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Background: Although loneliness and social isolation have been linked to an increased risk of non-communicable diseases such as cardiovascular disease and dementia, their association with the risk of severe infection is uncertain. We aimed to examine the associations between loneliness and social isolation and the risk of hospital-treated infections using data from two independent cohort studies. Methods: We assessed the association between loneliness and social isolation and incident hospital-treated infections using data for participants from the UK Biobank study aged 38–73 years at baseline and participants from the nationwide population-based Finnish Health and Social Support (HeSSup) study aged 20–54 years at baseline. For inclusion in the study, participants had to be linked to national health registries, have no history of hospital-treated infections at or before baseline, and have complete data on loneliness or social isolation. Participants with missing data on hospital-treated infections, loneliness, and social isolation were excluded from both cohorts. The outcome was defined as a hospital admission with a primary diagnosis of infection, ascertained via linkage to electronic health records. Findings: After exclusion of 8·6 million participants for not responding or not providing appropriate consent, the UK Biobank cohort consisted of 456 905 participants (249 586 women and 207 319 men). 26 860 (6·2%) of 436 001 participants with available data were reported as being lonely and 40 428 (9·0%) of 448 114 participants with available data were socially isolated. During a median 8·9 years (IQR 8·0–9·6) of follow-up, 51 361 participants were admitted to hospital due to an infectious disease. After adjustment for age, sex, demographic and lifestyle factors, and morbidities, loneliness was associated with an increased risk of a hospital-treated infection (hazard ratio [HR] 1·12 [95% CI 1·07–1·16]), whereas social isolation was not (HR 1·01 [95% CI 0·97–1·04]). Of 64 797 individuals in the HeSSup cohort, 18 468 (11 367 women and 7101 men) were eligible for inclusion. 4466 (24·4%) of 18 296 were lonely and 1776 (9·7%) of 18 376 socially isolated. During a median follow-up of 10·0 years (IQR 10·0–10·1), 814 (4·4%) participants were admitted to hospital for an infectious disease. The HRs for the HeSSup study replicated those in the UK Biobank (multivariable-adjusted HR for loneliness 1·32 [95% CI 1·06–1·64]; 1·08 [0·87–1·35] for social isolation). Interpretation: Loneliness might increase susceptibility to severe infections, although the magnitude of this effect appears modest and residual confounding cannot be excluded. Interventional studies are required before policy recommendations can advance. Funding: Academy of Finland, the UK Medical Research Council, and Wellcome Trust UK. CC BY 4.0This is an Open Access article under the CC BY 4.0 license© 2023 The Author(s)Correspondence Address: M. Elovainio; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland; email: marko.elovainio@helsinki.fiME was supported by the Academy of Finland (339390). PNS was supported by the Emil Aaltonen Foundation and Finnish Medical Foundation. JV was supported by the Academy of Finland (321409 and 329240). MK was supported by the UK Medical Research Council (S011676), Wellcome Trust UK (221854/Z/20/Z), National Institute on Aging USA (R01AG056477), and the Academy of Finland (350426). STN was supported by NordForsk (75021) and the Finnish Work Environment Fund (190424). CH was supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant number 101040247). This research has been done using the UK Biobank Resource under application number 14801.

Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.