Thyroid Function and the Risk of Alzheimer Disease<subtitle>The Framingham Study</subtitle>

Abstract

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 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 (Ͻ1.0 mIU/L) and highest (Ͼ2.1 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] [PϽ.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.

Mild Thyroid Deficiency in the Elderly

“…To date, the actual relationship between mild thyroid hormone deficiency and cognitive impairment in the elderly is not well understood. In fact, there are several contrasting data resulting from cross-sectional and clinical experiments (Gussekloo et al, 2004;Roberts et al, 2006;Tan et al, 2008;Ceresini et al, 2009). Moreover, the available published data, in many cases, are not easily comparable considering the differences in inclusion criteria of each clinical study.…”

“…Interestingly, epidemiological surveys using the revised Wechsler Adult Intelligence Scale (WAIS-R) and the Mini-Mental State Examination (MMSE) showed a relationship between plasma thyroid hormone levels and cognitive status in subjects with thyroid function still within the upper limit of the normal range (Prinz et al, 1999;Volpato et al, 2002). Accordingly, altered plasma thyroid hormone concentrations have been recognized as a risk factor for cognitive impairment or dementia (Bulens, 1981;Kalmijn et al, 2000;Tan et al, 2008). More specifically, with the increasing sensitivity of neuropsychological tools, it has become evident that thyroid hormone deficiency might produce measurable deficits in very specific neuropsychological functions (Zoeller & Rovet 2004).…”

“…Conflicting data were obtained by large, population-based studies, leading to uncertain conclusions regarding the association between (mild) thyroid failure and cognition (Gussekloo et al, 2004;Roberts et al, 2006;Tan et al, 2008;Ceresini et al, 2009). In this setting, one critical point that could affect the results of these studies is the diverse age groups of the enrolled patients (moderate or v e r y o l d ) a s w e l l a s t h e p r e s e n c e o f comorbidity.…”

“…Indeed, arterial stiffness is a potential mechanism of advancing cognitive decline in sHT (Yamamoto et al, 2012) and elevated TSH values might negatively affect vascular function through systemic low-grade inflammation (Taddei et al, 2006). Moreover, whereas in moderate older people sHT might produce a detrimental effect on cognitive performance, in very old individuals (mild) thyroid failure might be not associated to a negative outcome (Gussekloo et al, 2004;Tan et al, 2008). To determine whether subclinical thyroid dysfunction should be treated in old age and the long-term impact of thyroid dysfunction on performance and survival in the elderly, a prospective, observational, population-based survey was carried out within the Leiden 85-Plus Study.…”

“…sHT is a frequent condition among the general population, especially middle-aged and elderly women (Canaris et al, 2000). Depending on the degree of TSH elevation, sHT has been associated with hyperlipidemia, intermediary metabolism alterations, arterial hypertension and cardiovascular disease (CVD) as well as neuropsychiatric features, including cognitive impairment (Ashizawa et al, 2010;Biondi & Cooper., 2008;Cappola et al, 2006;Ceresini et al, 2010;Mitrou et al, 2011;Monzani et al, 2006;Rodondi et al, 2010;Tan et al, 2008;Tappy, 1987). Interestingly, the analysis of variation in thyroid function tests in healthy volunteers has shown that the physiological individual reference ranges for test results are narrow compared with laboratory references (Andersen et al, 2002).…”