Beyond peripheral symptoms: Hyperthyroidism as a risk factor for neurodegenerative disorders

Normal thyroid hormone function

Thyroid hormones are essential for brain development and function. Thyroxine (T4) must be converted to the active triiodothyronine (T3) form by deiodinase enzymes to exert effects on brain tissues. T3 acts through nuclear thyroid hormone receptors to regulate gene expression, influencing neuronal differentiation, myelination, and synaptic function.^[1,2]

Thyroid hormone transport across the blood–brain barrier occurs through specific transporters, notably monocarboxylate transporter 8 (MCT8). Mutations in MCT8 cause Allan–Herndon–Dudley syndrome, demonstrating the critical importance of proper thyroid hormone brain transport.^[7]

Within the brain, thyroid hormones modulate neurotransmitter systems including catecholaminergic, serotonergic, and cholinergic pathways.^[8] They also influence neuronal energy metabolism, mitochondrial function, and neurotropic factor regulation.^[9,10]

Brain structural changes in hyperthyroidism

Hyperthyroidism is associated with structural and functional brain changes that may predispose to neurodegeneration. Neuroimaging studies reveal altered gray matter volume and density in untreated hyperthyroidism, primarily affecting the hippocampus, parahippocampal gyrus, and prefrontal cortex – regions critical for cognition and vulnerable to neurodegeneration.^[11]

Functional MRI studies demonstrate disrupted connectivity in hyperthyroid patients, particularly in networks associated with cognitive control, attention, and memory.^[12,13] A recent systematic review by Tesfaye et al. analyzing brain functional connectivity in hyperthyroid patients confirmed widespread alterations in multiple neural networks, including the default mode network, salience network, and executive control network.^[13] These alterations may represent early neural network dysfunction that could progress to neurodegenerative changes. Li et al. reported abnormal functional connectivity patterns leading to impaired mood and cognition in hyperthyroidism.^[12]

Cerebrovascular effects of hyperthyroidism may also contribute to neurodegeneration. Elevated thyroid hormones can increase cerebral blood flow while promoting atherosclerosis and endothelial dysfunction, potentially increasing cerebrovascular disease risk and associated cognitive decline.^[14]

Hyperthyroidism and cognitive impairment

Numerous epidemiological studies have identified associations between thyroid dysfunction and cognitive impairment. Both overt and subclinical hyperthyroidism are associated with deficits in memory, attention, and executive function.^[15,16]

Wu et al.’s meta-analysis of 11 studies found both elevated free T4 levels and thyroid-stimulating hormone (TSH) levels below the normal range associated with increased dementia risk.^[19] The Heinz Nixdorf Recall Study reported TSH levels in the lower normal range associated with mild cognitive impairment.^[20] A systematic review by Amirabadi et al. reported impaired memory in overt hyperthyroidism,^[21] a finding supported by Zhu et al.^[22] Koyama et al. reported a case of reversible cognitive impairment due to hyperthyroidism.^[23] A review by Witkowska et al. showed that Graves’ disease negatively impacts cognition, encompassing deficits in mental functions such as memory, attention, reasoning, perception, language, and executive functions.^[24]

A meta-analysis by Rieben et al. demonstrated subclinical thyroid dysfunction, including subclinical hyperthyroidism, associated with increased cognitive decline risk in prospective cohorts.^[25] The Korean Longitudinal Study (2014) found lower-but-normal serum TSH levels associated with cognitive impairment development in elderly individuals.^[26]

Hyperthyroidism and Alzheimer’s disease (AD)

The hyperthyroidism-AD relationship has received particular attention. Several studies report associations between elevated thyroid hormones and increased AD risk.

Yeap et al. found that higher free T4 levels predicted increased dementia incidence, particularly AD, in older men.^[27] A registry-based study by Folkestad et al. demonstrated Graves’ disease and toxic nodular goiter, aggravated by hyperthyroidism duration, are associated with increased AD and vascular dementia risk.^[28]

Döbert et al. found increased dementia probability, especially vascular dementia, among those with decreased or borderline TSH values.^[29] Agarwal et al. revealed consistent associations between subclinical hyperthyroidism and AD in a cross-sectional study.^[30]

Tang et al.’s dose-response meta-analysis of 344,248 individuals found a J-shaped relationship [Figure 1] between thyroid function and dementia risk, with both hypo- and hyperthyroidism associated with increased risk, notably stronger for hyperthyroidism.^[31]

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Figure 1:

J-shaped relationship between thyroid function and dementia risk. Both hypothyroidism (RR=1.7) and hyperthyroidism (RR=2.2) show increased risk compared to the euthyroid state (RR=1.0). Error bars represent 95% confidence intervals.

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Li et al. demonstrated increased serum tau levels in hyperthyroidism patients, suggesting molecular links between thyroid hormone excess and AD pathogenesis.^[32] Li and Liu characterized the bidirectional thyroid dysfunctionAD relationship as a “vicious circle.”^[33] This complex interaction is illustrated in Figure 2.

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Figure 2:

Bidirectional relationship between hyperthyroidism and Alzheimer’s disease (AD). The diagram illustrates the complex interplay between hyperthyroidism and AD pathology, showing how elevated thyroid hormones can promote AD through oxidative stress, neuroinflammation, and tau phosphorylation, while AD-related changes can reciprocally affect thyroid function. The circular arrows represent the “vicious circle” concept where each condition exacerbates the other.

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Hyperthyroidism and Parkinson’s disease (PD)

The hyperthyroidism-PD relationship is less established but emerging evidence suggests connections. Charoenngam et al.’s meta-analysis found thyroid dysfunction, including hyperthyroidism, associated with increased PD risk.^[34]

Genetic studies by Xu et al. identified shared factors between thyroid hormone regulation and PD susceptibility.^[35] Epidemiological studies report increased PD risk in patients with autoimmune disorders, including autoimmune thyroid diseases.^[32]

Proposed mechanistic links involve altered dopaminergic neurotransmission, as thyroid hormones modulate dopamine synthesis, release, and receptor sensitivity.^[36]

Oxidative stress and mitochondrial dysfunction

Experimental evidence suggests that hyperthyroidism may promote neurodegeneration through increased oxidative stress. Elevated thyroid hormones enhance mitochondrial respiration and oxygen consumption, increasing reactive oxygen species (ROS) production and decreasing antioxidant metabolites.^[5,37]

In hyperthyroidism, the brain’s ROS production-antioxidant defense balance may become disrupted, leading to oxidative damage in neural tissues. Oxidative stress has been implicated in various neurodegenerative disorders including AD, PD, and amyotrophic lateral sclerosis.^[38]

Thyroid hormones influence mitochondrial biogenesis and function, critical for neuronal survival. Disrupted mitochondrial homeostasis in hyperthyroidism may compromise neuronal energy production, increasing vulnerability to neurodegeneration.^[10]

Neuroinflammation

Neuroinflammation represents another potential pathway linking hyperthyroidism to neurodegeneration. Experimental evidence suggests that elevated thyroid hormones may promote microglial and astrocyte activation, increasing pro-inflammatory cytokine and chemokine production in the brain.^[6]

Lou et al. demonstrated that hyperthyroidism exacerbated neuroinflammation, increased amyloid-β deposition, and accelerated cognitive decline in amyloid precursor protein (APP)/presenilin 1 mice. They observed increased pro-inflammatory markers including tumor necrosis factor-alpha, interleukin-1 beta (IL-1β), and IL-6 in hyperthyroid mouse brains.^[6]

Chronic neuroinflammation has been implicated in neuronal damage and dysfunction, potentially contributing to neurodegenerative disorder progression. Thyroid hormone modulatory effects on immune function suggest that thyroid dysfunction could influence neuroinflammatory processes.^[38]

Protein aggregation and clearance alterations

Neurodegenerative disorders often feature misfolded protein accumulation and aggregation, such as amyloid-β and tau in AD and α-synuclein in PD.^[39] Evidence suggests that thyroid hormones may influence these processes and cellular protein clearance mechanisms.

Li et al. reported elevated serum tau levels in hyperthyroidism patients, suggesting thyroid hormone excess promotes tau phosphorylation and aggregation, key AD pathogenesis events.^[40] Hyperthyroidism may impair autophagy and ubiquitin-proteasome function, compromising misfolded protein clearance.^[33]

Subhadra et al. suggested that AD neuroserpin up-regulation, which inhibits tissue plasminogen activator activity, affecting amyloid-beta plaque clearance, may result from thyroid hormone response system activation.^[41]

Thyroid hormone signaling influences enzymes involved in APP processing, potentially affecting amyloid-β production and deposition.^[28] These protein homeostasis effects may represent important mechanisms by which hyperthyroidism contributes to neurodegeneration.

Vascular mechanisms

Thyroid dysfunction may be linked to dementia through vascular mechanisms, as vascular risk factors and cardiovascular disease increase AD incidence risk.^[42] Both clinical and subclinical thyroid dysfunction are associated with increased cardiovascular risk.^[43]

Hyperthyroidism may affect blood–brain barrier integrity, potentially allowing harmful substances brain entry contributing to neurodegeneration.^[14] Combined altered neural connectivity and compromised blood–brain barrier effects may create neural environments conducive to neurodegenerative processes.

Figure 4 demonstrates the progressive deterioration of neural network connectivity from healthy controls through hyperthyroidism to neurodegeneration, showing how hyperthyroidism can create hyperconnectivity in certain brain regions (particularly involving the prefrontal cortex) that may precede the hypoconnectivity patterns characteristic of neurodegenerative disorders.

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Figure 4:

Neural network connectivity changes from health to neurodegeneration. Orange lines indicate hyperconnectivity, black lines show normal connectivity, and dashed lines represent reduced connectivity.

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Laboratory and imaging assessment

Hyperthyroidism diagnosis involves clinical assessment, biochemical testing, and imaging studies. Serum thyroid function tests, including TSH and free T4 (FT4) levels, represent diagnostic cornerstones. Primary hyperthyroidism shows suppressed TSH with elevated FT4 and/or free T3 (FT3).^[3,4]

Subclinical hyperthyroidism, characterized by suppressed TSH with normal FT4 and FT3, is particularly relevant for neurodegenerative disorders, potentially exerting subtle but significant cognitive effects over time.^[3,21,44]

Additional testing determines etiology, influencing management decisions. Thyroid autoantibodies, radioactive iodine uptake and scan, and thyroid ultrasonography are commonly employed.^[4]

Cognitive assessment should be considered in hyperthyroidism patients, particularly those at neurodegenerative risk. Standardized tools like Montreal Cognitive Assessment or Mini-Mental State Examination can identify cognitive deficits warranting further evaluation.^[45]

Neuroimaging studies provide valuable information about structural and functional brain changes. These may include gray matter volume alterations, particularly in the hippocampus and prefrontal cortex and functional connectivity disruptions.^[11,12]

Differential diagnosis considerations

Hyperthyroidism’s neuropsychiatric manifestations can mimic primary psychiatric or neurodegenerative disorders, creating diagnostic challenges. Anxiety disorders, bipolar disorder, and attention-deficit/hyperactivity disorder may present with similar symptoms.^[15]

In elderly patients, cognitive and behavioral changes may be misattributed to neurodegenerative disorders like AD or vascular dementia. Conversely, hyperthyroidism may be overlooked as a contributing factor in established neurodegenerative disorders, potentially missing intervention opportunities.^[30]

Thyroid dysfunction and neurodegenerative disorder coexistence is common in older adults. Careful thyroid function evaluation should be considered in cognitive impairment and neurodegeneration workup, even without classic thyroid dysfunction symptoms.^[46]