The role of thyroid hormones in Alzheimer's disease: Associations with cerebrospinal fluid biomarkers and diagnostic performance

Background The relationship between serum thyroid function indicators and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology, as well as their diagnostic value in dementia differentiation, remains poorly understood in individuals without overt thyroid dysfunction. Objective The study aims to evaluate the diagnostic value of thyroid hormones in AD. Methods 225 participants including controls and Alzheimer's disease dementia (ADD), and 322 participants including controls, ADD and other neurodegenerative dementia (NonADD), were selected from cohort 1 and 2, respectively. CSF biomarkers (Aβ 42 , pTau181, tTau) and thyroid function indicators including free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3), total thyroxine (TT4), and other related parameters, were measured. Statistical analyses assess predictive performance and correlations. Results In both cohorts, ADD patients exhibited significantly lower levels of FT3, FT4, TT3, and TT4 compared to CN and NonADD groups ( p < 0.001). ROC analyses demonstrated moderate diagnostic performance: serum thyroid hormones reached 0.763–0.856. Combined models integrating AD CSF biomarkers, thyroid hormones, and APOE genotype significantly improved classification (AUCs 0.906–0.952). Notably, across all participants, serum thyroid hormone levels correlated positively with Aβ 42 ( p < 0.01) and negatively with tau pathology ( p < 0.05), suggesting a link between thyroid hormone level and AD-related neurodegeneration. Conclusions Our findings demonstrate that AD patients exhibit distinct reductions in thyroid hormones (FT3/FT4/TT3/TT4) that correlate strongly with hallmark AD CSF biomarkers and the integration of thyroid indicators with CSF biomarkers significantly improves dementia subtype differentiation, supporting their potential as complementary diagnostic tools in clinical practice.