Alzheimer's disease genetic risk variants beyond APOE ε4 predict mortality

INTRODUCTION: We hypothesized that, like apolipoprotein E (APOE), other late-onset Alzheimer's disease (LOAD) genetic susceptibility loci predict mortality. METHODS: We used a weighted genetic risk score (GRS) from 21 non-APOE LOAD risk variants to predict survival in the Adult Changes in Thought and the Health and Retirement Studies. We meta-analyzed hazard ratios and examined models adjusted for cognitive performance or limited to participants with dementia. For replication, we assessed the GRS-longevity association in the Cohorts for Heart and Aging Research in Genomic Epidemiology, comparing cases surviving to age ≥90 years with controls who died between ages 55 and 80 years. RESULTS: Higher GRS predicted mortality (hazard ratio = 1.05; 95% confidence interval: 1.00–1.10, P = .04). After adjusting for cognitive performance or restricting to participants with dementia, the relationship was attenuated and no longer significant. In case-control analysis, the GRS was associated with reduced longevity (odds ratio = 0.64; 95% confidence interval: 0.41–1.00, P = .05). DISCUSSION: Non-APOE LOAD susceptibility loci confer risk for mortality, likely through effects on dementia incidence.