Alzheimer's Linked to Thyroid-Related Hormone

By Crystal Phend
BOSTON, 29 july 2008 -- Abnormal levels of the hormone thyrotropin, which controls thyroid function, may be associated with an increased risk of Alzheimer's disease in women, researchers found.
Alzheimer's disease was more than twice as common among women with the highest and lowest levels of serum thyrotropin compared with those in the more normal range (P<0.001 and P=0.003, respectively), reported Zaldy S. Tan, M.D., M.P.H., of Harvard and Beth Israel Deaconess Medical Center, and colleagues in the July 28 issue of the Archives of Internal Medicine.
However, the associations did not extend to men for either high or low levels of the hormone in the analysis of the longitudinal Framingham Study.
Further confirmation is needed, though, before clinical conclusions could be drawn from the findings, the researchers said.
Both hypo- and hyperthyroidism have long been recognized as causes of reversible cognitive impairment such that routine screening of serum thyrotropin levels is included in evaluation of patients with suspected dementia, the researchers said.
Several epidemiologic studies have also suggested thyroid function may play a role in irreversible dementia.
So, the researchers analyzed thyrotropin levels in 1,864 men and women participating in the larger, community-based Framingham Study. None of these participants had cognitive problems when assessed for dementia at baseline from 1977 through 1979.
Overall, serum thyrotropin levels were greater than 10.0 mIU/L among 4.2% of participants and less than 0.1 mIU/L in 5% of patients.
During 12.7 years of biennial follow-up assessments, 209 patients developed Alzheimer's disease.
For women, thyrotropin levels were significantly linked to Alzheimer's disease with a 2.20-fold higher risk for both those in the lowest tertile (with levels below 1.0 mIU/L) and for those in the highest tertile, with levels above 2.1 mIU/L (multivariate adjusted P=0.003 and P=0.002, respectively).
Even among women who did not have overt thyroid dysfunction --thyrotropin levels of 0.1 to 10.0 mIU/L -- the same U-shaped relationship was seen for Alzheimer's risk.
In the fully adjusted model, women in the upper tertile were at a 2.09-times higher risk (P=0.001) and those in the lower tertile were at a 1.70-fold elevated risk (P=0.02).
The same was not true for men, however. Compared with men in the middle third for thyrotropin levels, risk of Alzheimer's disease was not elevated whether thyrotropin levels were high (hazard ratio 1.07, P=0.85) or low (HR 1.10, P=0.78).
The results were unchanged when controlling for patients taking thyroid supplements and when assessed by all-cause dementia rather than Alzheimer's disease.
Sex differences related to thyroid hormone are well known for bone density, as are higher incidences of clinical and subclinical thyroid disease in women compared with men, the researchers noted, suggesting an effect modification by sex.
Whether the effect of thyrotropin was causative could not be determined from the observational study and either direction of causality is plausible, they noted.
Neurodegeneration related to Alzheimer's disease could lead to a reduction in thyrotropin secretion or alter pituitary responsiveness, or depletion of the hormone could lead to Alzheimer's abnormalities by enhancing phosphorylation of tau proteins, they suggested.
Another possibility is that low or high thyrotropin levels could damage neurons or blood vessels, leading to cognitive problems.
The researchers cautioned that the study may have been limited by the availability of only a single thyrotropin measure without data on thyroxine levels, depression status, other illnesses that could affect thyroid levels, or the use of antithyroid medications.
And the almost exclusively Caucasian population in the study suggests that the findings need validation in more diverse populations, Dr. Tan and colleagues said.
The authors also noted that when analyses were limited to individuals with thyrotropin levels of 0.5 to 5.0 mIU/L, the U-shaped relationship between thyrotropin levels and Alzheimer's disease was attenuated.
This, they wrote "suggests that the relationship may have been accounted for by individuals with more extreme thyrotropin values in the full tertile analysis."
The study was supported by the Framingham Heart Study of the National Heart, Lung, and Blood Institute and grants from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the National Heart, Lung, and Blood Institute.
The researchers reported no conflicts of interest.
Primary source: Archives of Internal MedicineSource reference:Tan ZS, et al "Thyroid function and the risk of Alzheimer disease: The Framingham Study" Arch Intern Med 2008; 168: 1514-1520.