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Østergaard, S.D.* ; Mukherjee, S.* ; Sharp, S.J.* ; Proitsi, P.* ; Lotta, L.A.* ; Day, F.* ; Perry, J.R.* ; Boehme, K.L.* ; Walter, S.* ; Kauwe, J.S.* ; Gibbons, L.E.* ; Alzheimer's Disease Neuroimaging Initiative (*) ; Genetic and Environmental Risk for Alzheimer's Disease (GERAD1) Consortium (Klopp, N. ; Wichmann, H.-E.) ; EPIC-Interact Consortium (Scott, R.A.*) ; Larson, E.B.* ; Powell, J.F.* ; Langenberg, C.*

Associations between potentially modifiable risk factors and Alzheimer disease: A mendelian randomization study.

PLoS Med. 12:e1001841 (2015)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 1549-1277
e-ISSN 1549-1676
Journal PLoS Medicine
Quellenangaben Volume: 12, Issue: 6, Pages: , Article Number: e1001841 Supplement: ,
Publisher Public Library of Science (PLoS)
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)