Association of Thyroid Dysfunction with Cognitive Function: An Individual Participant Data Analysis

Nicolien A. Van Vliet*, Diana Van Heemst, Osvaldo P. Almeida, Bjørn O. Åsvold, Carole E. Aubert, Jong Bin Bae, Linda E. Barnes, Douglas C. Bauer, Gerard J. Blauw, Carol Brayne, Anne R. Cappola, Graziano Ceresini, Hannie C. Comijs, Jean Francois Dartigues, Jean Marie Degryse, Robin P.F. Dullaart, Marlise E.A. Van Eersel, Wendy P.J. Den Elzen, Luigi Ferrucci, Howard A. FinkLeon Flicker, Hans J. Grabe, Ji Won Han, Catherine Helmer, Martijn Huisman, M. Arfan Ikram, Misa Imaizumi, Renate T. De Jongh, J. Wouter Jukema, Ki Woong Kim, Lewis H. Kuller, Oscar L. Lopez, Simon P. Mooijaart, Jae Hoon Moon, Elisavet Moutzouri, Matthias Nauck, Jim Parle, Robin P. Peeters, Mary H. Samuels, Carsten O. Schmidt, Ulf Schminke, P. Eline Slagboom, Eystein Stordal, Bert Vaes, Henry Völzke, Rudi G.J. Westendorp, Michiko Yamada, Bu B. Yeap, Nicolas Rodondi, Jacobijn Gussekloo, Stella Trompet

*Corresponding author for this work

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Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74565 total participants, 66567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism - cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P =.40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P =.09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines..

Original languageEnglish
Article numbere215078
Pages (from-to)1440-1450
Number of pages11
JournalJAMA Internal Medicine
Issue number11
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
reported grants from European Commission Horizon 2020 program during the conduct of the study. Dr van Heemst reported grants from European Commission during the conduct of the study; grants from Velux Stiftung (grant No. 1156) outside the submitted work. Dr Almeida reported grants from National Health and Medical Research Council of Australia during the conduct of the study and outside the submitted work. Dr Brayne reported grants from Medical Research Council during the conduct of the study. Dr Degryse reported grants from Fondation Louvain during the conduct of the study. Dr Flicker reported grants to the University of Western Australia from Australian National Health and Medical Research Council during the conduct of the study. Dr Grabe has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care outside the submitted work. Dr Huisman reported grants from Ministry of Health, Welfare and Sport for setting up and maintaining a prospective cohort study, of which data were used during the conduct of the study. Dr Lopez reported personal fees for consulting from Biogen and Grifols outside the submitted work. Dr Mooijaart reported nonfinancial support (provision of medication free of charge) from Merck during the conduct of the study. Dr Nauck reported grants from Federal Ministry of Education and Research, Germany, European Union Interreg IVa grants No. 01ZZ9603, 01ZZ0103, 01ZZ0403, 81Z7400171, 81Z7400173, INT-10-0008; personal fees for advisory boards and presentations from Radiometer, Becton Dickinson, AstraZeneca, Technopath Clinical Diagnostics, Novartis, Sysmex, Tosoh, medpoint Medizinkommunikations GmbH, ProteinT, and MDI Limbach; and travel/ accommodations expenses covered or reimbursed from German Medical Association (BÄK), German Centre for Cardiovascular Research (GCCR), National Cohort, German Society for Clinical Chemistry and Laboratory Medicine e.V. (DGKL), ISBER, DAkkS, Deutsche Forschungsgemeinschaft (DFG), European Association for the Study of Diabetes (EASD), and Max Rubner-Institut outside the submitted work. Dr Yeap reported grants from National Health and Medical Research Council of Australia during the conduct of the study. Dr Rodondi reported grants from Swiss National Science Foundation during the conduct of the study. No other disclosures were reported.

Funding Information:
9164 and 263 MD 821336), supported in part by the Intramural Research Program of the NIH National Institute on Aging, Baltimore, Maryland. This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (grant no. HI09C1379 [A092077]). The Longitudinal Aging Study Amsterdam is supported by a grant from the Netherlands Ministry of Health Welfare and Sports, Directorate of Long-Term Care. The Osteoporotic Fractures in Men Study is supported by NIH funding. The following institutes provide support: the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. MHS is supported by NIH NCATS UL1TR002369, The Oregon Clinical and Translational Institute. The PREVEND study was funded by the Dutch Kidney Foundation (https://; grant E.033). This study was partly funded by the Dutch Alzheimer Foundation ( The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a public interest foundation funded by the Japanese Ministry of Health, Labour and Welfare and the US Department of Energy. This publication was supported by RERF Research Protocol RP-A2-16. The views of the authors do not necessarily reflect those of the 2 governments. SHIP (Study of Health in Pomerania) is part of the Community Medicine Research Network of the University Medicine Greifswald, which is supported by the German Federal State of Mecklenburg-West Pomerania.

Funding Information:
Funding/Support: This work was supported by the European Commission project THYRAGE (Horizon 2020 research and innovation program, 666869). The Thyroid Studies Collaboration is funded by a grant from the Swiss National Science Foundation (SNSF 320030-172676 to Dr Rodondi). This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging. Dr Cappola received additional support from R01AG027058, Dr Kuller from R01AG15928, and Dr Lopez from R01AG20098. A full list of principal Cardiovascular Health Study investigators and institutions can be found at The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). This research was supported by National Institute on Aging contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; National Institute on Aging grant R01-AG028050, and National Institute of Nursing Research grant R01-NR012459. This research was funded in part by the Intramural Research Program of the NIH National Institute on Aging. The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. Information on incident dementia diagnoses for the HUNT study population was provided by Nord-Trøndelag Hospital Trust. The InCHIANTI study was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts: 263 MD

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