July 31, 2008 — Older women who have high or low levels of the thyroid hormone thyrotropin have more than twice the risk for the development of Alzheimer's disease vs those with more moderate thyroid hormone levels, according to a new study.

The study, published in the July 28 issue of the Archives of Internal Medicine, did not find an association between extreme thyroid hormone levels and Alzheimer's disease in men.

Although still hypothetical and subject to verification by further research, the results of this study suggest that it might be time to question whether target thyroid hormone levels (now typically between 0.5 and 5.0 mIU/L) should be narrowed to a more moderate range, said Zaldy S. Tan, MD, MPH, of Hebrew SeniorLife, Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts.

"The most important thing to take away from this study is the question of whether our currently accepted standard of what normal thyroid levels are is too broad," said Dr. Tan, one of the study authors. However, he cautioned that these results are from an observational study and "so are not meant to be prescriptive in any way, and have to be validated in other populations and perhaps clinical trials to prove or disprove these associations."

Between March 1977 and November 1979, Dr. Tan and his colleagues measured thyrotropin levels of 1864 participants in the Framingham longitudinal, community-based, observational study who had been free of dementia for 3 years (this window of time minimized the risk of inadvertently including patients with early Alzheimer's disease in this study). They later divided these hormone levels into tertiles according to serum concentrations.

Thyroid Function Intricately Linked to Central Nervous System

At this baseline and then biennially, researchers used neurologic and neuropsychological examinations, plus interviews and various other expert sources, to establish dementia status of the study participants, whose mean initial age was 71 years.

During a mean follow-up of 12.7 years (range, 1 - 25 years), Alzheimer's disease developed in 209 participants (including 142 women [12.8%]). After adjusting for confounders such as age, educational level, smoking, body mass index, and various cardiovascular risks, the researchers observed that women with the lowest serum thyrotropin concentrations (< 1.0 mIU/L) and those with the highest (> 2.1 mIU/L) were more than twice as likely to have Alzheimer's disease vs women with mid-range levels of the hormone (hazard ratio, 2.39; 95% confidence interval [CI], 1.47 - 3.87; P < .001 for those in the lowest levels and hazard ratio 2.15; 95% CI, 1.31 - 3.52; P = .003 for those in the highest levels).

In contrast, the researchers did not find such a U-shaped relationship between thyrotropin levels and Alzheimer's disease risk in men. At the mean follow-up, 8.9% (52) of the 621 male participants were diagnosed with Alzheimer's disease.

The relationship between thyroid hormone levels and the risk for Alzheimer's disease was maintained in women without overt thyroid dysfunction: those with serum thyrotropin levels of 0.1 to 10.0 mIU/L but not among those with thyrotropin levels limited to between 0.5 and 5.0 mIU/L.

The relationship held when researchers controlled for patients taking thyroid supplements, but because the numbers were too small, it could not be extended to all dementias, said Dr. Tan.

Thyroid hormone function is intricately linked to the central nervous system. Adults with hypothyroidism are more prone to depression, whereas those with hyperthyroidism are subject to confusion. Also, recent studies have related thyroid dysfunction to an increased risk for irreversible dementia. "So we know there are some connections (between thyroid function and cognition), but I don't think anyone has figured out yet what the exact connection is," said Dr. Tan.

Mechanism Unclear

This study, he said, was an effort to shed more light on this connection. "We thought maybe we'd find a relationship one way or the other, but it was interesting to find that both low and high levels were associated" with Alzheimer's disease, Dr. Tan told Medscape Neurology & Neurosurgery.

Finding that this association existed at both ends of the spectrum was enlightening, he added. "The fact that the brain tries to maintain thyroid levels at a relatively narrow range may suggest that for it to function optimally, it has to be maintained within this range and going below or above that is not a good thing."

It's not clear, though, how thyroid hormone levels outside this optimal range might trigger Alzheimer's disease. High levels of the hormone could increase oxidative stress, and low levels might affect brain tissue and circulating levels of beta amyloid peptide, the study authors surmise.

Also, it is possible that changes in the brain may affect the amount of thyrotropin in the bloodstream. The study authors speculate that these brain changes could alter the body's ability to respond to this hormone.

It is also unclear why thyroid hormone levels affect Alzheimer's disease risk in women but not in men. "I don't think anyone has provided an answer to that yet," said Dr. Tan. "There's something about either the brain of women or the hormonal milieu of women that makes them more prone to this effect."

"What we do know is that, for some reason, thyroid problems — for example, hypothyroidism, which is related to depression — are more common in women," he said.

Another consideration is that thyroid problems simply become more common with age as does dementia. "One has to question whether these things are there just because one is getting old, or if there is some connection between the two conditions," said Dr. Tan.

Today, thyroid dysfunction is underdiagnosed in clinical practice, and some clinicians are advocating for more intense screening for thyroid problems, especially among older patients, said Dr. Tan. Some organizations have already formally questioned whether the currently accepted standard cutoff point should be narrowed for more optimal outcomes, he said. For example, the American Association of Clinical Endocrinologists has proposed modifying target thyrotropin levels from the widely accepted 0.5 to 5.0 mIU/L to the narrower range of 0.3 to 3.04 mIU/L.

Would maintaining a narrower range of thyroid hormone levels prevent Alzheimer's disease? This question will take some time to answer. Although thyroid dysfunction is linked to dementia, depression, and other cognitive problems, "whether maintaining hormone levels within limits will actually prevent dementia I think might be a big jump," said Dr. Tan. "That will have to be proven in clinical trials."

This study was supported by the Framingham Heart Study of the National Heart, Lung, and Blood Institute; the National Institutes of Health; the Precursors of Stroke from the National Institute of Neurological Disorders and Stroke; and the Magnetic Resonance Imaging, Genetic and Cognitive Precursors of Alzheimer's Disease and Dementia and the Epidemiology of Dementia in the Framingham Study from the National Institute on Aging. The study authors have disclosed no relevant financial relationships.

Arch Intern Med. 2008;168:1514-1520.

Clinical Context

Study Highlights

• The Framingham Study is a longitudinal, community-based, observational study of 5209 participants who have been evaluated biennially since 1948 for cardiovascular risk factor and the development of cardiovascular disease.
• In this study, it examined the related serum thyrotropin concentrations measured at baseline (March 1977 - November 1979) to the risk for Alzheimer's disease in 1864 cognitively intact, clinically euthyroid Framingham original cohort participants (mean age, 71 years; 59% women).
• All individuals identified as having dementia satisfied the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria, had dementia severity equivalent to a Clinical Dementia Rating of 1 or greater, and had symptoms of dementia for at least 6 months.
• Sex-specific Cox proportional hazards models were constructed with tertiles of thyrotropin concentration (tertile 2 as the referent) and adjustment for age, apolipoprotein E ε4 allele status, educational level, plasma homocysteine level, current smoking, body mass index, prevalent stroke, and atrial fibrillation.
• Results revealed that during a mean follow-up of 12.7 years (range, 1 - 25 years), Alzheimer's disease developed in 209 participants (142 women).
• Women in the lowest (< 1.0 mIU/L) and highest (> 2.1 mIU/L) tertiles of serum thyrotropin concentration were at increased risk for Alzheimer's disease (multivariate-adjusted hazard ratio, 2.39; 95% CI, 1.47 - 3.87; P < .001 for those in the lowest tertile and hazard ratio, 2.15; 95% CI, 1.31 - 3.52; P = .003 for those in the highest tertile) vs those in the middle tertile.
• Thyrotropin levels were not related to Alzheimer's disease 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 Alzheimer's disease risk was maintained in women but not when analyses were limited to those with thyrotropin levels of 0.5 to 5.0 mIU/L.
• Limitations to this study included the availability of only a single thyrotropin measure; the absence of data on thyroxine levels, depression status, and nonthyroidal illnesses that could potentially affect thyroid levels; and the use of antithyroid medications.

Pearls for Practice

• In addition to thyroid dysfunction, multiple studies have suggested that insulin resistance, elevated cortisol levels, and low estrogen and testosterone levels have all been linked in the development of dementia.
• Low and high thyrotropin levels were associated with an increased risk for incident Alzheimer's disease in women but not in men.

CME Test