F5-02-01: the interaction of genetic admixture and apoe4: implications for cognitive decline in alzheimer disease

Subsequent confirmations have established the APOE genotype as perhaps the most important biological marker for susceptibility in AD. However, this relation appears less consistent among African American and Hispanic populations. This association has been little studied in admixed (African/ European) Latin American populations. The present study aimed to identify the effects of genetic admixture as a modifier of the relation between ApoE, cognitive decline and mortality. We conducted a two-phase population-based study among residents aged 65 or more in seven different areas of Cuba. From a randomly selected subpopulation of 600 participants (350 cognitive normal and 250 cases with AD) DNA was extracted. Sixty SNPs were used to estimate three-way individual admixture proportions with a standard error less than 0.1. Apolipoprotein E genotype was determined using Hhal digestion of amplified products. The effects of heterozygosity or homozygosity of ε4 on cognitive decline were assessed using Cox's proportional hazards regression and mixed effects models. Our cognitive outcome measure was a global cognition score, calculated as a composite of four neuropsychological tests, each representing one of four cognitive domains: memory, language, processing speed, and executive functioning. Mean admixture level was significantly correlated with self-reported race. We found higher mean African admixture proportions among those with ApoE4; increasing from 0.15 among those with no e4 alleles to 0.29 with one and 0.35 for those with two e4 alleles (p=0.01). In a one-way ANOVA analysis, we did not find a relationship between Admixture proportions and Cognitive Score. Extending the model to include APOE genotype by African ancestry and adjusting for covariates, the interaction suggested that having any E4 allele had a weaker effect on the overall cognitive scores, memory, language, and executive functioning in those with higher African Admixture; showing a significant effect of ApoE4 on cognitive decline among those with lower African Admixture (p<0.001). E4 frequency was over-represented in those with higher African Ancestry. The effect of APOE e4 on cognitive decline was substantially attenuated among those with a higher proportion African ancestry, suggesting that genes linked to admixture may reduce the risk for dementia by modifying the effect of APOE genotype.