Circulating antioxidants and Alzheimer's disease prevention: A Mendelian randomization study

Abstract

Introduction Late-onset Alzheimer's disease (AD) has emerged as a paramount public health challenge in European countries. Of crucial importance is the identification of environmental risk factors that could be modified at a population level to help limit AD onset among ageing individuals. Higher circulating antioxidant concentrations are associated with a lower risk of AD in observational studies. However, this evidence is prone to substantial biases, including reverse causation and residual confounding. To further infer whether long-term circulating antioxidant exposure has a role in AD etiology, we tested the hypothesis that AD risk would be lower in individuals with lifelong, genetically predicted increases in concentrations of five circulating antioxidants. Methods Two-sample Mendelian randomization analyses were conducted. First, published genetic association studies were used to identify single nucleotide polymorphisms (SNPs) that determine variation in circulating ascorbate (vitamin C), beta-carotene, retinol (vitamin A), and urate. Second, for each set of SNP data, statistics for genotype associations with AD risk were extracted from data of a genome-wide association study of late-onset AD cases and controls (n = 17008; 37154, respectively). Inverse-variance weighted meta-analyses were primarily used to combine ratios of coefficients for the five sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates. Results Models suggested that genetically determined differences in circulating ascorbate, retinol and urate are not associated with AD risk. Also contrary to previous observational findings, higher predicted beta-carotene exposure was associated with a very slight increase in AD risk: odds ratio per 10% higher beta-carotene = 1.02 (95% confidence interval: 1.00, 1.04, P = 0.002). Potential limitations to the analyses included the possibilities of low power for the ascorbate and retinol analyses. Conclusions These findings suggest that higher exposure to several antioxidants would not lower risk of AD development. Replication Mendelian randomization studies could examine this question further, ideally with the use of additional variants to instrument each antioxidant, and with larger AD case-control samples.