Characterizing the Genetic Risk for Alzheimer Disease in African and Admixed African-American Ancestries

ABSTRACT AD is the leading cause of dementia in the elderly in all ethnic and racial groups, but most genetic studies for AD are in non-Hispanic Whites (NHW) of European ancestry, resulting in a lack of generalizability of findings across more diverse ancestries. This is problematic, as initial studies in African Americans (AA), who have a higher prevalence of AD compared to NHW, have already revealed differences in risk effect sizes in known loci (e.g., APOE; ABCA7), indicating multiple unique patterns of risk. Therefore, the Alzheimer's Disease Sequencing Project (ADSP) aims to encompass the richest possible ethnic diversity and currently includes over 55,000 funded samples for whole genome sequencing (> 19,000 NHW, >14,000 HL ancestry, and > 8,000 African Ancestry cases and controls). Thus, in this ADSP-FUS 2.0 application, which focuses on the PAR-21-212 goal to increase diversity cohorts in the ADSP, we are proposing generating whole genome sequencing, AD plasma biomarkers and cardiovascular disease biomarkers in an additional ~9,000 individuals of African ancestry (~5,000 African, ~4,000 African American) ascertained as part of the ongoing “Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP” (READD-ADSP U19 AG074865). Further, we will acquire MRI data from 200 Nigerian participants. We will perform longitudinal follow-up visits on mild cognitively impaired and cognitively unimpaired individuals after ~4 years to further evaluate clinical and biomarker level changes longitudinally associated with status conversion. This increase in sample size enhances our ability in this proposal to detect and analyze rare genetic variants contributing to the risk and protection of AD in individuals of African ancestry and understand underlying risk correlated with cardiovascular disease risk and AD plasma biomarkers. Taken together, this project will leverage the resources collected under the READD-ADSP to begin to unravel the AD risk for individuals of African ancestry while providing an invaluable resource for the AD research community at-large.