HABS-HD - Project 2

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HABS-HD PROJECT 2 ABSTRACT Milestone 1.I of the NIA Alzheimer’s Disease (AD) + Alzheimer’s Disease-Related Dementias (ADRD) Implementation Milestones explicitly calls for testing “early mechanistic pathways of multiple etiologies that may account for AD/ADRD health disparities”. Significant health disparities exist in the U.S. related to AD with African Americans (AAs) currently suffering the highest burden of AD/ADRD while Hispanics (65% of which are Mexican American [MA]) will experience the greatest increase in disease burden by 20602. MAs also develop cognitive loss at significantly younger ages. Despite these factors, AAs and MAs remain underrepresented in AD research. In fact, 83% of participants in the National Institute of Aging (NIA) Alzheimer’s Disease Centers (ADC) and 90% of the Alzheimer’s Disease Neuroimaging Initiative (ADNI)7 are non-Hispanic white (NHW). Additionally, the 2018 AT(N) framework, which represents the mechanistic pathways (amyloid [A], tau [T], neurodegeneration [N]) dominating the current clinical trial landscape, was built almost entirely on data from NHWs who are screened out for most medical comorbidities. Nevertheless, emerging data demonstrates racial/ethnic differences in AT(N) defined biomarkers and, therefore, the applicability of the framework to AAs and MAs remains unknown, which is the focus of Project 1. AAs and MAs also suffer a heavier burden of vascular, metabolic and inflammatory (VMI) factors, each of which have well-established links to AD, including AT(N) biomarkers. Therefore, VMI factors may be targetable “early mechanistic pathways” that contribute to AD health disparities that cannot be understood without inclusion of populations known to experience the highest burden from them. Project 2 will evaluate the impact of VMI factors on the prevalence, sequence and trajectories of AT(N) defined biomarkers and cognitive loss among the three largest racial/ethnic groups in the U.S. Aim 1: Examine the impact of VMI factors on the presence and progression of cognitive loss among African Americans, Mexican Americans, and non-Hispanic whites. Aim 2: Examine the impact of VMI factors on the presence, sequence and trajectories of AT(N) defined biomarkers among African Americans, Mexican Americans, and non-Hispanic whites. Aim 3: Determine if VMI factors explain the racial/ethnic specific impact of APOEε4 genotype - and other VMI-related AD genetic markers - on AT(N) defined biomarkers. Aim 4 (Project – Project Interactions): Collaborate with Projects 1 and 3 to develop a comprehensive understanding of AT(N) defined biomarkers across diverse populations. Exploratory Aim 5: Compare VMI data and VMI – AT(N) interaction data with that from other large-scale initiatives such as ADNI, LEADS, ADCs, WHICAP, SOL/INCA, ABC-DS, MarkVCID, INDEED, and others.