle pathology and lifetime depression history preceding ad diagnosis , offering support for the idea that , prior depression is a true , etiologic risk factor for ad , as suggested by other epidemiologic data ( eg , ref 11 ) .
furthermore , both stress and exogenous glucocorticoids increase p - amyloid production in rodent , models of ad , consistent , with a direct .
given the tremendous heterogeneity of late - life depression , various dementia pathologies , and the other clinical or subclinical disease inevitably present in older individuals , depressive symptoms should be expected to bear an inconsistent relationship with cognitive decline , dementia in general , and ad specifically .
such symptoms in a given elderly individual may potentially represent either prodromal ad , or an independent process interacting with ad - related pathophysiology . as discussed in this manuscript
, depression may furthermore contribute to cognitive decline and ad through glucocorticoid - relatcd hippocampal toxicity and interrelationships with other types of pathology such as vascular disease .
substantial data exist showing an association between latelife depression and cerebrovascular changes . in separate reports ,
alexopoulos and krishnan pointed to the thennascent evidence that a subgroup of individuals with latelife depression showed evidence of cerebrovascular changes .
alexopoulos coined the term  vascular depression ,  positing that , a subgroup of individuals experience disruption of prefrontal systems that mediate both mood and executive functions , by either single vascular lesions or accumulation of lesions . '
ihc concept of vascular depression has subsequently been supported and expanded by a growing literature .
depression increases risk for first - ever myocardial , infarction ( mi ) and stroke , and has been shown to predict worse outcomes in a wide range of concurrent vascular disease states ( reviewed in ref 67 ) .
notably , clinical diagnosis of major depression confers significant relative risk for mi , stroke , and post - mi cardiac mortality .
moreover , major depression confers greater relative risk than diagnosis of dysthymia or indices of self -reported depressive symptoms , suggesting a possible dose - response relationship between severity of depressive illness and excess cardiovascular risk . 
 
diverse mechanisms have been proposed to explain the link between prior depression and subsequent vascular disease .
depressed individuals exhibit poor treatment compliance and other behaviors such as smoking , substance abuse , and inactivity , which may cause or worsen comorbid disease .
depression is also associated with systemic physiologic derangements which may contribute to vascular pathology . as mentioned above , hpa axis dysregulation with hypercortisolemia is common in depressed individuals .
elevated cortisol levels independently predict several features of the metabolic syndrome including abdominal obesity , low high - density lipoprotein ( hdl ) levels , and hypertriglyceridemia .
they disrupt normal endothelial function and may contribute over time to the development , of hypertension in some cases .
depressed subjects with coronary artery disease ( cad ) exhibit , autonomic dysfunction with decreased heart rate variability , a condition that likely predisposes to both cardiac arrhythmias and episodic hypoperfusion .
cad show greater baseline platelet activation than nondepressed control subjects , suggesting greater susceptibility to thromboembolic events .
finally , cross - sectional studies have linked depression to elevations in proinflammatory cytokines . while the causal relationship between such immunologic changes and depression is unknown , a similar proinflammatory cytokine shift
c - reactive - protein is directly atherogenic , and high levels of several proinflammatory cytokines have been found to predict cardiovascular events . 
  in a reciprocal fashion , many acute and chronic vascular disease states may promote depression .
mi and stroke substantially increase risk for depression during the immediate postacute period , with depressive symptoms reported in 25% to 50% of individuals ( reviewed in ref 67 ) .
one study comparing cumulative 1 -year incidence of major and minor depression immediately following stroke or mi found no difference between these groups .
this finding suggests that the loss of specific neuronal populations is less important than more global postischemic vascular or inflammatory mechanisms in the pathogenesis of poststroke depression .
accordingly , depression is more frequent and severe in vascular dementia than ad , despite widespread neuronal loss in both dementia syndromes .
studies of individuals with chronic cardiovascular diseases show that diabetes mcllitus ( sec meta - analysis in ref 89 ) and cad , each approximately double risk for depression .
not all studies of older subjects indicate a longitudinal association between vascular disease / risk and subsequent depression .
several prospective studies in elderly subjects report that clusters of cardiovascular risk factors or pre - existing cad independently predict incident depression , while at least , one large prospective study found no relationship between an index of generalized atherosclerosis and incident depression . in old age , the observed association between vascular disease and depression
may be attenuated by the fact that persons with severe or long - standing disease of either type incur substantial morbidity and mortality .
surviving individuals with significant , vascular or depressive pathology might , actually be expected to possess protective biopsychosocial factors which interrupt the positive bidirectional relationship described above .
strong supporting evidence for the notion that vascular disease contributes to late - life depression comes from structural mri studies showing a robust association between ischemic brain lesions and depression diagnosis or selfreported symptoms in older persons .
large communitybased studies have demonstrated independent cross - sectional relationships between late - life depression and small basal ganglia lesions and white matter abnormalities visualized as hyperintense regions on t2-weighted m'ri ( wmhs ) in deep or subcortical areas .
longitudinal studies suggest white matter changes may both predate and independently predict late - life depression . 
 
the ischemic etiology of wmhs is suggested by several lines of evidence , including post - mortem histopathologic studies in patients with late - life depression and in the general population , correlating wmhs with both evidence of cerebrovascular disease and systemic hypotensive , or hypoxemic disease . 
 
ischemic damage to frontostriatal brain regions may explain the executive dysfunction , psychomotor slowing and resistance to treatment common in late - life depression .
the few studies examining wmhs and cognition in late - life depression have found associations with psychomotor slowing , memory , language , and executive functioning .
the relationship between wmhs and executive function may be particularly strong in individuals with late - onset depression .
taken together , these studies suggest a relationship among late - onset depression , ischemic wmhs ( especially in the frontostriatal region ) and executive dysfunction , raising the possibility that ischemic structural changes in the brain are a common etiologic factor of both the depression and the associated cognitive dysfunction . the cognitive impairment related to this ischemic damage may be severe enough to culminate in a clinical diagnosis of dementia .
high prevalence in the population ( up to 44% of all dementia ) . in accordance with the bidirectional relationship described here , prior depression independently predicts subsequent vascular dementia ( or = 2.1 5 ) and individuals with late - life depression who develop clinical ad
indeed , prospective community - based studies report associations between baseline systemic vascular disease / risk and both higher rates of incident ad , and more rapid cognitive decline in established ad .
moreover , rapid progression of cerebrovascular disease as inferred from serial mri predicts subsequent dementia diagnosis . 
  in sum
, mounting evidence suggests factors associated with late - life depression may predispose to persistent cognitive impairment and dementia .
plausible moderators of this relationship include glucocorticoid - related hippocampal damage , an interaction between depression and ad neuropathology , and increased vascular disease , but .
the potential importance of other factors ( eg , neurotransmitter and immunologic abnormalities ) can not , be excluded . moreover , in reality there appear to be abundant , interactions between the three distinct links described here and depicted in figure 1 .
hypertension , for instance , is associ ated with diminished regional cerebral blood flow in the hippocampus and related limbic and paralimbic structures of cognitivcly normal older adults .
these findings suggest ischemic and inflammatory insults related to cerebrovascular disease may affect the same neuronal populations endangered by hypercortisolemia and ad .
it is conceivable that hippocampal insults related to vascular disease , hypercortisolemic depression or prodromal ad which are insufficient to cause significant , cellular damage or death by themselves may produce cell death through synergistic interaction with co - occurring insults . in the context of neurodegenerative disease , cerebral ischemia may contribute to cell death outside the hippocampus , as suggested by an independent association between wmh volume and cortical grey matter atrophy in ad .
notably , plasma levels of p - amyloid predict the extent , of ischemic white matter damage in mci and ad , suggesting a reciprocal interaction between cerebrovascular and ad pathophysiology .
together these examples suggest that , particular combinations of insults arising from different pathophysiologics may play a crucial role in promoting cognitive decline and progressive dementia subsequent to depression , an effect , related to extensive crosstalk between links and synergism of insults at . the cellular level .
clearly , many factors influence the impact , a particular risk or disease factor will have on expression of dementia . in the following section ,
we describe how the concepts of brain and cognitive reserve can be used to explain this multifactorial process and account for the highly variable clinical course , cognitive course and neuropathology associated with late - life depression .
brain and cognitive reserve are often used interchangeably , but in fact , have subtle but .
distinct differences in meaning . nevertheless , either may account , equally well for the relationship between depression and dementia .
tltic concept of brain reserve capacity , first proposed by satz varies across individuals such that those with greater neuronal redundancy are able to tolerate more cell loss than those with less redundancy , before manifesting clinical symptoms .
the concept of redundancy refers to the notion that , circuits contain more than the minimum number of neurons needed to perform an operation .
redundancy is evident when individuals incur substantial neuronal loss before the appearance of clinical symptoms .
thus , brain reserve capacity posits that individual differences in neural redundancy translate into differences in thresholds for vulnerability to or protection from clinical symptoms after brain damage .
the concept of cognitive reserve developed by stern ( eg , refs 121 , 122 ) is similar but rather than being based on differences in brain size or neuronal count , emphasizes differences in the efficiency or manner in which tasks are performed or information is processed . both brain reserve and cognitive reserve explain the role of risk and protective factors for cognitive impairment ( including progressive decline into dementia ) , associated with brain damage . for example , higher educational attainment , larger head size , larger brain volume , social engagement ,   physical activity , and leisure cognitive activity may result in greater redundancy and/or efficiency and therefore reserve , thereby offering protection against exhibiting clinical symptoms of dementia . similarly ,
lower levels of these protective factors may reduce neuronal or functional redundancy leading to earlier dementia symptom onset for a given level of cns damage . while certain mechanisms may alter an individual 's risk to develop ( or change the rate of development of ) adrelated pathology ( eg , p - amyloid deposition ) , other mechanisms alter the strength of association between these biological changes and the time to develop clinical disease .
we propose that depression alters an individual 's risk of cognitive dysfunction , shortening the latent period between the development , of ad neuropathology and the onset , of clinical dementia , thus increasing the incidence and prevalence of ad among older adults with depression .
we propose that the reserve threshold theory is the key explanatory mechanism behind the late - life depression / dementia association .
that is , through a number of processes ( several described here ) , depression injures neurons , thus lowering reserve such that cognitive impairment is expressed earlier and/or more frequently than it would otherwise .
as depicted in , depression is linked to vascular disease , especially in the frontostriatal area .
depression also is linked to elevated glucocorticoid production , as well as amyloid deposition and neurofibrillary formation , each of which may lead to hippocampal injury .
bach of these processes adds to the total brain injury burden , lowering reserve and vulnerability to express cognitive impairment .
these links and processes are not mutually exclusive ; many are likely synergistic , so that , they act to varying degrees across groups of individuals .
this accounts for the substantial heterogeneity of the mood disorder and the presence ( or absence ) of a cognitive disorder and its clinical course .
for example , it is possible that the diminished hippocampal volume identified in group studies could be the result , of more than one underlying process .
individuals with early - onset , recurrent , depression may have hippocampal volume loss due to the repeated stress associated with multiple depressive episodes .
many individuals with later - onset depression may be in the prodromal stage of ad , their hippocampi having already sustained substantial neuronal injury due to cumulative ad neuropathology . there may be additional pathologic processes , independent of depression , which can affect cognition .
for example , amyloid plaques and neurofibrillary tangles commonly accumulate in aging brains , and it is likely that in some cases ad pathology represents an independent , co - occurring process ( ie , depression is the first manifest symptom of ad ) . vascular disease accompanying ad pathology in the absence of depression , promotes cognitive decline and an earlier expression of dementia ( eg , refs 111 - 115,131 ) .
in fact , the growing evidence that ad and cerebrovascular pathology co - occur with high frequency has led some to conclude that the strict distinction between ad and vascular dementia is artificial .
social isolation , physical inactivity , and lack of leisure cognitive activity may result , in lowered reserve and therefore confer additional risk for exhibiting clinical symptoms of dementia .
moreover , late -life depression frequently occurs in the context of chronic medical illness , and major organ system dysfunction is frequently associated with cognitive impairment , acting to further lower reserve .
thus , each of the processes mentioned above and depicted in figure 1 , independently adds to the total brain injury burden , lowers reserve , and strengthens the association between the neurodegenerative process and the clinical change in cognitive functions .
we believe that this explanation underlies the relationship between latelife depression and dementia in general , and ad in particular ( see figure 1 ) .
this conceptualization de - emphasizes the importance of the distinctions between early and late - onset depression and the relative risk for ad vs vascular dementia in the context of late - life depression .
the cognitive outcome of any given individual who has late - life depression depends largely on the predominance or particular mix of pathophysiology in that individual .
the additive or synergistic effects of vascular disease , glucocorticoid - related brain injury , and intrinsic ad pathophysiology are refl.ect.ed in the empirical findings of heterogeneous neuropathology in late - life depression and dementia .
this framework , by focusing on the key concept , of reserve threshold , delineates testable ( and falsifiable ) links between depression and subsequent dementia . 

figure 2 depicts various pathways through which the key processes outlined in figure 1 may lead to the heterogeneous cognitive and disease outcomes reported in the literature .
ill e pathways include ( in order of figure presentation ) : ( i ) individuals who develop depression at any point in their lives , sustain minimal or no depression - related neuropathology ( eg , glucocorticoid neurotoxicity ) , and who have stable , normal cognitive functioning ; ( ii ) individuals who develop depression at any point and who experience depression - related neuropathology that results in mci that is stable ( unless they experience additional depressive episodes ) ; ( iii ) individuals who accumulate ad neuropathology over many years and who develop late - life depression ( related or unrelated to ad pathology ) , that lowers brain reserve capacity , and results in expression of mci earlier than otherwise would be the case , and given the underlying neuropathology , progress to ad ; ( iv ) individuals who accumulate ad neuropathology over many years along with co - occurring cerebrovascular disease , which damages the frontostriatal circuitry , leading to late - life depression .
the total neuropathologic burden , combined with depressed mood , lowers brain reserve capacity , leads to expression of mci ( eg , memory and executive dysfunction ) earlier than otherwise would be the case , and , given the underlying neuropathology , progresses to ad along with co - occurring cerebrovascular disease ; and ( v ) individuals who develop cerebrovascular disease ( with variable neuropathologic burden ) , that damages the frontostriatal circuitry , leading to late - life depression and mci ( eg , executive dysfunction ) , that , will follow the course of the underlying cerebrovascular disease .
based on the weight of the findings in the published literature and consistent with our model depicted in figure 1 , we suggest that pathway # 4 ( figure 2 ) leading to ad with co - occurring cerebrovascular disease is the most frequently occurring pathway among individuals with late - onset depression .
understanding the pathways through which individuals with late - life depression develop progressive dementia in general , and ad in particular , is critical as novel treatment may prevent , forestall , or slow cognitive and/or disease progression .
we propose that the reserve threshold theory is the key explanatory mechanism behind the late - life depression / dementia association .
that is , through a number of processes ( several described here ) , depression injures neurons , thus lowering reserve such that cognitive impairment is expressed earlier and/or more frequently than it would otherwise .
as depicted in , depression is linked to vascular disease , especially in the frontostriatal area .
depression also is linked to elevated glucocorticoid production , as well as amyloid deposition and neurofibrillary formation , each of which may lead to hippocampal injury .
bach of these processes adds to the total brain injury burden , lowering reserve and vulnerability to express cognitive impairment .
these links and processes are not mutually exclusive ; many are likely synergistic , so that , they act to varying degrees across groups of individuals .
this accounts for the substantial heterogeneity of the mood disorder and the presence ( or absence ) of a cognitive disorder and its clinical course .
for example , it is possible that the diminished hippocampal volume identified in group studies could be the result , of more than one underlying process .
individuals with early - onset , recurrent , depression may have hippocampal volume loss due to the repeated stress associated with multiple depressive episodes .
many individuals with later - onset depression may be in the prodromal stage of ad , their hippocampi having already sustained substantial neuronal injury due to cumulative ad neuropathology .
there may be additional pathologic processes , independent of depression , which can affect cognition .
for example , amyloid plaques and neurofibrillary tangles commonly accumulate in aging brains , and it is likely that in some cases ad pathology represents an independent , co - occurring process ( ie , depression is the first manifest symptom of ad ) .
vascular disease accompanying ad pathology in the absence of depression , promotes cognitive decline and an earlier expression of dementia ( eg , refs 111 - 115,131 ) . in fact ,
the growing evidence that ad and cerebrovascular pathology co - occur with high frequency has led some to conclude that the strict distinction between ad and vascular dementia is artificial .
social isolation , physical inactivity , and lack of leisure cognitive activity may result , in lowered reserve and therefore confer additional risk for exhibiting clinical symptoms of dementia .
moreover , late -life depression frequently occurs in the context of chronic medical illness , and major organ system dysfunction is frequently associated with cognitive impairment , acting to further lower reserve .
thus , each of the processes mentioned above and depicted in figure 1 , independently adds to the total brain injury burden , lowers reserve , and strengthens the association between the neurodegenerative process and the clinical change in cognitive functions .
we believe that this explanation underlies the relationship between latelife depression and dementia in general , and ad in particular ( see figure 1 ) .
this conceptualization de - emphasizes the importance of the distinctions between early and late - onset depression and the relative risk for ad vs vascular dementia in the context of late - life depression .
the cognitive outcome of any given individual who has late - life depression depends largely on the predominance or particular mix of pathophysiology in that individual .
the additive or synergistic effects of vascular disease , glucocorticoid - related brain injury , and intrinsic ad pathophysiology are refl.ect.ed in the empirical findings of heterogeneous neuropathology in late - life depression and dementia .
this framework , by focusing on the key concept , of reserve threshold , delineates testable ( and falsifiable ) links between depression and subsequent dementia . 

figure 2 depicts various pathways through which the key processes outlined in figure 1 may lead to the heterogeneous cognitive and disease outcomes reported in the literature .
ill e pathways include ( in order of figure presentation ) : ( i ) individuals who develop depression at any point in their lives , sustain minimal or no depression - related neuropathology ( eg , glucocorticoid neurotoxicity ) , and who have stable , normal cognitive functioning ; ( ii ) individuals who develop depression at any point and who experience depression - related neuropathology that results in mci that is stable ( unless they experience additional depressive episodes ) ; ( iii ) individuals who accumulate ad neuropathology over many years and who develop late - life depression ( related or unrelated to ad pathology ) , that lowers brain reserve capacity , and results in expression of mci earlier than otherwise would be the case , and given the underlying neuropathology , progress to ad ; ( iv ) individuals who accumulate ad neuropathology over many years along with co - occurring cerebrovascular disease , which damages the frontostriatal circuitry , leading to late - life depression .
the total neuropathologic burden , combined with depressed mood , lowers brain reserve capacity , leads to expression of mci ( eg , memory and executive dysfunction ) earlier than otherwise would be the case , and , given the underlying neuropathology , progresses to ad along with co - occurring cerebrovascular disease ; and ( v ) individuals who develop cerebrovascular disease ( with variable neuropathologic burden ) , that damages the frontostriatal circuitry , leading to late - life depression and mci ( eg , executive dysfunction ) , that , will follow the course of the underlying cerebrovascular disease .
based on the weight of the findings in the published literature and consistent with our model depicted in figure 1 , we suggest that pathway # 4 ( figure 2 ) leading to ad with co - occurring cerebrovascular disease is the most frequently occurring pathway among individuals with late - onset depression .
understanding the pathways through which individuals with late - life depression develop progressive dementia in general , and ad in particular , is critical as novel treatment may prevent , forestall , or slow cognitive and/or disease progression .
 there is a strong association between late - life depression , cognitive impairment , cerebrovascular disease , and poor cognitive outcomes , including progressive dementia , especially alzheimer 's disease . 
 while neuroimaging evidence suggests that cerebrovascular disease plays a prominent role , it seems that depression alone may also confer substantial risk for developing alzheimer 's disease . 
 the relationships between the prominent cerebrovascular changes , other structural abnormalities , specific forms of cognitive dysfunction , and increased risk for developing alzheimer 's disease among those with late - life depression have been difficult to reconcile . 
 the varied findings suggest that there are likely multiple pathways to poor cognitive outcomes . 
 we present a framework outlining multiple , non - mutually exclusive etiologic links between depression , cognitive impairment , and progressive decline , including dementia . 
 importantly , the model is both testable and falsifiable . 
 going forward , using models such as this to inform research should accelerate knowledge acquisition on the depressionldemeniia relationship thai may be useful for dementia prevention , monitoring the impact of depression treatment on clinical status and course of illness . 
Does depression increase risk of subsequent cognitive decline and dementia?
Neurobiologie substrates mediating the depression-cognitive decline-dementia links

Glucocorticoids contribute to hippocainpal atrophy and learning/episodic memory impairment


Biologic relationships between depression and Alzheimer's disease


Role of vascular disease in late-life depression, cognitive decline, and dementia

Brain and cognitive reserve; the final common pathway linking depression to dementia

Proposed multiple pathways model
