Diverse Ancestral Populations and the ADSP

Background A major goal of the ADSP is to fully reveal the genetic architecture of AD/ADRD across diverse ancestral populations with the hope that new discoveries and the therapeutic or prevention strategies they enable will benefit all ancestral groups. Method While the project’s ‘Discovery Phase’ (2012‐2017) sequenced predominantly non‐Hispanic White individuals of European ancestry (NHW‐EA) [whole‐exome sequencing: N = 10,061; whole‐genome sequencing (WGS): 197 NHW‐EA and 351 Hispanic/Latino (HL) familial individuals], the ‘Discovery‐Extension Phase’ of the project added WGS on 1,183 NHW‐EA, 1,141 HL, and 1,070 non‐Hispanic Black individuals with African ancestry (NHB‐AA). The ADSP’s current phase, the Follow‐Up Study (FUS) (2018‐2023) has targeted existing ancestrally diverse and unique cohorts with clinical AD/ADRD data. Over 40,000 individuals have been ascertained and ∼32,000 sequenced to date (ancestry distribution: 9,192 NHB‐AA; 9,952 HL; 13,531 NHW‐EA, 4,600 East Asian, 2,760 Indian, 89 Amerindian). Result Despite relatively small sample sizes, important instances of unique AD/ADRD genetic variation have been identified in HL and NHB‐AA studies, including population‐specific rare/low‐frequency variants, and evidence of the importance of ancestral background in conferring risk for genetic factors such as APOE ε4. Power studies show ∼16,100 cases and ∼16,100 controls are needed per ancestry for discovery of risk/protective variants with minor allele frequency (MAF) of 0.5% and odds ratios (OR) of 2.0 at genome‐wide significance (P = 5×10−8). Using region‐based testing ∼10,000 cases and ∼10,000 controls are needed for finding variants with MAF = 0.005% and ORs = 1.4. To this end, the next phase of the ADSP, the “ADSP‐FUS 2.0: The Diverse Population Initiative” NIH_PAR‐21‐212 aims to ensure there are enough study participants to achieve statistical power for rare variant analysis in the largest US populations, with a particular focus on HL, NHB‐AA, and Asian populations. Initiatives such as the Asian cohort for Alzheimer’s disease (ACAD), focusing on increasing recruitment of Asians in AD/ADRD studies, are also in development. Conclusion These datasets, some of which will include data for assessing social and environmental influences of AD/ADRD, will be an invaluable resource for the AD research community and will enhance ongoing efforts for the identification of shared and novel genetic risk factors for AD/ADRD across populations