Thyroid function and the risk of Alzheimer disease: The Framingham study

Background: Clinical hypothyroidism and hyperthyroidism are recognized causes of reversible dementia, but previous studies relating thyrotropin levels to cognitive performance in clinically euthyroid persons have yielded inconsistent results. Methods: We related serum thyrotropin concentrations measured at baseline (March 1977-November 1979) to the risk of Alzheimer disease (AD) in 1864 cognitively intact, clinically euthyroid Framingham original cohort participants (mean age, 71 years; 59% women). Sex-specific Cox proportional hazards models were constructed using tertiles of thyrotropin concentration (fertile 2 as the referent) and adjusting for age, apolipoprotein E ε4 allele status, educational level, plasma homocysteine level, current smoking, body mass index, prevalent stroke, and atrial fibrillation. Results: During a mean follow-up of 12.7 years (range, 1-25 years), 209 participants (142 women) developed AD. Women in the lowest (<1.0 mIU/L) and highest (>2.1 mIU/L) tertiles of serum thyrotropin concentration were at increased risk for AD (multivariate-adjusted hazard ratio, 2.39 [95% confidence interval, 1.47-3.87] [P<.001] and 2.15 [95% confidence interval, 1.31-3.52] [P=.003], respectively) compared with those in the middle tertile. Thyrotropin levels were not related to AD risk in men. Analyses excluding individuals receiving thyroid supplementation did not significantly alter these relationships. In analyses limited to participants with serum thyrotropin levels of 0.1 to 10.0 mIU/L, the U-shaped relationship between thyrotropin level and AD risk was maintained in women but not when analyses were limited to those with thyrotropin levels of 0.5 to 5.0 mIU/L. Conclusion: Low and high thyrotropin levels were associated with an increased risk of incident AD in women but not in men.