Research Article: Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study

Date Published: January 29, 2019

Publisher: Oxford University Press

Author(s): Dylan M Williams, Sara Hägg, Nancy L Pedersen.


Higher circulating antioxidant concentrations are associated with a lower risk of late-onset Alzheimer disease (AD) in observational studies, suggesting that diet-sourced antioxidants may be modifiable targets for reducing disease risk. However, observational evidence is prone to substantial biases that limit causal inference, including residual confounding and reverse causation.

In order to infer whether long-term circulating antioxidant exposure plays 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 4 circulating antioxidants that are modifiable by diet.

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), β-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 = 17,008 and 37,154, respectively). Ratio-of-coefficients and inverse-variance-weighted meta-analyses were the primary methods used to assess the 4 sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates.

The models suggested that genetically determined differences in circulating ascorbate, retinol, and urate are not associated with differences in AD risk. All estimates were close to the null, with all ORs for AD ≥1 per unit increase in antioxidant exposure (ranging from 1.00 for ascorbate to 1.05 for retinol). There was little evidence to imply that pleiotropy had biased results.

Our findings suggest that higher exposure to ascorbate, β-carotene, retinol, or urate does not lower the risk of AD. Replication Mendelian randomization studies could assess this further, providing larger AD case-control samples and, ideally, using additional variants to instrument each exposure.

Partial Text

Late-onset Alzheimer disease (AD), the most common form of dementia, is likely to be determined by a combination of inherited genetic risk and environmental influences (1). Identifying modifiable, environmental determinants of AD is crucial for informing public health policies to reduce disease burden in populations.

In primary results (Table 1) there were no apparent differences in AD risk according to genetically predicted increases in exposure to circulating ascorbate, retinol, or urate. Higher predicted exposure to circulating β-carotene was associated with marginally elevated AD risk—although the OR was similar to results for other antioxidants, it was estimated with more precision. Figure 2 shows a scatterplot of individual urate results, along with the meta-analysis IVW estimate; the lack of trend indicates a null finding.

The findings of these MR analyses suggest that increasing individuals’ long-term exposure to circulating ascorbate, β-carotene, retinol, and urate would not mitigate their risk of developing AD. All estimates of effects of antioxidant exposure on AD risk were close to null, with ORs for retinol, β-carotene, and urate >1, implying that higher exposure confers slightly more risk of AD (if any difference at all), rather than neuroprotection.




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