ORIGINAL RESEARCH article
Front. Neurol.
Sec. Dementia and Neurodegenerative Diseases
Thyroid Function Status and Heterogeneity of Efficacy of Maintenance Cognitive Stimulation in Late‑Life Dementia: A Stratified Observational Study of Subclinical Hypothyroidism/Hyperthyroidism
Provisionally accepted
Ruili ZhangYongling ZhouShan WangFeng LiXuan ZhaoBowen JiaXiaxia LiJunhui YangLing YangHaiyuan YuXiaomin Yu
Xuebing Xu*- Ning An Hospital of Ningxia, Yinchuan, China
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Background: Cognitive Stimulation Therapy (CST) and its maintenance phase (MCST) can benefit dementia. We evaluated treatment-effect heterogeneity by euthyroid versus subclinical hypothyroidism/hyperthyroidism during the 16-week maintenance period following CST. Methods: We conducted a prospective single-center cohort embedded in routine CST to MCST. All entrants to 7-week CST were assessed at baseline/8/16/24 weeks. Sixteen-week MCST occurred per usual care. Baseline TSH/FT4/FT3 classified euthyroid, subclinical hypothyroidism (SCH) or hyperthyroidism (SHyper). Co-primary outcomes were 24-week MoCA and Zarit changes. We used doubly robust inverse‑probability‑of‑treatment weighting combined with linear mixed‑effects models to test MCST×thyroid interactions and controlled for multiple testing with a false‑discovery‑rate approach. Results: Of a total of 242 participants screened, 200 were enrolled, and 174 (87.0%) completed 24 weeks study session. MCST continuation was 112/200 (56.0%). Thyroid status was available for 196 participants, with 137 (69.9%) were euthyroid, 45 (23.0%) were SCH, and 14 (7.1%) were SHyper. The MCST×thyroid interaction for 24-week MoCA change was −0.9 (95% CI −1.6 to −0.2; p=0.012; q=0.012); MCST improved MoCA by +1.4 (95% CI +0.6 to +2.2) in euthyroid versus +0.5 (−0.4 to +1.3) in subclinical dysfunction. For Zarit, the interaction was +2.1 (95% CI +0.5 to +3.7; p=0.011; q=0.012), with larger burden reduction in euthyroid (−3.4; 95% CI −5.3 to −1.5) than subclinical (−1.3; −3.1 to +0.4). Secondary outcomes favored MCST but attenuated at higher TSH (spline χ²=8.9; p=0.030). Agitation occurred in 3 out of 200 participants (1.5%). Conclusions: MCST improved cognition and reduced caregiver burden over 24 weeks, with smaller benefits in subclinical thyroid dysfunction. Thyroid-aware personalization may better target maintenance cognitive interventions in late-life dementia.
Keywords: cognitive stimulation therapy, Dementia, Observational cohort, Subclinical hyperthyroidism, subclinical hypothyroidism, Thyroid function, treatment-effect heterogeneity
Received: 22 Sep 2025; Accepted: 18 Dec 2025.
Copyright: © 2025 Zhang, Zhou, Wang, Li, Zhao, Jia, Li, Yang, Yang, Yu, Yu and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xuebing Xu
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