Hyperthyroidism May Raise Individual Risk of Dementia

Graves’ disease and toxic nodular goiter increase the odds that these patients will develop dementia, including Alzheimer’s disease and vascular dementia, a relationship perhaps driven by prolonged low TSH.

with Douglas Ross, MD, Huntington Potter, PhD, Virginia Sarapura, MD

The prevalence of diabetes in the United States is highest among minority populations and older Americans, with the rates rising in tandem with the increase in overweight and obesity.1 Alzheimer’s disease and vascular dementia (an adverse outcome of stroke or multiple transient ischemic attacks) are the two most prominent forms of dementia.2,3

In addition to the usual list of diabetes-related complications facing these individuals, dementia is becoming an increasingly concern particularly for these patients but its connection to thyroid function is too often overlooked.

Photo:Henadzi Pechan @ iStock

In a recent population-based study out of Denmark, investigators from the University of Southern Denmark examined the prevalence of dementia in individuals with hyperthyroidism to ascertain the relative risk of developing dementia in hyperthyroid patients.Their results may stand as a clinical reality check of a patient's cognitive health status as an element of the ongoing management of their hyperthyroidism.

What is the Connection between the Thyroid and the Brain?

For thyroid hormones, thyroxine (T4) and triiodothyronine (T3) to cross the blood-brain barrier, a transfer protein is required. Transthyretin (TTR), found in the serum and cerebral spinal fluid functions to move thyroid hormones into and around the brain where they provide neuronal and glial maintenance.5-7

In a very early study,8 investigators revealed lower levels of circulating TTR in patients with hyperthyroidism. In addition, they reported a negative correlation between TTR and free T4 levels with increased fT4 associated with lower TTR. When patients were treated for hyperthyroidism, an increase in TTR levels occurred as they shifted to a more euthyoidal state.Findings from another study demonstrated that TTR levels in spinal fluid were lower in individuals diagnosed with Alzheimer’s disease.9

Thus, the connection between hyperthyroidism and dementia was made; the significance of this association and to what degree these two conditions intersect was the aim of this recent Danish study.4

Noting Concordance between Dementia, Hyperthyroidism

The study,4 led by Lars Folkestad and colleagues, was a retrospective analysis of data obtained from the Danish National Patient Registry (DNPR) and the OPENTHYRO registry at Odense University Hospital. These patient records provided confirmation of primary and secondary diagnoses in two cohorts, accounting for nearly 99% of the Danish population.

In the DNPR cohort, data from patients diagnosed with Graves’ disease or toxic nodular goiter comprised the hyperthyroid group; individuals were excluded if dementia was diagnosed before hyperthyroidism. For every person with hyperthyroidism, reference data was collected from four control individuals and matched for age, sex, and risk (density sampling).

Sample sizes for each group were:

  • Hyperthyroidism—Cohort of n=55,656
    • Graves: n = 35,522 individuals
    • Goiters: n = 20,134 individuals
  • Reference sample: n = 220,561 individuals

Pattern Points to Risk of Cognive Decline with Low TSH 

Following analysis of the DNPR data, a strong association was reported with dementia. Individuals with hyperthyroidism were 13% more likely to develop dementia compared with the reference group (hazard ratio (HR ) = 1.13, 95% confidence interval (CI) = 1.07-1.19). The hazard ratios for cohorts with Graves' disease and goiter was similar at 1.13 and 1.18, respectively.

In breaking out the numbers for dementia into Alzheimer's disease and vascular dementia, the data revealed a greater risk in both dementias. Compared to the reference group, patients with hyperthyroidism had a 21% greater probability (HR = 1.21, CI = 1.04-1.40) of Alzheimer’s disease. Vascular dementia, too, was elevated with a 28% increased probability (HR = 1.28, CI = 1.03-1.57).

Results were similar for people with a goiter, in which the investigators reported a 41% increased probability of Alzheimer’s disease (HR = 1.41, CI = 1.21-1.63) occurring, and a 43% greater risk of vascular dementia (HR = 1.43, CI = 1.14-1.80). While not analyzed statistically, goiter-based hyperthyroidism appeared to have an increased probability of developing dementia than those with Graves’ disease in this Danish population.4

TSH Levels May Offer Indication of Dementia Risk

Data from the second cohort, the OPENTHYRO registry, was used to evaluate dementia based on thyroid-stimulating hormone (TSH) values taken during patient follow-up appointments. Patients with a diagnosis of hyperthyroidism and who had TSH samples measured at Odense University Hospital were categorized by baseline TSH, T4, and T3 levels. Hyperthyroid patients were then separated into two groups:

  • Overt Hyperthyroidism: two TSH measures < 0.3 mIU/L and a T4 > 135 ng/dLor T3 > 2.2 M/L  
  • Subclinical Hyperthyroidism: two TSH measures < 0.3 mIU/L and a T4< 135 ng/dL or T3 < 2.2 ng/dL  

The reference group had no diagnosis of hyperthyroidism and had measured TSH values between 0.3 and 4.0 mIU/L. The median follow-up time for each group was 5.2 years (IQR 5.1-11.9) for the reference group and 8.7 years (IQR 31.-7.9) for the hyperthyroid groups. Total patient numbers were 1,793 overt hyperthyroid patients, 445 subclinical patients, and 8,952 for the euthyroid references. As in with the DNPR, reference patients were matched for age, sex, and density sampling. 

Prolonged Low TSH Levels Portend Onset of Alzheimers'

The researchers found that for every six-month increment that TSH levels were low, the risk of dementia was 16% higher in hyperthyroidism than in euthyroid individuals (HR = 1.16, CI = 1.12-1.22).

When a patient experienced five years of low TSH levels, they were 4.4 times more likely to develop dementia compared to those with more normative TSH levels.

In reviewing the findings, Douglas S. Ross, MD, professor of medicine at Harvard Medical School and co-director of Thyroid Associates at Massachusetts General Hospital in Boston, Massachusetts, told  EndocrineWeb: "This should certainly be part of the discussion with patients whose hyperthyroidism is poorly managed due to poor compliance with treatment, or failure to accept treatment."

There was another key finding—Rates of subclinical hyperthyroidism were associated with greater risk of dementia than in patients with overt hyperthyroidism and the reference group. There was no significant difference between the latter two groups (HR=0.86, CI=0.66-1.10). Individuals with subclinical hyperthyroidism, though, had a 57% greater risk for dementia than the reference group (HR=1.57, CI= 1.16-2.13).

The authors reported that since patients were grouped using baseline TSH levels, it is possible that many overt hyperthyroid patients were treated during the follow-up period- reducing their risk of dementia. Subclinical hyperthyroid patients are not typically treated such that their TSH levels may remain depressed for longer, revealing a possible relationship between dementia and low TSH status in untreated patients. 

Dementia Link to Thyroid Disease Worthy of Attention

“The two interesting aspects of this study are that the increased risk of dementia was seen in both Graves’ disease and toxic nodular goiter. While the former is an autoimmune disorder, the latter is not, suggesting that it is the hyperthyroidism per se and not autoimmunity that is contributing to the increased dementia risk,” Dr. Ross told EndocrineWeb.

While dementia has been linked to many different other conditions,1thyroid function  rarely, if ever, makes the list, so EndocrineWeb reached out to Huntington Potter, PhD, Kurt N. and Edith von Kaulla Memorial Professor of Neurology, and director of the Alzheimer's and Cognition Center at the University of Colorado School of Medicine in Aurora, for his insights on the study findings.

“There is increasing interest in the relationship between hyperthyroidism and associated low thyroid-stimulating hormone and Alzheimer's disease. This [paper] reports a clear correlation between hyperthyroidism and risk of dementia in two large cohorts, thus reinforcing the need to understand the mechanism linking these two disorders,” Dr. Potter said.

For clinicians, this study emphasizes the importance of following through with patients who demonstrate consistently low TSH levels, even if they exhibit no overt signs of hyperthyroidism, a conclusion to which Virginia Sarapura, MD, professor of endocrinology, aat the University of Colorado School of Medicine, also agreed.

“This study highlighted the importance of maintaining a euthyroid state, not only to preserve cardiac and bone health, as is well known, but also to prevent the development of dementia,” Dr. Sarapura told EndocrineWeb.

What to do for older patients with subclinical hyperthyroidism?

"Treatment for subclinical hyperthyroidism can be controversial but guidelines suggest treatment for TSH levels below 0.1 mIU/L in the elderly, which is the population at risk for dementia," said Dr. Ross. "While the hyperthyroidism is treated by endocrinologists, referral to a neurologist [may be considered] based on symptoms, signs and concerns of dementia."

The authors report no competing financial conflicts with regard to their involvement in conducting or discussing this study

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