The thyroid gland is the master metabolic regulator, coordinating the metabolism of every bodily organ and system. The thyroid and the brain are intricately linked through the hypothalamic-pituitary-thyroid axis. The brain acts as the conductor, informing the thyroid of hormone needs. Thyroid hormones in turn support neurological function by stimulating energetic pathways that fuel brain cells in addition to regulating neurotransmitter turnover. Age-associated disruptions in thyroid hormone availability have been linked with depression and accelerated neurodegeneration. Restoration of thyroid hormone levels and potency has thus been presented as a therapeutic tool to mitigate brain aging, cognitive decline, and mood disorders.
The thyronines T3 and T4 have been identified to influence GABAergic tone through inhibition of both nicotinic acetylcholine receptors (nAChRs) involved in attention, learning, and memory, and GABA-A receptors implicated in neuronal excitability. T3 exerts contrasting effects on NMDA (N-methyl-D-aspartate) receptors based on whether it is signaling through genomic vs. non-genomic pathways. In non-genomic scenarios, T3 inhibits NMDA receptors, while its genomic behavior promotes synaptic plasticity. Such a dual relationship provides clarity on the observation that both elevated and deficient thyronine levels contribute to cognitive impairment.
Thyronines also sensitize β-adrenoceptors to the effects of catecholamines while blocking muscarinic receptors. Furthermore, thyronines alter energy and calcium dynamics by modulating the Na+/K+/ATPase pump. Excess T3 intensifies mitochondrial respiration and reactive oxygen species generation without improving ATP synthesis, and stimulates JNK and p38 MAPK pathways, thereby potentiating hyperphosphorylated tau. Hyperthyroidism may subsequently attenuate focus and retention, amplify neuronal excitability, and exacerbate oxidative stress and tau protein accumulation. These effects translate into sympathetic overdrive that causes anxiety, restlessness, and insomnia; a lower seizure threshold; and finally neurotoxicity and neuronal loss.
In aging, the brain becomes resistant to thyroid hormone signaling. This may in part stem from diminished T4 to T3 conversion in the periphery, a weaker response of the thyroid to thyroid-stimulating hormone, lower thyronine transporter expression, or disrupted thyronine-related gene expression. Hypothyroidism can consequently go unnoticed in the geriatric population, demonstrated by the common finding of normal TSH in spite of inadequate serum free T4. It has been noted that Alzheimer’s disease is correlated with normal to slightly elevated TSH in spite of severely restricted T4 in the cerebrospinal fluid. Brain-specific hypothyroidism persists unaddressed. This condition alters processing of the amyloid precursor protein and reduces transthyretin-assisted amyloid-beta transport, culminating in accumulation of tau protein aggregates.
The implication of thyronine dysregulation in brain aging may also be related to the hormones’ impact on mitochondrial dynamics. As critical orchestrators of energetic pathways, thyronines moderate glucose uptake, mitochondrial biogenesis, oxidative phosphorylation, and generation of reactive oxygen species. Lower levels of thyroid hormones promote hypometabolism as well as poor mitochondrial performance that induces excess electron leakage and declines in ATP output. Mitochondrial impairment also undermines deiodinase activity and thyroid hormone signaling.
Finally, the chronic inflammatory state that accrues with age hinders adequate delivery of thyronines by thyroid hormone transporters to further compromise local thyronine availability. T3 itself is anti-inflammatory, triggering brain-derived neurotrophic factor transcription, inhibiting NF-kB, and prompting misfolded protein removal and microgial M2 polarization. The combined deficits of thyroid hormone and brain energy alongside neuroimmune activation collide to erode neuronal function and viability. The mechanistic underpinnings of impaired thyroid activity in brain aging support the potential of supplemental T3 and T4 to decrease the risk of dementia and improve cognitive status.
Last but not least are the thyronamines, derivatives of thyronines that are highly concentrated in the brain. T1AM is one of the most well characterized and demonstrates neuroprotective qualities. It affects histaminergic pathways, prompts autophagy through inhibition of mTOR and stimulation of trace amine-associated receptor 1 (TAAR1), and enhances neuronal survival and neuroplasticity via its interaction with ERK1/2, collectively attenuating amyloid-beta neurotoxicity. Furthermore, T1AM may act as a regulator for neuromodulators and neurotransmitters to influence cognition and behavior. It has thus been proposed that T1AM be used in the therapeutic management of dementia and neurocognitive deficits in the absence of thyroid dysfunction.
Alruwaili NS, Al-Kuraishy HM, Fawzy MN, Al-Gareeb AI, Fahad EH, Batiha GE. Thyronines and thyronamines: dual modulators of synaptic plasticity, cognitive decline, and geriatric depression in the aging brain. Behav Brain Res. Published online May 27, 2026. doi:10.1016/j.bbr.2026.116296