Nancy A Melville

October 23, 2015

ORLANDO, Florida — High-functioning thyroid levels, including those falling within the normal range, show an association with an increased likelihood of dementia, even after adjustment for cardiovascular disease risk factors, suggesting a possible target for dementia and Alzheimer's disease therapies, according to new research.

"In our study we show that not only high but also high-normal thyroid function is related to an increased risk of dementia," first author Layal Chaker, MD, of Erasmus University Medical Center, in Rotterdam, the Netherlands, told Medscape Medical News.

"The clinical implications [of the findings] could include the use of thyroid function, an easily obtained measure in serum, in screening for and risk prediction of dementia."

While previous research has suggested a role of thyroid dysfunction in dementia, studies evaluating the multiple aspects of thyroid function have been lacking.

Vascular Factors Don't Explain Thyroid-Dementia Link

For the new prospective study, presented here at the 2015 International Thyroid Congress and Annual Meeting of the American Thyroid Association (ITC/ATA, Dr Chaker and colleagues evaluated 9495 participants with a mean age of 64.9 who were enrolled in the Rotterdam Study, with measurements available on thyroid function as well as dementia assessment.

Over a mean follow-up of 7.8 years, 603 patients developed dementia.

After adjustment for variables including age, sex, and cardiovascular disease risk factors, those with higher thyroid-stimulating-hormone (TSH) levels — typically a sign of an underactive thyroid — had a lower risk of dementia (HR 0.76, 95% CI 0.64–0.91).

Meanwhile, higher levels of free thyroxine 4 (T4) — a sign of an overactive thyroid — were associated with a significantly higher risk of dementia (HR, 1.04; 95% CI, 1.01–1.07).

Higher TSH levels in women were linked to an absolute 10-year risk of dementia that was decreased from 6% to nearly 3%; however, a similar effect was not seen in men.

Further assessment in the form of MRI of brain structures related to thyroid function showed that higher free T4 levels in older participants were associated with smaller parenchymal volumes (−2.1 mL per 1-pmol/L increase of free T4), but no link was observed with hippocampal volumes.

The fact that the link between thyroid function and dementia was seen even after adjustment for cardiovascular risk factors was particularly notable, Dr Chaker said.

"Even though there are several mechanisms biologically that can explain a relation between thyroid status and dementia risk, we were surprised to see that vascular mechanisms are seemingly not one of them," she explained.

"Thyroid function is known to increase cardiovascular risk, and cardiovascular risk factors are also linked to an increased risk of dementia, providing a biologically plausible explanation for the link. However, we do not find that vascular mechanisms explain this relation in our population."

Important Clues in Thyroid-Dementia Puzzle

The study could provide important clues in the thyroid-dementia puzzle, Dr Chaker added.

"This finding provides more insight into the possible importance of other pathways connecting thyroid function to dementia and could provide new targets for therapeutic agents," she said.

In terms of the gender differences, the researchers initially hypothesized that differences in prevalence of autoimmune thyroid pathology between men and women might explain the findings, but this was not the case.

"We do not know why these differences exist between women and men, but one of the explanations might be due to differences in sex hormonal profiles. However, we were unfortunately not able to assess this hypothesis in our study."

Session comoderator Marco Centanni, MD, of the University of Rome, Medicosurgical Sciences and Biotechnologies, Italy, agreed that the gender differences observed in the study are notable.

"A novel issue is that the effects of thyroid excess are evident only in women, suggesting that this effect is mediated by some other key factor, which may possibly be estrogen exposure," he told Medscape Medical News.

He added that the differences seen even with high-normal levels of thyroid function are not necessarily unusual.

"It is not surprising, since brain atrophy may depend on the rate of cell death and apoptosis, mechanisms that can be regulated by triiodothyronine (T3)."

First Research to Use Mass Spectrometry for Thyroid Hormone in CSF

A poster presented at the meeting provided some additional evidence in support of the association, with researchers reporting on the first use of a mass-spectrometry–based technique to assay thyroid hormone levels in cerebrospinal fluid.

They found that in 35 subjects — including 15 with a diagnosis of Alzheimer's disease, 10 with frontotemporal dementia (FTD), and 10 with normal cognitive function — there were no significant differences in cerebrospinal fluid (CSF) thyroid hormones between the Alzheimer's disease patients, those with frontotemporal dementia, or the individuals with normal cognitive function.

However, there were some signs of a link with disease severity.

"Interesting results were obtained when we investigated whether CSF thyroid hormones were related to clinical indices of disease severity and progression," wrote the authors, with the University of Pisa, in Italy.

The findings "suggest the existence of a link between Alzheimer's disease progression and local alterations of thyroid hormone metabolism," they concluded.

Dr Chaker and the University of Pisa authors had no relevant financial relationships.

2015 International Thyroid Congress and Annual Meeting of the American Thyroid Association. Abstracts 5 and 771, presented October 19, 2015.

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