ABSTRACT. Hispanics/Latinos (“HL”, genetically admixed of European [EU], African [AF] and Native American [NA] ancestry) show higher prevalence and incidence of Alzheimer's disease (AD) compared to non-Hispanic Whites. Numbers of HL and other admixed groups in the US remain insufficient to provide statistical significance in identifying risky and protective genetic variants, especially if rare. To this end, we introduce our study: Global LAtinos Sequencing Study for AD (“GLASS-AD”). We will contribute to generate necessary numbers for rare variants (RV) discovery in HL phenotyped for AD. Our proposal responds to the Alzheimer’s Disease Sequencing Project (ADSP) Follow-Up Study 2.0 (PAR 21-212) FOA, which urges to ensure appropriate representation of diverse populations in genetic studies of AD by leveraging existing cohorts and/or planning new recruitment to obtain sufficient sample sizes and power. In this study we will generate new whole genome sequencing data (WGS) in 6,000 HL: N=4,000 as part of our recently funded study “Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP” (READD-ADSP AG074865) and N=2,000 newly recruited individuals from Peru and Bolivia, leveraging the established local networks of two ongoing recruitment studies (R56AG069118; R01AG070864). GLASS-AD, together with other independent HL cohorts, will ultimately provide us with a large set of individuals with wide range of ancestry proportion, particularly for NA ancestry (8% in Caribbean Hispanics, ~50% in Mexicans, 70% in Peruvian mestizos, >90% in Peruvian and Bolivian indigenous groups). Importantly, we will increase representation of samples with substantial NA ancestry, which are needed because currently underrepresented compared to samples with predominant African ancestry (e.g., African Americans, Caribbean Hispanics). In addition to new recruitment and WGS data, we will I) generate AD-biomarkers (Aβ42, tau proteins etc.) in the 2,000 Peruvians/Bolivians and II) conduct a follow-up visit in a subset of healthy controls and mild cognitive impairment recruited by GLASS-AD in Peru/Bolivia (N=1,000) and READD-ADSP (N=1,000) at ~3 years from initial visit to assess clinical progress. We will also elucidate the association between AD and collected risk factors (cognition, health conditions and behaviors, blood biomarkers) cross-sectionally and longitudinally and perform traditional and innovative RV analyses. GLASS-AD is fully integrated with major ADSP consortia: samples will be deposited at the National Cell Repository for Alzheimer's Disease (NCRAD), genetic data will be quality controlled and harmonized following Genome Center for Alzheimer's Disease (GCAD) guidelines, deposited and shared by NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). GLASS data will be shared with the ADSP Follow-Up Study (“FUS” AG057659, AG062943 and AG076482), which is sequencing several independent HL cohorts and will ensure the largest collection of HL with WGS data. Importantly, our analyses methods will be harmonized with ongoing ADSP analyses consortia (e.g. Collaborative for Alzheimer’s Disease Research [CADRE]).

NARRATIVE. Hispanics/Latinos show higher prevalence and incidence of AD compared to non-Hispanic Whites but their representation in genetic studies remains insufficient to provide statistical significance, especially for rare variant discovery. In this study we will generate whole genome sequencing data (WGS) on N=2,000 newly-recruited Peruvian and Bolivian individuals (with extensive clinical, cognitive assessment and AD-biomarkers panel) and N=4,000 HL from US (part of our recently funded study “Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP” U19AG074865). These new cohorts will increase representation of HL in AD genetic studies, particularly for samples with substantial Native American ancestry that are currently underrepresented compared to other admixed samples with predominant African ancestry (e.g., African Americans, Caribbean Hispanics).