The thyroid regulates metabolism throughout the body through the release of thyroid hormones [1]. Thyroid function can be influenced by a variety of dietary micronutrients, such as iodine and vitamin B12 [2]. Reduced thyroid function, called hypothyroidism, slows the metabolism, leading to weight gain, while elevated thyroid activity, called hyperthyroidism, speeds up the metabolism, leading to weight loss. While the effects on body weight are often the most visible, changes to thyroid function impact all metabolically active tissues, including the most energetically demanding organ- the brain.
The brain is highly sensitive to levels of thyroid hormone. Insufficient thyroid hormone during development can result in mental retardation. In adults, clinical hypothyroidism is a cause of cognitive impairment which can be reversible upon the restoration of thyroid hormone levels [3]. In subclinical hypothyroidism, there are signs of reduced thyroid activity, but thyroid hormone levels are above the threshold for a clinical diagnosis. While obvious effects on cognitive function tend to be absent in individuals with subclinical hypothyroidism [4], sensitive brain imaging techniques indicate that brain activity is suboptimal [5]. In healthy individuals, having thyroid hormone levels near the higher end of the normal range has been associated with better performance in specific cognitive domains [6; 7]. Together, this indicates that proper thyroid function is important for optimal cognitive function. Due to conflicting evidence, it has been less clear whether thyroid dysfunction also poses a risk for irreversible forms of cognitive impairment, such as dementia. This has led to confusion about whether thyroid hormone replacement therapy enhances or reduces dementia risk.
A deeper dive into the biology of thyroid hormone helps explain both why hypothyroidism poses a risk for dementia and why thyroid hormone replacement is ineffective in reducing that risk for many people. Although hypothyroid-related cognitive impairment is considered reversible, the response to thyroid hormone replacement therapy is variable and often incomplete [3]. This is likely related to the way thyroid hormone works in the body. The thyroid primarily releases thyroid hormone in a low activity form called T4 [1]. T4 gets taken up into cells where it is locally converted into a highly active form called T3. Therefore, what matters most is the amount of T3 within a given tissue, like the brain, rather than the circulating level.
If someone has a deficit in the ability of their brain cells to take up T4 and make T3, then they could have brain-specific hypothyroidism, even though blood levels have been normalized. What would cause this to happen? It turns out there is genetic variation in the ability to convert T4 to T3, and some of the genetic variants that reduce this capacity are fairly common, with estimates ranging up to 30% of the population [8]. This may help explain why thyroid hormone therapy, which is usually given as T4, may not alleviate cognitive symptoms in some people, and why clinical trials testing this type of therapy for cognition have failed [5]. With respect to dementia, there is evidence that the levels of T3 are reduced in the Alzheimer’s disease brain [9], and that some of these genetic variants are associated with dementia risk [10].
While some studies indicate that hypothyroidism is associated with increased risk for dementia, others find no association, or that thyroid hormone therapy increases risk [11; 12; 13]. This may stem from the way hypothyroidism is measured in different studies. Since we currently lack a good way to measure brain levels of thyroid hormone, diagnoses are made from blood levels. Dementia risk, then, may be different for people classified as hypothyroid based on blood levels. People who have low thyroid hormone in the blood may still have normal thyroid hormone levels in the brain, and vice versa. Due to this variability, different studies can come to different conclusions depending on the composition of their study population. Additionally, very high levels of thyroid hormone can be toxic, so supplementation without a clear deficit can be harmful.
Overall, the risk from mild hypothyroidism appears to be low and most relevant in combination with other risk factors [10; 12]. Changes in thyroid function, such as subclinical hypothyroidism, is often seen in aging, but findings from clinical trials do not support the use of thyroid hormone supplementation for this indication [14]. Changes to certain dietary micronutrients also impact thyroid function. Thus, it is better to focus on interventions to improve overall health, such as diet, exercise, and the management of other chronic conditions.
Betsy Mills, PhD, is a member of the ADDF's Aging and Alzheimer's Prevention program. She critically evaluates the scientific evidence regarding prospective therapies to promote brain health and/or prevent Alzheimer's disease, and contributes to CognitiveVitality.org. Dr. Mills came to the ADDF from the University of Michigan, where she served as the grant writing manager for a clinical laboratory specializing in neuroautoimmune diseases. She also completed a Postdoctoral fellowship at the University of Michigan, where she worked to uncover genes that could promote retina regeneration. She earned her doctorate in neuroscience at Johns Hopkins University School of Medicine, where she studied the role of glial cells in the optic nerve, and their contribution to neurodegeneration in glaucoma. She obtained her bachelor's degree in biology from the College of the Holy Cross. Dr. Mills has a strong passion for community outreach, and has served as program presenter with the Michigan Great Lakes Chapter of the Alzheimer's Association to promote dementia awareness.
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