ABSTRACT The prevention of Alzheimer’s dementia and cognitive decline in our aging population is a major public health priority. Older Black adults are disproportionately burdened by Alzheimer’s dementia compared to other racial and ethnic groups. Reasons for the increased burden are unknown and traditional factors, including vascular, socioeconomic, and healthcare utilization, do not fully account for the disparity. Two important research directions are needed to fill the current gap in knowledge regarding Alzheimer’s dementia and cognitive decline for older Black adults, one of the most vulnerable segments of our older population. First, studies which collect ante- and postmortem biospecimens from well-characterized older Blacks with sufficient cognitive follow-up are needed to advance our understanding of the pathologic substrates underlying dementia. Second, the investigation of novel factors uniquely tied to the lived experience of Blacks is essential to identify new targets for intervention, policy, and therapeutics. The devastating effects of COVID-19 on Blacks coupled with the increased awareness of interrelated systems of structural racism, have shone a spotlight on the importance of race-specific stress as an understudied risk factor. It is well-documented that general stress has a negative impact on the psychological and physical health of older Blacks, but few studies have examined the impact of race-specific stress on brain health. The overall goal of the proposed continuation of the Minority Aging Research Study (MARS) is to measure individual- and environmental-level race-specific stressors and identify the biologic mechanisms linking them to late-life cognitive decline, incident AD, and other poor health outcomes in aging. Leveraging harmonized clinical and neuropathological data from two other ongoing studies at Rush, we will increase our sample size of Blacks to more than 1200 persons to address new Specific Aims. We propose to continue collecting clinical and postmortem data on MARS participants, test the association of novel race-specific stressors with cognitive decline and AD, and quantify inflammation and vascular pathology in blood and brain, respectively, to test two potential biologic pathways linking stress to brain health in older Blacks. Aim 1 will examine the relationship between individual and environmental race-specific stressors with incident AD and cognitive decline. Aim 2 will leverage Medicare claims data to examine the relationship of these stressors with other chronic vascular-related health conditions. Aim 3 will employ proteomics to measure inflammatory proteins in plasma and examine their association with stressors and AD. Finally, Aim 4 will examine the association of stressors with vascular neuropathologies and microglia measured in the brain, and test whether these pathologies account for the association of race-specific stress with AD. The proposed study provides a unique opportunity to answer critical...