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

Area of Science:

• Neuroscience
• Endocrinology
• Genetics

Background:

• Observational studies show conflicting results on the association between thyroid function (thyrotropin [TSH] and free thyroxine [FT4] levels) and Alzheimer's disease (AD).
• Understanding the causal relationship is crucial for potential therapeutic strategies.

Purpose of the Study:

• To investigate the causal relationship between genetically determined TSH and FT4 levels within the reference range and Alzheimer's disease (AD).
• To explore a bidirectional causal association between thyroid function and AD using Mendelian randomization.

Main Methods:

• A bidirectional, two-sample Mendelian randomization (MR) study was employed.
• Utilized large-scale genome-wide association study (GWAS) summary statistics for TSH (n≥54,288), FT4 (n=49,269), and AD (71,880 cases; 383,378 controls).
• The inverse-variance weighted (IVW) method was the primary analysis technique.

Main Results:

• A one standard deviation increase in genetically determined TSH levels within the reference range was causally associated with a reduced risk of AD (OR: 0.988; 95% CI: 0.977-0.998).
• This inverse association was also observed in sex-specific analyses and was attenuated after adjusting for atrial fibrillation and blood pressure.
• A positive causal effect of AD on TSH levels was detected specifically in males, suggesting a potential male-specific feedback loop.

Conclusions:

• Increased genetically determined TSH levels, even within the normal range, may be associated with a lower risk of AD.
• Atrial fibrillation and blood pressure are potential mediators in the causal pathway between TSH and AD.
• No significant causal association was found between FT4 levels and AD in either direction.