The Origins of Alzheimer Disease in Individuals of African Ancestry

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ABSTRACT The goal of this proposal is to increase our understanding of the genetic etiology of Alzheimer disease (AD) risk in understudied and underserved populations. Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups, but most genetic studies for AD have been performed in non- Hispanic Whites (NHW) of European ancestry. The lack of diversity in AD genetics studies is problematic as studies in African Americans (AA), who have a higher prevalence of AD compared to NHW, have differences in risk effect sizes in known loci (e.g., APOE; ABCA7), indicating multiple unique patterns of risk. Genetic ancestry (including variability in allele frequencies and novel variants modulating known and novel risk loci), as opposed to only environmental/cultural factors, likely underlies at least part of this heterogeneity. With only a small number of the whole genome sequences in the Alzheimer’s Disease Sequencing Project coming from AA, better characterization of the genetic risk for AD requires increased sample sizes for individuals of African (AF) ancestry. To understand the totality of AD risk, we need to elucidate the pan-population genetic architecture of AD as it will enhance our understanding of the genotype to phenotype relationships for AD, and provide the bases for identifying druggable targets. Using ancestral populations, such as those from Africa, to study risk modifiers is critical to dissecting risk not only in those populations but also among all populations with AF ancestry. Our efforts will allow for improved disease prediction, prevention, diagnosis, and treatment through precision medicine, in AA, AF, and other AF admixed populations (e.g. Caribbean Hispanics). We will accomplish these goals through the following: 1.) expanding existing and recruiting new AA multiplex families for family- based discovery of AD risk loci, 2.) increasing the number of available AA brains for functional studies, 3.) determining the AF origins of genetic variation in AD, 4.) Extending genomic analysis of AD to include cardiovascular phenotypes, 5.) Evaluating the molecular and genomic function of known AD associated variants (e.g., ABCA7) as well as significant variants identified through this project.