The Alzheimer’s Disease Sequencing Project – Follow Up Study (ADSP‐FUS): APOE genotype status and demographic characteristics across datasets

Abstract

AbstractBackgroundThe ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP beyond non‐Hispanic Whites of European Ancestry (NHW‐EA) populations. Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to whole genome sequence (WGS) existing ethnically diverse and unique cohorts. The upcoming phase ADSP‐ FUS 2.0: The Diverse Population Initiative, focuses on inclusion of Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA), and Asian populations.MethodsADSP‐FUS cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications are assigned based on standard criteria from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, genome‐wide array and APOE genotyping is acquired or performed for all ADSP‐FUS samples.ResultsThe ADSP‐FUS currently consists of 38 cohorts comprised of ∼40,000 individuals, with plan to sequence >100,000 individuals from diverse ancestries. Genotyping, sequencing, and clinical adjudication has been performed on 23,428 participants (cases N = 6,961, median age = 73; controls N = 13,007, median age = 72; ADRD N = 3,460, median age = 77. More participants are female (62.3%) than male and are evenly distributed across cases (61.0%), controls (63.1%), and ADRD (61.8%). As expected, the most prevalent APOE genotype is APOE 3/3 (% by cases/controls for 2/2 = 0.2,0.4; 2/3 = 4.3, 8.2; 2/4 = 2.2, 1.8; 3/3 = 43.8, 64.4; 3/4 = 39.5, 23.0; 4/4 = 10.1, 2.2). These proportions vary greatly between ethnicities, with the highest for APOE 4/4 observed in Asian participants (8.8%) and the lowest in Hispanic participants (2.5%), for example. Mean Braak stage for AD cases is higher (5.1+1.2) than controls (2.6+1.3) and ADRD participants (3.5+1.6).ConclusionThe results provide an overview of features of ADSP‐FUS cohorts. As the ADSP‐FUS expands in size and diversity, this genomic resource, available via NIAGADS, will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP‐FUS will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective.