Abstract
Dementia incidence increases steadily with age at rates that may vary across racial groups. This racial disparity may be attributable to polygenic risk, as well as lifestyle and behavioural factors. We examined whether Alzheimer's disease polygenic score and race predict Alzheimer's disease and other related dementia incidence differentially by sex and mediation through polygenic scores for other health and behavioural conditions. We used longitudinal data from the nationally representative Health and Retirement Study. We restricted participants to those with complete data on 31 polygenic scores, including Alzheimer's disease polygenic score (2006-2012). Among participants aged 55 years and older in 2008, we excluded those with any memory problems between 2006 and 2008 and included those with complete follow-up on incident Alzheimer's disease and all-cause dementia, between 2010 and 2018 (N = 9683), based on self- or proxy-diagnosis every 2 years (2010, 2012, 2014, 2016 and 2018). Cox proportional hazards and 4-way decomposition models were conducted. Analyses were also stratified by sex and by race. There were racial differences in all-cause dementia incidence (age and sex-adjusted model, per standard deviation: hazard ratio, HR = 1.34, 95% confidence interval, CI: 1.09-1.65, P = 0.007), partially driven by educational attainment and income. We also found independent associations of race (age and sex-adjusted model, African American versus White adults: HR = 2.07, 95% CI: 1.52-2.83, P < 0.001) and Alzheimer's disease polygenic score (age and sex-adjusted model, per SD: HR = 1.37, 95% CI: 1.00-1.87, P < 0.001) with Alzheimer's disease incidence, including sex differences whereby women had a stronger effect of Alzheimer's disease polygenic score on Alzheimer's disease incidence compared with men (P < 0.05 for sex by Alzheimer's disease polygenic score interaction) adjusting for race and other covariates. The total impact of Alzheimer's disease polygenic scores on Alzheimer's disease incidence was mostly direct, while the effect of race on all-cause dementia incidence was mediated through socio-economic, lifestyle and health-related factors. Finally, among the 30 polygenic scores we examined, the total effects on the pathway Alzheimer's disease polygenic score --> Other polygenic score --> Incident Alzheimer's or all-cause dementia, were statistically significant for all, driven primarily by the controlled direct effect (P< 0. 001). In conclusion, both race and Alzheimer's disease polygenic scores were associated independently with Alzheimer's disease and all-cause dementia incidence. Alzheimer's disease polygenic score was more strongly linked to incident Alzheimer's disease among women, while racial difference in all-cause dementia was explained by other factors including socio-economic status.