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The association between endogenous estrogen exposure and Alzheimer's disease (AD) remains inconclusive in previous observational studies, and few Mendelian randomization (MR) studies have focused on their causality thus far. We performed a bidirectional MR study to clarify the causality and causal direction of age at menarche and age at menopause, which are indicators of endogenous estrogen exposure, on AD risk. We obtained all genetic datasets for the MR analyses using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. The MR analyses indicated no significant causal relationship between the genetically determined age at menarche (outlier-adjusted inverse variance weighted odds ratio [IVWOR] = 0.926; 95% confidence interval [CI], 0.803-1.066) or age at menopause (outlier-adjusted IVWOR = 0.981; 95% CI, 0.941-1.022) and AD risk. Similarly, AD did not show any causal association with age at menarche or age at menopause. The sensitivity analyses yielded similar results. In contrast, an inverse association was detected between age at menarche and body mass index (BMI, outlier-adjusted IVW β = -0.043; 95% CI, -0.077 to -0.009). Our bidirectional MR study provides no evidence for a causal relationship between the genetically determined age at menarche or age at menopause and AD susceptibility, or vice versa. However, earlier menarche might be associated with higher adult BMI.

The role of age at menarche and age at menopause in Alzheimer’s disease: evidence from a bidirectional mendelian randomization study