PROJECT SUMMARY/ABSTRACT Older adults (85 and older), the fastest growing segment of the population, are at very high risk of dementia. Some minority groups, such as African Americans, are at higher risk of dementia compared to Whites. However, little is known about the risk factors that might be involved in their high susceptibility to dementia. Depression, one of the most frequent and debilitating psychiatric conditions in older adults, has been consistently associated with cognitive decline in Whites. Although depression in African Americans is more chronic and untreated, compared with Whites, only a handful of studies have investigated the relationship between depression and cognitive decline in this racial/ethnic group. To our knowledge, this relationship has not been examined in oldest-old (≥80) African Americans. Chronic inflammation is also associated with both depression and cognitive decline. Because depression and inflammation are treatable conditions, better understanding of their role in cognition may lead to reduced dementia risk in this very high risk, growing, and understudied population. This study will examine the inter-relationships of depression and inflammation with change in cognition over time in 192 non-demented community-dwelling oldest-old African Americans. We will examine the following three Specific Aims: Aim 1: To examine the association between depression measures and cognitive decline over time. We hypothesize that: a) Depression is related to a greater rate of cognitive decline. b) Based on compelling preliminary data, apathy is the depression measure hypothesized to be most strongly related to a greater rate of cognitive decline. Aim 2: To examine the association between baseline inflammation and cognitive decline. We hypothesize that higher levels of inflammatory cytokines at baseline are related to a greater rate of cognitive decline. Aim 3: To examine the inter-relationships of depression, inflammation and cognitive decline. a) We hypothesize that inflammation serves as a moderator in the relationship between depression and cognitive decline in oldest-old African Americans. If significant results are generated, they can lead to increasing public awareness about the importance of timely depression diagnosis and development of mechanism-based effective and well-targeted treatment for the oldest-old community of African Americans, who are at particularly high-risk for dementia.