Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

TitleAssociations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.
Publication TypeJournal Article
Year of Publication2015
AuthorsØstergaard SD, Mukherjee S, Sharp SJ, Proitsi P, Lotta LA, Day F, Perry JRB, Boehme KL, Walter S, Kauwe JS, Gibbons LE, Larson EB, Powell JF, Langenberg C, Crane PK, Wareham NJ, Scott RA
Corporate AuthorsAlzheimer’s Disease Genetics Consortium, GERAD1 Consortium, EPIC-InterAct Consortium
JournalPLoS Med
Volume12
Issue6
Paginatione1001841; discussion e1001841
Date Published2015 Jun
ISSN1549-1676
KeywordsAlzheimer Disease, Female, Genetic Predisposition to Disease, Humans, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Factors
Abstract

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.

DOI10.1371/journal.pmed.1001841
Alternate JournalPLoS Med.
PubMed ID26079503
PubMed Central IDPMC4469461
Grant ListMH60451 / MH / NIMH NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
UL1 TR001445 / TR / NCATS NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
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MR/L501529/1 / / Medical Research Council / United Kingdom
P50 AG016577 / AG / NIA NIH HHS / United States
MC_U123160651 / / Medical Research Council / United Kingdom
U01 AG032984 / AG / NIA NIH HHS / United States
U01 HG008657 / HG / NHGRI NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
167 / / Alzheimer's Society / United Kingdom
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089703 / / Wellcome Trust / United Kingdom
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