Conversely, postmortem AD studies suggest an association between more severe plaque and tangle pathology and lifetime depression history preceding AD diagnosis,56 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. biologic role of human depression in AD pathogenesis. ‘Ihesc disparate hypothesized relationships arc not exclusive of one another. Given the tremendous Inhibitors,research,lifescience,medical 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 Inhibitors,research,lifescience,medical in a given GSK126 elderly individual may potentially represent either prodromal AD, or an independent process interacting with AD-related pathophysiology. As discussed in this manuscript, Inhibitors,research,lifescience,medical 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. Role of vascular disease in late-life depression, cognitive decline, and dementia Substantial data exist showing an association between latelife

depression and cerebrovascular changes. In separate reports, Alexopoulos65 and Krishnan66 Inhibitors,research,lifescience,medical 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 Inhibitors,research,lifescience,medical 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 and vascular disease display much an interesting bidirectional relationship. 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,68 stroke,69 and post-MI cardiac mortality.70,71 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.67 Diverse mechanisms have been proposed to explain the link between prior depression and subsequent vascular disease.