The total neuropathologic burden, combined with depressed mood,

lowers brain reserve capacity, leads to PHA-665752 in vivo 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 Inhibitors,research,lifescience,medical 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 Inhibitors,research,lifescience,medical 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. Figure 2. Pathways Inhibitors,research,lifescience,medical linking depression to predominant cognitive outcomes. MCI, mild cognitive impairment; AD, Alzheimer’s disease; CVD, cerebrovascular disease. Understanding the pathways through Inhibitors,research,lifescience,medical which individuals with late-life depression develop progressive dementia in general, and AD in particular, is critical as novel treatment may Inhibitors,research,lifescience,medical prevent, forestall, or slow cognitive and/or disease progression. Selected abbreviations and acronyms AD Alzheimer’s disease CAD coronary

artery disease HPA hypothalamic-pituitary-adrenal MCI mild cognitive impairment MDE major depressive episode WMH hyperintense white matter regions Notes This work was supported in part by USPHS grants R01 MH072947, P50 AG05133, P50 Calpain MH071944, R37/R01 MH43832 and T32MH19986. We would f like to thank several colleagues with whom we have discussed many of the topics discussed in this manuscript. These individuals at the University of Pittsburgh include Mary Ganguli, Ari Gildengers, Robert IMebes, Robert y Sweet and Ellen Whyte, and those at other universities include Rishi Bhalla, ‘ Gwenn Smith, David Steffens, Alan Thomas, George Alexopoulos, John O’ Brien, and Yvette Sheline.