HABS-HD OVERALL ABSTRACT The 2018 AT(N) framework provided the field with the first biological conceptualization of Alzheimer’s disease (AD) for the explicit purpose of advancing clinical trials. In fact, the first amyloid-lowering drug (aducanumab) has now received FDA clearance. However, nearly all data supporting the framework itself, as well as clinical trials, comes from research among non-Hispanic white (NHW) individuals. By 2060 the U.S. will become largely “non-white” with 15% of the population being African American (AA) and 27.5% being Hispanic (65% of which are Mexican American [MA]). Therefore, there is an urgent need to understand the relevance of the AT(N) framework, and associated biomarker-based therapeutics, for 43% of the U.S. population. AAs currently have the highest burden of AD and AD related dementias (ADRD) while Hispanics will experience the greatest increase in AD/ADRDs by 2060. Moreover, Milestone 1 of the NIA AD+ADRD Implementation Milestones explicitly call for examination of “early mechanistic pathways of multiple etiologies” (1.I), sociocultural (1.I) and exposome (1.B) factors among community-based cohorts that include cutting edge imaging, fluid, genetic and other biomarkers in diverse populations to understand health disparities in AD. The Health & Aging Brain Study – Health Disparities (HABS-HD) is the first large-scale, community-based project to simultaneously study each of the AT(N) defined biomarkers, in alignment with the NIA Health Disparities Research Framework, across the three most prevalent racial/ethnic groups in the U.S., AA, MA, and NHW. The Aims of the HABS-HD U19 are as follows: Aim 1: To collect imaging, clinical, biological and genetic data which will result in the largest longitudinal cohort of diverse populations that examines AT(N) biomarkers across adulthood. Aim 2: To collect life-course exposome (via the Area Deprivation Index), as well as sociocultural data and examine how these factors affect the timing, sequence and trajectories of AT(N) biomarkers among diverse populations. Aim 3: To disseminate HABS-HD data and samples to the global scientific community. HABS-HD data will be made available via LONI while biofluid samples will be made available through the HABS-HD Omics Core. Genomics data will be made available per NIH/NIA guidelines. The long-term goal of HABS-HD is to establish population- specific informed precision medicine for novel treatment and prevention strategies for AD. To advance this goal, we will conduct the following Projects: Project 1) Examine the timing, sequence and trajectories of AT(N) biomarkers across diverse populations; Project 2) Examine the impact of vascular, metabolic and inflammatory factors on the timing, sequence and trajectories of AT(N) biomarkers across diverse populations; and Project 3) Examine the impact of the exposome (via neighborhood disadvantage) and sociocultural factors on the timing, sequence and trajectories of AT(N) biomarkers across diverse populations.

HABS-HD OVERALL SUMMARY By 2060 the U.S. will become largely “non-white” with 15% of the population being African American and 27.5% being Hispanic (65% of which are Mexican American). African Americans currently have the highest burden of Alzheimer’s Disease (AD) while Hispanics will experience the greatest increase in AD by 2060; however, our understanding of the factors that contribute to these health disparities remains very limited. HABS-HD is conducting the first-ever comprehensive simultaneous study of the biological, medical, environmental and social factors, all within a health disparities framework, to understand the factors that contribute to AD risk over adulthood across the three largest racial/ethnic groups in the U.S.