Cumulative Genetic Risk and APOE ε4 Are Independently Associated With Dementia Status in a Multiethnic, Population-Based Cohort

Objective Alzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample.

Methods In the US population-based Health and Retirement Study (waves 1995–2014), we evaluated the role of cumulative genetic risk of AD, with and without the APOE ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.

Results In the European ancestry sample (n = 8,399), both AD polygenic score excluding the APOE genetic region (odds ratio [OR] = 1.10; 95% confidence interval [CI]: 1.00–1.20) and the presence of any APOE ε4 alleles (OR = 2.42; 95% CI: 1.99–2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any APOE ε4 alleles was associated with 1.77 (95% CI: 1.20–2.61) times higher odds of dementia, whereas the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97–1.30).

Conclusions Cumulative genetic risk of AD and APOE ε4 are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.