Association of thyroid dysfunction with cognitive function: An individual participant data analysis

N.A. Van Vliet, D. Van Heemst, O.P. Almeida, B.O. Åsvold, C.E. Aubert, J.B. Bae, L.E. Barnes, D.C. Bauer, G.J. Blauw, C. Brayne, A.R. Cappola, G. Ceresini, H.C. Comijs, J.-F. Dartigues, J.-M. Degryse, R.P.F. Dullaart, M.E.A. Van Eersel, W.P.J. Den Elzen, L. Ferrucci, H.A. FinkL. Flicker, H.J. Grabe, J.W. Han, C. Helmer, M. Huisman, M.A. Ikram, M. Imaizumi, R.T. De Jongh, J.W. Jukema, K.W. Kim, L.H. Kuller, O.L. Lopez, S.P. Mooijaart, J.H. Moon, E. Moutzouri, M. Nauck, J. Parle, R.P. Peeters, M.H. Samuels, C.O. Schmidt, U. Schminke, P.E. Slagboom, E. Stordal, B. Vaes, H. Völzke, R.G.J. Westendorp, M. Yamada, B.B. Yeap, N. Rodondi, J. Gussekloo, S. Trompet

Research output: Contribution to JournalReview articleAcademicpeer-review

Abstract

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 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 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 74 565 total participants, 66 567 (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; 42 847 (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 74 000 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
Pages (from-to)1440-1450
Number of pages11
JournalJama internal medicine
Volume181
Issue number11
Early online date7 Sept 2021
DOIs
Publication statusPublished - Nov 2021

Funding

FundersFunder number
Becton Dickinson
BÄK
DGKL
Dutch Alzheimer Foundation
European Commission Horizon 2020
European Union Interreg01ZZ0403, INT-10-0008, 81Z7400171, 01ZZ0103, 01ZZ9603, 81Z7400173
GCCR
German Federal State of Mecklenburg-West Pomerania
German Medical Association
ISBER
Max Rubner-Institut
Netherlands Ministry of Health Welfare and Sports, Directorate of Long-Term Care
RERFRP-A2-16
National Institutes of Health
U.S. Department of Energy
National Institute on AgingICS110.1/RF97.71, N01-AG-6-2106, 263 MD, N01-AG-6-2101, R01-AG028050, N01-AG-6-2103
National Heart, Lung, and Blood Institute
National Institute of Nursing ResearchR01-NR012459
National Institute of Neurological Disorders and StrokeR01AG023629
National Institute of Arthritis and Musculoskeletal and Skin Diseases
AstraZeneca
National Center for Advancing Translational SciencesUL1TR002369, U01 AG027810, U01 AG042140, U01 AG042139, U01 AR066160, U01 AG042124, U01 AG042168, U01 AG042145, UL1 TR000128, U01 AG042143
Velux Stiftung1156
Oregon Clinical and Translational Research Institute
Deutsches Zentrum für Herz-Kreislaufforschung
Fresenius Medical Care North America
European Commission
National Health and Medical Research Council
Deutsche Forschungsgemeinschaft
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung75N92021D00006, HHSN268200800007C, N01HC55222, N01HC85081, U01HL080295, N01HC85082, HHSN268201800001C, N01HC85080, HHSN268201200036C, N01HC85086, N01HC85083, N01HC85079, SNSF 320030-172676, U01HL130114
Bundesministerium für Bildung und Forschung
NierstichtingE.033
Ministero della Salute
Ministry of Health, Labour and Welfare
Ministry of Health and WelfareA092077, HI09C1379
Horizon 2020666869
European Association for the Study of Diabetes

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