Several recent, selleck products 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,56 and more severe cortical neurofibrillary tangle pathology in the brains of AD subjects who suffered from comorbid depression.57 The hippocampal findings, combined with the observation of

marked hippocampal neurofibrillary pathology early in the course of AD,58,59 provoke speculation that depression-associated Inhibitors,research,lifescience,medical hypercortisolemia may facilitate AD pathogenesis by rendering hippocampal neurons and glia vulnerable to toxic insults, Inhibitors,research,lifescience,medical 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.61 The prolonged hypercortisolemia Inhibitors,research,lifescience,medical associated with both diseases may partially account for these findings, as glucocorticoids can induce proinflammatory changes within the CNS.62 Overall, these findings provide associational evidence for a link between late-life depression and AD, yet offer little insight into whether depression history Inhibitors,research,lifescience,medical 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 colleagues63 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 Inhibitors,research,lifescience,medical enzyme. This group also found increased tau aggregation within neuronal cell bodies and dendrites of dexamethasone-treated animals. Kang and colleagues64 demonstrated increased hippocampal interstitial P-amyloid levels in another mouse model why 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 atrophy54,55 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.