Genetically determined TSH level within reference range is inversely associated with Alzheimer's disease.

Context Contradictory findings were reported in observational studies on the association of thyroid function [thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels] with Alzheimer's disease (AD). Objective To determine whether genetically determined TSH/FT4 levels within reference range are causally associated with AD. Design Bi-directional two-sample Mendelian randomization (MR) study. Setting and participants 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 MR approach to evaluate the bi-directional causal relationship between TSH/FT4 levels and AD. Inverse-variance weighted method was adopted as the main analysis. Results One standard deviation increase in genetically determined TSH level within reference range was causally associated with reduced risk of AD (Odds ratio:0.988; 95% CI:0.977-0.998). 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. Positive causal effect of AD on TSH level was only detected in male. 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. Conclusions 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 Rotterdam study, whether the causal estimates derived from this MR study are underestimated warrants further investigations.