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The Framingham Study

Zaldy S. Tan, MD, MPH; Alexa Beiser, PhD; Ramachandran S. Vasan, MD; Rhoda Au, PhD; Sanford Auerbach, MD; Douglas P. Kiel, MD, MPH; Philip A. Wolf, MD; Sudha Seshadri, MD

Arch Intern Med. 2008;168(14):1514-1520.

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 (tertile 2 as the referent) and adjusting for age, apolipoprotein E 4 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.

Author Affiliations: Department of Medicine and Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Center and Harvard Medical School (Drs Tan and Kiel); Departments of Neurology (Drs Beiser, Au, Auerbach, Wolf, and Seshadri) and Medicine (Dr Vasan), Boston University School of Medicine; and Department of Biostatistics, Boston University School of Public Health (Dr Beiser); Boston, Massachusetts.

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