Genetic architecture of Alzheimer’s disease in a West African Cohort: Insights from the READD ‐ ADSP

Background The “Recruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD‐ADSP)” is developing a resource to expand ancestral diversity in Alzheimer disease (AD) studies to dissect the genetic architecture of AD across different populations. In addition to US sites, READD‐ADSP includes four US sites and nine countries in sub‐Saharan Africa through the Africa Dementia Consortium (AfDC). The overall goal of READD‐ADSP is to identify genetically driven targets in diverse groups including African Americans and Hispanic/Latinos in US, and Africans. In this preliminary analysis we investigated the ancestral genetic differences and the impact of known AD risk factors within West African cohorts. Method Genome‐wide genotyping was performed on 91 AD cases and 97 cognitive unimpaired controls from Nigeria and Ghana. APOE alleles and ABCA7 deletion (rs142076058) were sequenced using Sanger. We calculated global ancestry (principal components) using the PC‐AiR approach that is robust to known and cryptic relatedness. We investigated known AD loci from non‐Hispanic White (NHW) and AA genome wide association studies. For association analysis, we employed a mixed‐model regression approach (SAIGE) where we controlled for age, gender, population substructure (first three principal components), and relatedness. Result Principal component analysis identified a distinction between the Ghana and Nigerian cohorts along the first principal component (PC1). Among the genetic loci examined, several showed nominal significance. Notably, the most prominent marker was found in SORL1 (rs17125523; p = 2 × 10‐3). Additionally, we discovered an exonic nonsynonymous marker in the BIN1 gene (rs112318500), which is specific to African ancestry and showed a protective effect. APOE e4 allele showed a significant association with AD risk (OR = 2.5; CI:1.5‐4.2; pv = 0.001), while the e2 indicated a protective trend but did not reach statistical significance. No statistical difference in the frequency of ABCA7 deletion was observed between AD and CU individuals. Conclusion Our findings highlight the presence of genetic variations between West African populations that warrant further investigation, potentially offering new insights into the genetic underpinnings of AD. Data collection is ongoing across the AfDC and updated data will be presented.