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

Jesse Mez; Jessica R Marden; Shubhabrata Mukherjee; Stefan Walter; Laura E Gibbons; Alden L Gross; Laura B Zahodne; Paola Gilsanz; Paul Brewster; Kwangsik Nho; Paul K Crane; Eric B Larson; M Maria Glymour

doi:10.1016/j.dadm.2017.07.002

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

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

Authors

Jesse Mez^{1

2}, Jessica R Marden^{3

4}, Shubhabrata Mukherjee⁵, Stefan Walter⁶, Laura E Gibbons⁵, Alden L Gross⁷, Laura B Zahodne⁸, Paola Gilsanz⁶, Paul Brewster⁹, Kwangsik Nho¹⁰, Paul K Crane⁵, Eric B Larson¹¹, M Maria Glymour⁶

Affiliations

¹ Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA, USA.
² Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
⁵ Department of Medicine, University of Washington, Seattle, WA, USA.
⁶ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
⁷ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins University Center on Aging and Health, Baltimore, MD, USA.
⁸ Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
⁹ Institute on Aging & Lifelong Health, University of Victoria, Victoria, BC, Canada.
¹⁰ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.

Abstract

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.

Keywords: 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.

Abstract

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