Project Summary African Americans (AAs) are two to three times more likely to have Alzheimer's disease (AD) and related- dementias than Non-Hispanic Whites (NHWs). AAs comprise 20 percent of AD sufferers to-date, while only making up 13 percent of the US population. AAs with AD also have high incidences of vascular risk factors including hypertension, hypercholesterolemia, and diabetes. The prevalence of hypertension for AAs in the US is 47% and occurs at early adult ages. Hypertension is a major risk factor for AD and related-dementias especially when present in mid-life. Because of this inherent relationship between hypertension and AD especially in AAs, the question must be asked ?What are the underlying biochemical pathways that link hypertension and AD in AAs?? This proposal directly responds to the goal of PA-15-349 by ?examining mediators of disparities in Alzheimer's disease, using diverse cohorts of subjects?. Specially, we propose to examine biochemical markers of hypertension, which is a mediator of racial disparities and increases AD risk in AAs. Based on preliminary proteomics data in obtained our laboratory, our working hypothesis is that shared biological responses in immune response and lipid metabolism pathways contribute to both high prevalence of hypertension and AD in AAs. Alterations in both immune response and lipid metabolism pathways are well recognized as contributors to AD, and also play roles in hypertension. We have assembled a stellar team of interdisciplinary experts in the areas of Alzheimer's and vascular diseases and will study biospecimens from diverse cohorts of African American participants that focus on hypertension, AD, or AD risk: BioVU, Rush ADC Clinical Core/MARS/ROSMAP, Vanderbilt MAP, and Offspring. We will use advanced proteomic approaches to study plasma and postmortem brain tissue from participants in these cohorts and complete two primary aims. Aim 1. Establishing the molecular signature of hypertension in AAs and Aim 2. Establishing the molecular signature of AD in AAs. Successfully identifying proteomics signatures will lead to a better understanding of AD pathogenesis and the molecular architecture of hypertension, a major vascular risk factor for AD in AAs. This proposal is highly innovative, ambitious, extremely urgent, and will provide critical information about disease biology in a population that has been underrepresented throughout the current literature.