Abstract
INTRODUCTION: Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian randomization (MR) approach. METHODS: An inverse-variance weighting (IVW) MR analysis was performed using effect estimates from external genome-wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R(2) < 0.001) and a p-value threshold of 5 × 10(-8) . RESULTS: An increase in androgens was associated with a decreased AD risk among men: testosterone (odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.32-0.88; p-value: 0.01; false discovery rate [FDR] p-value: 0.03); dehydroepiandrosterone sulfate (DHEAS; OR: 0.56; 95% CI: 0.38-0.85; p-value: 0.01; FDR p-value: 0.03); and androsterone sulfate (OR: 0.69; 95% CI: 0.46-1.02; p-value: 0.06; FDR p-value: 0.10). There was no association between sex steroid hormones and AD among women, although analysis for estradiol had limited statistical power. DISCUSSION: A higher concentration of androgens was associated with a decreased risk of AD among men of European ancestry, suggesting that androgens among men might be neuroprotective and could potentially prevent or delay an AD diagnosis. HIGHLIGHTS: Sex hormones are hypothesized to play a role in developing Alzheimer's disease (AD). The effect of sex hormones on AD was assessed using Mendelian randomization (MR) analysis. Among women, genetically determined effects of sex hormones were limited or null. Among men, a higher concentration of androgens decreased AD risk. This study suggests a causal relationship between androgens and AD among men.