Genetics of Alzheimer’s Disease in the African American Population

Abstract

Black/African American (AA) individuals have a higher risk of Alzheimer’s disease (AD) than White non-Hispanic persons of European ancestry (EUR) for reasons that may include economic disparities, cardiovascular health, quality of education, and biases in the methods used to diagnose AD. AD is also heritable, and some of the differences in risk may be due to genetics. Many AD-associated variants have been identified by candidate gene studies, genome-wide association studies (GWAS), and genome-sequencing studies. However, most of these studies have been performed using EUR cohorts. In this paper, we review the genetics of AD and AD-related traits in AA individuals. Importantly, studies of genetic risk factors in AA cohorts can elucidate the molecular mechanisms underlying AD risk in AA and other populations. In fact, such studies are essential to enable reliable precision medicine approaches in persons with considerable African ancestry. Furthermore, genetic studies of AA cohorts allow exploration of the ways the impact of genes can vary by ancestry, culture, and economic and environmental disparities. They have yielded important gains in our knowledge of AD genetics, and increasing AA individual representation within genetic studies should remain a priority for inclusive genetic study design.

Transferability of a European-derived Alzheimer’s Disease Genetic Risk Score across Multi-Ancestry Populations.

“…All the GRS distributions in cases and controls are shown in Supplementary Figure 4-6. Of note, the association of APOE with AD risk was heterogonous between these different populations as previously described in several prior studies (Figure 4 and Supplementary Table 5) 14,15 . As expected, the AD risk associated with GRS ALZ or GRS ALZadjAPOE was highly similar between European and other European-ancestry populations (USA).…”

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer’s Disease and Older Controls in Multi-Ethnic Populations

“…We must emphasize that multi-omics studies alone are unlikely to be sufficient to discover all causes of ADRD or explain the disparities in risk observed for AA and LA participants [4,6,90]. Rather, this requires a full understanding of the role of the exposome, including sex, race, ethnicity, lifetime health measures, co-morbidities, and additional structural and social determinants of health (SSDoH) [54,91–96].…”

“…The prevalence of AD in AA is about twice that of non-Hispanic whites (NHW), while LA face a 1.5 times higher risk. Despite these alarming disparities in risk, AA and LA populations remain significantly underrepresented in AD research, including clinical trials, biomarker and genomic studies [3][4][5][6].…”

“…The largest AD GWAS to date comprises over 1 million individuals [7] and, collectively with other studies, identified 75 genetic risk loci [8] in non-Hispanic white (NHW) populations of European ancestry. In contrast, GWAS in AA and LA populations have suffered from limited power [3,4,[9][10][11][12][13], with sample sizes less than one to two orders of magnitude of those for NHW populations. Despite limited sample sizes, GWAS and sequencing studies in AA populations identified novel AD risk loci [13][14][15] and demonstrated allelic heterogeneity for AD risk genes initially discovered in NHW populations, including TREM2 [14,16] and ABCA7 [9,14,17].…”

The African American Dementia and Aging Project (AADAPt): An Oregon-based Longitudinal Study

“…Apolipoprotein E was assessed in 121 of the AADAPt participants. Of these, 67.5% of the sample had no 𝜖4 alleles, 30% of the sample had one 𝜖4 allele, and 2.6% of the sample had two 𝜖4 alleles (Farrer et al, 1997;Logue et al, 2023).…”