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Alzheimers Dement (Amst). 2017 Aug 14;8:188-195. doi: 10.1016/j.dadm.2017.07.002. eCollection 2017.

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

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Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins University Center on Aging and Health, Baltimore, MD, USA.
Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
Institute on Aging & Lifelong Health, University of Victoria, Victoria, BC, Canada.
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.



We hypothesized that, like apolipoprotein E (APOE), other late-onset Alzheimer's disease (LOAD) genetic susceptibility loci predict mortality.


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.


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).


Non-APOE LOAD susceptibility loci confer risk for mortality, likely through effects on dementia incidence.


APOE; Adult Changes in Thought (ACT); Alzheimer's disease; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE); Collider stratification bias; Genetic risk score; Genome-wide association study (GWAS); Health and Retirement Study (HRS); Longevity; Mortality; Selection bias; Survival analysis; Survivor bias

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