Genetically Determined TSH Level Within Reference Range Is Inversely Associated With Alzheimer Disease

Abstract Context Contradictory findings were reported in observational studies on the association of thyroid function (thyrotropin [TSH] and free thyroxine [FT4] levels) with Alzheimer disease (AD). Objective This work aims to determine whether genetically determined TSH/FT4 levels within reference range are causally associated with AD. Methods A bidirectional, 2-sample mendelian randomization (MR) study was conducted. With summary statistics from the largest genome-wide association studies (GWAS)/GWAS meta-analysis of TSH level(n ≥ 54 288), FT4 level(n = 49 269), and AD (71 880 cases; 383 378 controls), we used an MR approach to evaluate the bidirectional causal relationship between TSH/FT4 levels and AD. The inverse-variance weighted method was adopted as the main analysis. Results One SD increase in genetically determined TSH level within reference range was causally associated with a reduced risk of AD (odds ratio: 0.988; 95% CI, 0.977-0.998). A similar inverse association was observed in sex-specific analysis. The causal association was attenuated after adjustment for atrial fibrillation and blood pressure, suggesting they may mediate the causal pathway. A positive causal effect of AD on TSH level was detected only in male participants. This male-specific feedback loop may explain why the largest cohort study to date (Rotterdam Study) demonstrated a null observational association in men. Null association was observed between FT4 level and AD in both directions. Conclusion Genetic predisposition to increased TSH level, even within reference range, may lower the risk of AD, with atrial fibrillation, systolic, and diastolic blood pressure as possible mediators. Given the higher magnitude of risk reduction observed in the Rotterdam Study, whether the causal estimates derived from this MR study are underestimated warrants further investigation.