PROJECT SUMMARY Ten percent of adults over 65 suffer from Alzheimer’s disease (AD), and this number is projected to double by 2050. Thus, understanding and reducing AD risk factors is of critical importance, particularly in the absence of an effective treatment. Epidemiological evidence suggests that depression throughout the lifespan contributes to AD risk, although depression in late life also may be part of the dementia prodrome. Clinicopathological studies have provided robust support for the importance of amyloid-beta (Aβ) deposition in the pathogenesis of AD, and evidence supports an association between Aβ and depression. However, most studies that have examined the relationship between MDD and Aβ have included individuals with mild cognitive impairment (MCI), complicating our understanding of the relationship between MDD and Aβ. Levels of soluble Aβ are influenced by the presence of deposited Aβ and our preliminary data suggests that they also are associated with the severity of depression symptoms. Using a number of depression rating scales, our data also show that changes in residual symptoms in people with geriatric depression who do not have significant cognitive decline are correlated with Aβ changes in both cerebrospinal fluid (CSF) and plasma. However, the direction and nature of the causal relationship between MDD symptoms and Aβ peptide levels are unknown. Given the relationship between Aβ and AD risk, elucidating the relationship between amyloid dynamics and depression symptoms would allow us to better understand the mechanism for heightened AD risk imparted by MDD. Since the direction of causation between depression and Aβ is unknown, the only way to understand cause and associated risk is to treat the depressive symptoms and examine the effects on AD biomarkers in relation to antidepressant treatment response. We propose to study 90 cognitively-normal older adults with current episode of MDD and no evidence of MCI in an 8-week, parallel-group, double-blind, placebo-controlled randomized study using the SSRI antidepressant escitalopram. The hypothesis is that a reduction in depressive symptoms and treatment response will be associated with an increase in the levels of CSF Aβ40 and Aβ42, as well as a reduction in vascular dysfunction markers, including platelet activation. The results of the proposed clinical trial will build on our understanding of the relationship between MDD symptoms and the biological variables implicated in AD, and thus provide a significant target for reducing AD risk. If successful, this approach might lead to more effective strategies for reducing the risk of developing AD through more effective treatment of late-life MDD.