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

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.

Fig 1. Mendelian randomization estimates of the association of systolic blood pressure with AD in individual ADGC studies and overall in ADGC, GERAD1, and IGAP.

This figure shows MR estimates for the association of SBP-associated variants with AD in each of the participant studies in ADGC [24] and in GERAD1 [25] using individual SNP-level data compared to that observed in IGAP [12] using summary-level data. See S1 Text (supplemental results) for individual study name abbreviations.

Fig 2. Associations of the systolic blood pressure genetic score with quantitative traits in the EPIC-InterAct study.

This figure shows the investigation of pleiotropic associations of genetic score for SBP with quantitative traits in the EPIC-InterAct study [26]. Effect sizes are expressed in SDs per SBP-raising allele. Analyses were adjusted for age, sex, center of recruitment, and subcohort status.

Fig 3. Association of the systolic blood pressure genetic score with systolic blood pressure by age stratum in the EPIC-InterAct subcohort.

This figure shows the association between the genetic score for SBP and SBP in the EPIC-InterAct study by age stratum [26]. Analyses were adjusted for sex, center of recruitment, and subcohort status.

Fig 4. Associations of the systolic blood pressure genetic score with binary outcomes in the EPIC-InterAct study.

This figure shows the investigation of pleiotropic associations of the genetic score for SBP with binary outcomes in the EPIC-InterAct study [26]. The OR per SBP-raising allele is shown.