THE RELEVANCE OF APOE4 TO ALZHEIMER’S DISEASE IN THE PRESENCE OF LOCAL ANCESTRY DIFFERENCES

Abstract

Variants at the apolipoprotein E gene (APOE) are major risk factors for Alzheimer's disease (AD). Strong associations between E4 and AD risk and E2 and AD protection have been confirmed worldwide, but there is variability in the effect size across populations. The Puerto Rican (PR) population is highly admixed and the individual ancestries are highly variable. We have collected a set of PR AD and control samples (who represents the second largest Hispanic/Latino population in the continental US) to assess the relevance of ApoE4 and other genetic risk factors to AD in the presence of admixture and local ancestry variability. To date we have ascertained 170 unrelated individuals including 108 AD cases and 62 cognitively intact controls with additional ascertainment ongoing. The percentage of females is 71.3% and 54.8% in cases and controls, respectively, with mean age at exam is 77.7 + 8.41and 71.6 +7.3 for cases and controls, respectively. ApoE4 genotyping and genome-wide genotyping (with Illumina MEGA and GSA arrays) was performed. Global ancestry was assessed using Eigenstrat. To assess local ancestry phasing was performed using SHAPEIT (with 1kGP reference) followed by RFMix (using HGDP reference panels). Association between affection status and ApoE4 genotype was analyzed using logistic regression, adjusting for age at exam, gender, PC1 and PC2. The E4 allele frequency in the PR cases and controls was 29.2% and 14.5% respectively (p-value=0.0145, OR=2.36). Global ancestry was only nominally associated with disease, when adjusting for sex (p=0.048; p=0.17 without sex adjustment). However, when accounting for local ancestry, E4 alleles on an European background were more associated with disease than those on an African background (p-value=0.031; OR=5.71). This study confirms the effect of ApoE4 in the PR population, but notes an attenuated effect, similar to that seen in other Hispanic or African populations. While global ancestry was only nominally associated, the ApoE4 allele on an African background shows less effect than on European backgrounds. These results suggest the APOE region from non-European populations may harbor protective factors that help mitigate the effect of the detrimental E4 allele.