APOE missense variant R145C is associated with increased Alzheimer's disease risk in African ancestry individuals with the APOE ϵ3/ϵ4 genotype

BACKGROUNDThe APOE gene has two common missense variants that greatly impact the risk of late-onset Alzheimers disease (AD). Here we examined the risk of a third APOE missense variant, R145C, that is rare in European-Americans but present in 4% of African-Americans and always in phase with APOE {varepsilon}3. METHODSIn this study, we included 11,790 individuals of African and Admixed-African ancestry (4,089 cases and 7,701 controls). The discovery sample was composed of next generation sequencing data (2,888 cases and 4,957 controls), and the replication was composed of microarray data imputed on the TOPMed reference panel (1,201 cases and 2,744 contols). To assess the effect of R145C independently of the{varepsilon} 2 and{varepsilon} 4 alleles, we performed stratified analyses in{varepsilon} 2/{varepsilon}3, {varepsilon}3/{varepsilon}3, and{varepsilon} 3/{varepsilon}4 subjects. In primary analyses, the AD risk associated with R145C was estimated using a linear mixed model regression on case-control diagnosis. In secondary analyses, we estimated the influence of R145C on age-at-onset using linear-mixed-model regression, and risk of conversion to AD using competing risk regression. RESULTSIn{varepsilon} 3/{varepsilon}4-stratified meta-analyses, R145C carriers had an almost three-fold increased risk compared to non-carriers (odds ratio, 2.75; 95% confidence interval [CI], 1.84 to 4.11; P = 8.3x10-7) and had a reported AD age-at-onset almost 6 years younger ({beta}, -5.72; 95% CI, 7.87 to -3.56; P = 2.0x10-7). Competing risk regression showed that the cumulative incidence of AD grows faster with age in R145C carriers compared to non-carriers (hazard ratio, 2.42, 95% CI, 1.81 to 3.25; P = 3.7x10-9). CONCLUSIONThe R145C variant is a potent risk factor for AD among African ancestry individuals with the{varepsilon} 3/{varepsilon}4 genotype. Our findings should enhance AD risk prediction in African ancestry individuals and help elucidate the mechanisms linking the apoE protein to AD pathogenesis. The findings also add to the growing body of evidence demonstrating the importance of including ancestrally-diverse populations in genetic studies.