The type 2 deiodinase Thr92Ala polymorphism and cognitive aging: current evidence and biological context

Type 2 iodothyronine deiodinase (DIO2) plays a central role in regulating thyroid hormone (TH) metabolism in the brain by catalyzing the conversion of thyroxine (T4) to the active triiodothyronine (T3), thereby ensuring adequate local TH signaling in neural tissues. Among DIO2 genetic variants, the Thr92Ala (rs225014) polymorphism has been extensively investigated in relation to TH homeostasis and diverse clinical phenotypes. Accumulating evidence suggests a potential association between the Thr92Ala variant and cognitive aging; however, findings across studies remain inconsistent. Proposed mechanisms include altered local TH availability, mitochondrial dysfunction, oxidative stress, and cerebrovascular regulation, although the relative contribution of these pathways has not been fully clarified. Emerging data further indicate that the cognitive effects attributed to the Thr92Ala polymorphism may be context-dependent and influenced by factors such as thyroid functional status, sex, genetic background, and age. In this narrative review, we integrate molecular, physiological, and clinical evidence linking the DIO2 Thr92Ala polymorphism to cognitive aging, with particular emphasis on biological context and sources of heterogeneity that may underlie divergent findings across populations. Rather than providing a quantitative synthesis, we aim to contextualize existing data within the broader regulatory framework of TH signaling to better understand how DIO2-related variation may contribute to brain aging.