Associations between reproductive milestones and Alzheimer's disease risk: a Mendelian randomization study

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. Previous studies have suggested associations between female reproductive history and AD risk, but the causal nature of these relationships remains unclear. This study aimed to investigate the causal relationships between key female reproductive milestones (age at menarche, age at first birth, and menopause) and AD risk using Mendelian randomization (MR) and multivariate MR analysis.

Two-sample MR and multivariate MR analyses were conducted using pooled data from large-scale genome-wide association studies. Genetic variants associated with female reproductive milestones served as instrumental variables. Replication phase data were provided by the Medical Research Council Integrative Epidemiology Unit consortium. Core single-nucleotide polymorphisms were selected to examine the effects of age at menarche, age at first birth, and menopause on AD risk. The inverse variance weighting method was the primary analytical approach, with causality assessed using MR-Egger regression and weighted median estimation. Sensitivity analyses and pleiotropy assessments were performed using Cochran's Q test and the MR-PRESSO global test. This study followed the STROBE-MR checklist for reporting MR studies.

MR analysis revealed that genetically predicted earlier age at menarche and age at first birth are potentially associated with increased risk of AD (OR = 0.92, 95 % CI: 0.85-0.99, p = 0.022; OR = 0.90, 95 % CI: 0.84-0.96, p = 0.002, respectively). Conversely, genetically predicted menopause was associated with increased AD risk (OR = 2.55, 95 % CI: 1.06-6.14, p = 0.036).

This MR study provides evidence suggesting that genetically predicted age at menarche, age at first birth, and menopause are significantly associated with AD risk, operating independently of each other. These findings highlight the potential role of female reproductive milestones in AD pathogenesis.