Abstract
BackgroundPotentially 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 FindingsWe used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, N SNPs = 49), fasting glucose (N SNPs = 36), insulin resistance (N SNPs = 10), body mass index (BMI, N SNPs = 32), total cholesterol (N SNPs = 73), HDL-cholesterol (N SNPs = 71), LDL-cholesterol (N SNPs = 57), triglycerides (N SNPs = 39), systolic blood pressure (SBP, N SNPs = 24), smoking initiation (N SNPs = 1), smoking quantity (N SNPs = 3), university completion (N SNPs = 2), and years of education (N SNPs = 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.ConclusionsInherited 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.
Highlights
Modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention
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
Given the overlap of single nucleotide polymorphism (SNP) associated with systolic, diastolic, mean arterial, and pulse pressures, we focused on systolic blood pressure (SBP), which had the largest number of associated SNPs [17,18]
Summary
About 44 million people have dementia, a group of brain degeneration disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. In Mendelian randomization, causal associations are inferred from the effects of genetic variants (which predict levels of modifiable risk factors) on the outcome of interest. The researchers identified causal associations between potentially modifiable risk factors and AD risk by analyzing the occurrence of single nucleotide polymorphisms (SNPs, a type of gene variant) known to predict levels of each risk factor, in genetic data from 17,008 individuals with AD and 37,154 cognitively normal elderly controls collected by the International Genomics of Alzheimer’s Project. The UK not-for-profit organization Alzheimer’s Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer disease. A PLOS Medicine Research Article by Proitsi et al describes a Mendelian randomization study that looked for a causal association between dyslipidemia and Alzheimer disease
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