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.

Keywords: AKAP9; APOE; African American; Alzheimer disease; candidate gene studies; genetics; genome-wide association studies; genomic/exomic sequencing; polygenic risk score.

Figure 1

Discovery cohort sample sizes for AD cases in the largest European ancestry and African American AD GWAS by year. The number of cases in the AD case-control cohort GWAS is indicated in blue, and the number of proxy cases (i.e., AD status in the parents) is indicated in green. Although the sample size is much smaller for African American compared to European ancestry GWAS, the size of African American GWAS surged after the publication of a recent study [69].

Figure 2

Linkage disequilibrium (LD) among TREM2 variants associated with AD risk in African American cohorts and the R47H variant associated with AD in European ancestry cohorts [35,69,75]. LD presented for both African-ancestry (AFR) and European ancestry (EUR) populations from the 1000 Genomes reference panel. NA indicates that LD was not estimated because one or both variants were too rare or absent in that population. Values on the diagonals which are necessarily 1.0 are shaded in black.

Figure 3

Linkage disequilibrium (LD) of ABCA7 variants associated with AD risk in African American cohorts and the peak AD SNP (rs12151021) associated with AD in European ancestry cohorts [33,67,69,74,76,77]. LD presented for both African-ancestry (AFR) and European ancestry (EUR) populations from the 1000 Genomes reference panel. NA indicates that LD was not estimated because one or both of the variants were too rare or absent in that population. Values on the diagonals which are necessarily 1.0 are shaded in black.