Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP)

ABSTRACT The goal of this proposal is to create a resource for studying the genetic etiology of Alzheimer disease (AD) 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. The majority of genetic studies for AD have been

performed in non-Hispanic Whites (NHW) of European ancestry. While recent studies have begun expanding into other populations, these populations are still under-represented in AD genomics, particularly for cases. A major barrier to participation has been a lack of community-sensitive recruitment approaches that overcome

historical mistrust of research participation. Genetic studies across populations, in particular African Americans (AA), have shown differences in both risk effect size (e.g., APOE) and risk loci (e.g., ABCA7). Further evaluation suggests that genetic ancestry (independently or interacting with environmental/cultural factors) likely underlies

at least part of this heterogeneity. However, these efforts have been significantly underpowered to fully characterize genetic risk factors of AD in US individuals of African (Af) and Hispanic/Latinx (HL) Ancestry. Full characterization requires inclusion of additional populations of African genetic ancestry. To address this, we

propose here the creation of a large genomics resource for the study of AD in Af and HL Ancestry. This effort will recruit, assess, sample, and genotype 13,000 individuals of diverse race/ethnicity, including 5,000 from Africa, 4,000 AA, and 4,000 HL. Clinical, phenotypic, and genetic data will be harmonized to other existing AD genomics

efforts (such as the Alzheimer Disease Genetics Consortium and the Alzheimer Disease Sequencing Project; ADSP). Furthermore, we include two hypothesis-based Projects to demonstrate the utility and value of this resource and begin understanding the genetic etiology of AA and HL populations. Broadly speaking, Project 1

tests genomic and phenotypic hypotheses within cohorts, while Project 2 tests ancestry-based hypotheses across populations. These projects make extensive use of the data generated as part of this resource, as well as taking advantage of existing data from the ADSP Follow-up Study (ADSP-FUS). Through the ADSP-FUS and

related studies we will access existing genomic case and control data from 13,100 African ancestry individuals, 15,900 HL individuals, and an additional 51,000 non-Hispanic whites. These studies, together with the focused resource being generated here, represent a powerful approach to understanding the totality of AD risk, with new

loci and the mapping modifier loci that alter effect sizes. These studies will help illuminate the pan-population genetic architecture of AD and provide the basis for identifying druggable targets. Using ancestral populations, such those from Africa, to study risk modifiers is central to dissecting risk not only in those populations but also

among AA and Caribbean Hispanics (CHI), both with significant admixture. This resource will enable improved disease prediction, prevention, diagnosis, and treatment through precision medicine, not only in in AA, Africans, and other African admixed populations, but all individuals with AD.