Beyond the Thyroid: Associations Between Thyroglobulin Antibody Burden and Neuropsychological Symptoms in Euthyroid Adults

Abstract

Background: Many adults with Hashimoto thyroiditis remain symptomatic while thyroid function tests stay within reference limits. Whether the concentration of circulating thyroglobulin antibodies (TgAb), rather than antibody positivity alone, relates to the severity of neuropsychological symptoms in euthyroid people has not been established.

Objective: To test whether TgAb concentration is independently associated with depressive symptoms, insomnia severity, and apathy in biochemically euthyroid adults.

Methods: A retrospective observational study was conducted using records from a private endocrine clinic (January 2022 to December 2024). Two hundred adults (120 men, 80 women; 69 TgAb-positive, 131 TgAb-negative) had TSH and free thyroxine within reference intervals, a same-day TgAb measurement, and complete Arabic-language PHQ-9, Insomnia Severity Index (ISI), and Apathy Evaluation Scale (AES-S) scores obtained during routine intake. Linear regression modeled each symptom score against log-transformed TgAb concentration with adjustment for age, sex, body mass index, TSH, FT4, thyroid peroxidase antibody (TPOAb) positivity, levothyroxine, psychotropic medication, documented psychiatric history, smoking, and chronic conditions. Six prespecified sensitivity analyses (seven model specifications including the primary model) examined TPOAb burden, medication use, psychiatric history, and influential observations.

Results: Each one-unit increase in log TgAb, equivalent to a 2.72-fold higher antibody concentration, was associated with a 0.93-point higher PHQ-9 score (95% CI 0.50–1.37) and a 0.97-point higher ISI score (95% CI 0.50–1.45), but showed no independent association with apathy (0.69; 95% CI −0.27–1.65). Coefficients were stable across all sensitivity models (PHQ-9 0.79–0.95; ISI 0.83–0.99). Across a ten-fold range of antibody concentration, adjusted predicted differences remained below 3 points on either scale. The full models explained 23.5% of PHQ-9 variance and 21.6% of ISI variance.

Conclusions: In euthyroid adults, higher TgAb concentrations showed modest, log-linear associations with depressive and insomnia symptom severity that persisted after adjustment and sensitivity testing; apathy was not associated. These findings are associational and do not support antibody-directed treatment or the use of TgAb as a diagnostic test.