University of Oulu

Pyry N Sipilä, Nelli Heikkilä, Joni V Lindbohm, Christian Hakulinen, Jussi Vahtera, Marko Elovainio, Sakari Suominen, Ari Väänänen, Aki Koskinen, Solja T Nyberg, Jaana Pentti, Timo E Strandberg, Mika Kivimäki, Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort, The Lancet Infectious Diseases, Volume 21, Issue 11, 2021, Pages 1557-1567, ISSN 1473-3099,

Hospital-treated infectious diseases and the risk of dementia : a large, multicohort, observational study with a replication cohort

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Author: Sipilä, Pyry N.1,2,3; Heikkilä, Nelli4,5; Lindbohm, Joni V.1,6;
Organizations: 1Clinicum, Department of Public Health, University of Helsinki, Helsinki, Finland
2Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
3Finnish Institute of Occupational Health, Helsinki, Finland
4Medicum, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
5Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
6Department of Epidemiology and Public Health, University College London, London, UK
7Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
8Finnish Institute for Health and Welfare, Helsinki, Finland
9Department of Public Health, University of Turku, Turku, Finland
10Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
11Research Programs Unit, University of Helsinki, Helsinki, Finland
12Research Services, Turku University Hospital, Turku, Finland
13School of Health Sciences, University of Skövde, Skövde, Sweden
14Department of Medicine, Helsinki University Hospital, Helsinki, Finland
15Center for Life Course Health Research, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: Elsevier, 2021
Publish Date: 2022-02-08


Background: Infections have been hypothesised to increase the risk of dementia. Existing studies have included a narrow range of infectious diseases, relied on short follow-up periods, and provided little evidence for whether the increased risk is limited to specific dementia subtypes or attributable to specific microbes rather than infection burden. We aimed to compare the risk of Alzheimer’s disease and other dementias across a wide range of hospital-treated bacterial and viral infections in two large cohorts with long follow-up periods.

Methods: In this large, multicohort, observational study, the analysis was based on a primary cohort consisting of pooled individual-level data from three prospective cohort studies in Finland (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study) and an independent replication cohort from the UK Biobank. Community-dwelling adults (≥18 years) with no dementia at study entry were included. Follow-up was until Dec 31, 2012, in the Health and Social Support study, Dec 31, 2016, in the public sector study and the Still Working study, and Feb 7, 2018, in the replication cohort. Through record linkage to national hospital inpatient registers, we ascertained exposure to 925 infectious diseases (using the International Classification of Diseases 10th Revision codes) before dementia onset, and identified incident dementia from hospital records, medication reimbursement entitlements, and death certificates. Hazard ratios (HRs) for the associations of each infectious disease or disease group (index infection) with incident dementia were assessed by use of Cox proportional hazards models. We then repeated the analysis after excluding incident dementia cases that occurred during the first 10 years after initial hospitalisation due to the index infection.

Findings: From March 1, 1986, to Jan 1, 2005, 260 490 people were included in the primary cohort, and from Dec 19, 2006, to Oct 1, 2010, 485 708 people were included in the replication cohort. In the primary cohort analysis based on 3 947 046 person-years at risk (median follow-up 15·4 years [IQR 9·8–21·0]), 77 108 participants had at least one hospital-treated infection before dementia onset and 2768 developed dementia. Hospitalisation for any infectious disease was associated with increased dementia risk in the primary cohort (adjusted HR [aHR] 1·48 [95% CI 1·37–1·60]) and replication cohort (2·60 [2·38–2·83]). The association remained when analyses were restricted to new dementia cases that occurred more than 10 years after infection (aHR 1·22 [95% CI 1·09–1·36] in the primary cohort, the replication cohort had insufficient follow-up data for this analysis), and when comorbidities and other dementia risk factors were considered. There was evidence of a dose-response association between the number of episodes of hospital-treated infections and dementia risk in both cohorts (ptrend=0·0007). Although the greatest dementia risk was seen for central nervous system (CNS) infections versus no infection (aHR 3·01 [95% CI 2·07–4·37]), excess risk was also evident for extra-CNS infections (1·47 [1·36–1·59]). Although we found little difference in the infection-dementia association by type of infection, associations were stronger for vascular dementia than for Alzheimer’s disease (aHR 2·09 [95% CI 1·59–2·75] versus aHR 1·20 [1·08–1·33] in the primary cohort and aHR 3·28 [2·65–4·04] versus aHR 1·80 [1·53–2·13] in the replication cohort).

Interpretation: Severe infections requiring hospital treatment are associated with long-term increased risk of dementia, including vascular dementia and Alzheimer’s disease. This association is not limited to CNS infections, suggesting that systemic effects are sufficient to affect the brain. The absence of infection specificity combined with evidence of dose-response relationships between infectious disease burden and dementia risk support the hypothesis that increased dementia risk is driven by general inflammation rather than specific microbes.

Funding: UK Medical Research Council, US National Institute on Aging, Wellcome Trust, NordForsk, Academy of Finland, and Helsinki Institute of Life Science.

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Series: The Lancet. Infectious diseases
ISSN: 1473-3099
ISSN-E: 1474-4457
ISSN-L: 1473-3099
Volume: 21
Issue: 11
Pages: 1557 - 1567
DOI: 10.1016/S1473-3099(21)00144-4
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3124 Neurology and psychiatry
3142 Public health care science, environmental and occupational health
Funding: This study was supported by grants from NordForsk (75021), the Academy of Finland (311492, 310591, 321409, 329240, 329202, 329224), Helsinki Institute of Life Science (H970), the US National Institute on Aging (R01AG056477), the UK Medical Research Council (MRC S011676/1, R024227/1), and the Wellcome Trust (221854/Z/20/Z). This research has been done using the UK Biobank Resource under application number 14801.
Copyright information: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.