Uncovering the Hidden Connections Between PCOS and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Perspective

Background: Polycystic ovary syndrome (PCOS) and Alzheimer’s disease (AD) are two prevalent and complex conditions characterized by overlapping features such as metabolic dysfunction, hormonal imbalance, and chronic inflammation. These commonalities raise the possibility of a shared causal pathway. However, observational studies often face limitations due to confounding factors, complicating causal inference. Objectives: The present study aimed to explore the causal link between PCOS and AD through Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR analysis using summary-level data from two large genome-wide association studies (GWAS). For the exposure, genetic variants strongly associated with PCOS were obtained from a GWAS meta-analysis involving 10,074 cases and 103,164 controls of European ancestry. For the outcome, AD data were sourced from a separate GWAS comprising 1,036,225 cases and 90,338 controls, also of European descent. Multiple MR approaches were employed, with inverse variance weighted (IVW) as the primary method, supported by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses were performed to assess the robustness of the findings. Results: The two-sample MR analysis did not provide evidence for a significant causal effect of genetically predicted PCOS on AD risk. The initial IVW analysis using all instrumental variables (IVs) yielded an odds ratio (OR) of 0.967 95% confidence interval (CI): 0.905 - 1.03; P = 0.311. After removing outlier single nucleotide polymorphisms (SNPs) based on sensitivity analyses, the refined IVW model showed an OR of 0.93 (95% CI: 0.866 - 1.002; P = 0.057), indicating no statistically significant association. The results were consistent across various MR methods, and sensitivity tests confirmed the robustness of the findings. Conclusions: This MR study found no evidence of a significant causal relationship between genetically predicted PCOS and AD. These findings suggest that genetic predisposition to PCOS does not increase the risk of AD, indicating that previously observed associations in epidemiological studies may not reflect a causal link. Further studies are needed to explore alternative explanations beyond genetic causality.