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Research

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies

BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1804 (Published 19 August 2021) Cite this as: BMJ 2021;374:n1804

Linked Editorial

Cognitive stimulation at work and dementia
  1. Mika Kivimäki, professor123,
  2. Keenan A Walker, tenure-track investigator45,
  3. Jaana Pentti, senior statistician236,
  4. Solja T Nyberg, postdoctoral fellow2,
  5. Nina Mars, postdoctoral fellow7,
  6. Jussi Vahtera, professor emeritus68,
  7. Sakari B Suominen, professor69,
  8. Tea Lallukka, professor2,
  9. Ossi Rahkonen, professor emeritus2,
  10. Olli Pietiläinen, postdoctoral fellow2,
  11. Aki Koskinen, statistician3,
  12. Ari Väänänen, research professor3,
  13. Jatinderpal K Kalsi, project manager1,
  14. Marcel Goldberg, professor emeritus1011,
  15. Marie Zins, director1011,
  16. Lars Alfredsson, professor1213,
  17. Peter J M Westerholm, professor emeritus14,
  18. Anders Knutsson, professor emeritus15,
  19. Töres Theorell, professor emeritus16,
  20. Jenni Ervasti, senior research fellow3,
  21. Tuula Oksanen, professor17,
  22. Pyry N Sipilä, postdoctoral fellow2,
  23. Adam G Tabak, postdoctoral fellow118,
  24. Jane E Ferrie, senior research fellow119,
  25. Stephen A Williams, director20,
  26. Gill Livingston, professor2122,
  27. Rebecca F Gottesman, professor4,
  28. Archana Singh-Manoux, research professor111,
  29. Henrik Zetterberg, professor2324,
  30. Joni V Lindbohm, postdoctoral fellow12
  1. 1Department of Epidemiology and Public Health, University College London, London, UK
  2. 2Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  3. 3Finnish Institute of Occupational Health, Helsinki, Finland
  4. 4Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA
  5. 5Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, MD, USA
  6. 6Department of Public Health, University of Turku, Turku, Finland
  7. 7Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
  8. 8Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
  9. 9School of Health Science, University of Skövde, Skövde, Sweden
  10. 10Inserm UMS 011, Population-Based Epidemiological Cohorts Unit, Villejuif, France
  11. 11Université de Paris, INSERM U1153, Epidemiology of Ageing and Neurodegenerative Diseases, Paris, France
  12. 12Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  13. 13Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden
  14. 14Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  15. 15Department of Health Sciences, Mid Sweden University, Sundsvall, Sweden
  16. 16Stress Research Institute, Stockholm University, Stockholm, Sweden
  17. 17Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
  18. 18Department of Internal Medicine and Oncology and Department of Public Health, Semmelweis University, Budapest, Hungary
  19. 19Bristol Medical School, University of Bristol, Bristol, UK
  20. 20SomaLogic, Boulder, CO, USA
  21. 21Division of Psychiatry, University College London, London, UK
  22. 22Camden and Islington NHS Foundation Trust, London, UK
  23. 23Department of Neurodegenerative Disease and UK Dementia Research Institute, University College London, London, UK
  24. 24Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, and Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  1. Correspondence to: M Kivimäki m.kivimaki{at}ucl.ac.uk
  • Accepted 14 July 2021

Abstract

Objectives To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association.

Design Multicohort study with three sets of analyses.

Setting United Kingdom, Europe, and the United States.

Participants Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies.

Main outcome measures Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations.

Results During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted β −0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted β −0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted β −0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD.

Conclusions The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.

Footnotes

  • Contributors: MK, JP, STN, and JVL generated the hypothesis and designed the study. JV and SBS (Health and Social Support study), JE and TO (Finnish Public Sector study), TL, OR, and OP (Helsinki Health study), AK and AV (Still Working study), MG and MZ (GAZEL study), LA, PJMW, AK, and TT (WOLF-Stockholm and WOLF-Norland studies), JKK, JEF, and AS-M (Whitehall II study), and KAW and RFG (Atherosclerosis Risk in Communities study, ARIC) were responsible for cohort data. SAW was responsible for the protein assessments. JP performed pooled analyses on cognitive stimulation and dementia. JVL conducted imputed analyses in pooled data and, with NM, analysed protein data from the Whitehall study. KAW supervised protein analyses in the ARIC study. GL, PNS, and JEF contributed to expertise in dementia risk factors. HZ and AGT contributed to dementia and metabolic biology expertise. MK wrote the first draft of the report and JEF helped in revising the text. All authors discussed results and commented on the manuscript. MK is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: The research consortium on dementia risk factors (principal investigator MK) has received funding from NordForsk (75021, the Nordic Research Programme on Health and Welfare), the UK Medical Research Council (MRC S011676), the Wellcome Trust (221854/Z/20/Z), the Academy of Finland (311492, 329202), and Helsinki Institute of Life Science (H970). Protein analyses and MK, AS-M, and GL were supported by the Wellcome Trust (221854/Z/20/Z). MK and AS-M were also supported by the US National Institutes of Health (NIH, RF1AG062553, R01AG056477). JP, STN, JV, PNS, AS-M, AGT, and JVL were supported by NordForsk (75021). NM (331671), JV (321409, 329240), TL (330527), and OR (1294514) were supported by the Academy of Finland. OR was also supported by the Juho Vainio Foundation. JKK and AGT were supported by MRC (S011676). PNS was supported by the Helsinki Institute of Life Science (H970). HZ was a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at University College London. The Atherosclerosis Risk in Communities study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HSN268201100010C, HHSN268201100011C, and HHSN268201100012C), with neurocognitive data collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, National Institute on Aging, and National Institute on Deafness and Other Communication Disorders). KAW was supported by contract K23 AG064122 and RFG by contract K24 AG052573 from NIA. SOMAscan assays in the Whitehall and ARIC studies were funded by Somalogic as part of an academic-industry partnership project.15 The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from NordForsk, the UK Medical Research Council, the Wellcome Trust, the Academy of Finland, and the Helsinki Institute of Life Science. SAW is an employee of SomaLogic. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx, has given lectures in symposiums sponsored by Fujirebio, Alzecure and Biogen, and is a cofounder of Brain Biomarker Solutions in Gothenburg (BBS), which is a part of the GU Ventures Incubator Program.

  • The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: The dissemination plan targets a wide audience, including members of the public, patients, patient and public communities, health professionals, and experts in the specialty through various channels: written communication, events and conferences, networks, and social media.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Pre-existing access policies for individual level data for each of the participating cohort studies specify that research data requests can be submitted to each steering committee; these will be promptly reviewed for confidentiality, data protection issues, or intellectual property restrictions and will not unreasonably be refused. Code for the statistical analyses of this paper is provided in the supplementary file (pp 26-33).

http://creativecommons.org/licenses/by/4.0/

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

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