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July 12, 2022; 99 (2) Research Article

Associations of Social Isolation and Loneliness With Later Dementia

Chun Shen, Edmund T. Rolls, Wei Cheng, Jujiao Kang, Guiying Dong, Chao Xie, Xing-Ming Zhao, Barbara J. Sahakian, Jianfeng Feng
First published June 8, 2022, DOI: https://doi.org/10.1212/WNL.0000000000200583
Chun Shen
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Edmund T. Rolls
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Wei Cheng
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Jujiao Kang
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Guiying Dong
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Chao Xie
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Xing-Ming Zhao
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Barbara J. Sahakian
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Jianfeng Feng
From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
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Associations of Social Isolation and Loneliness With Later Dementia
Chun Shen, Edmund T. Rolls, Wei Cheng, Jujiao Kang, Guiying Dong, Chao Xie, Xing-Ming Zhao, Barbara J. Sahakian, Jianfeng Feng
Neurology Jul 2022, 99 (2) e164-e175; DOI: 10.1212/WNL.0000000000200583

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Abstract

Background and Objectives To investigate the independent associations of social isolation and loneliness with incident dementia and to explore the potential neurobiological mechanisms.

Methods We utilized the UK Biobank cohort to establish Cox proportional hazard models with social isolation and loneliness as separate exposures. Demographic (sex, age, and ethnicity), socioeconomic (education level, household income, and Townsend deprivation index), biological (body mass index, APOE genotype, diabetes, cancer, cardiovascular disease, and other), cognitive (speed of processing and visual memory), behavioral (current smoker, alcohol intake, and physical activity), and psychological (social isolation or loneliness, depressive symptoms, and neuroticism) factors measured at baseline were adjusted. Then, voxel-wise brainwide association analyses were used to identify gray matter volumes (GMVs) associated with social isolation and with loneliness. Partial least squares regression was performed to test the spatial correlation of GMV differences and gene expression using the Allen Human Brain Atlas.

Results We included 462,619 participants (mean age at baseline 57.0 years [SD 8.1]). With a mean follow-up of 11.7 years (SD 1.7), 4,998 developed all-cause dementia. Social isolation was associated with a 1.26-fold increased risk of dementia (95% CI, 1.15–1.37) independently of various risk factors including loneliness and depression (i.e., full adjustment). However, the fully adjusted hazard ratio for dementia related to loneliness was 1.04 (95% CI, 0.94–1.16) and 75% of this relationship was attributable to depressive symptoms. Structural MRI data were obtained from 32,263 participants (mean age 63.5 years [SD 7.5]). Socially isolated individuals had lower GMVs in temporal, frontal, and other (e.g., hippocampal) regions. Mediation analysis showed that the identified GMVs partly mediated the association between social isolation at baseline and cognitive function at follow-up. Social isolation–related lower GMVs were related to underexpression of genes that are downregulated in Alzheimer disease and to genes that are involved in mitochondrial dysfunction and oxidative phosphorylation.

Discussion Social isolation is a risk factor for dementia that is independent of loneliness and many other covariates. Social isolation–related brain structural differences coupled with different molecular functions also support the associations of social isolation with cognition and dementia. Social isolation may thus be an early indicator of an increased risk of dementia.

Glossary

AD=
Alzheimer disease;
BMI=
body mass index;
FDR=
false discovery rate;
GMV=
gray matter volume;
GO=
Gene Ontology;
HR=
hazard ratio;
ICD-10=
International Classification of Diseases–10;
KEGG=
Kyoto Encyclopedia of Genes and Genomes;
MNI=
Montreal Neurological Institute;
PERM=
percentage of excess risk mediated;
PLS=
partial least squares;
TIV=
total intracranial volume

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • This manuscript was prepublished in MedRxiv (doi: doi.org/10.1101/2021.06.30.21259818).

  • Submitted and externally peer reviewed. The handling editor was Linda Hershey, MD, PhD.

  • Editorial, page 47

  • Received October 21, 2021.
  • Accepted in final form March 8, 2022.
  • © 2022 American Academy of Neurology
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Letters: Rapid online correspondence

  • Author Response: Associations of Social Isolation and Loneliness With Later Dementia
    • Chun Shen, Postdoctoral research fellow, Fudan University
    • Jianfeng Feng, Professor, Fudan University
    Submitted July 17, 2022
  • Reader Response: Associations of Social isolation and Loneliness With Later Dementia
    • Tjalling J Holwerda, MD, PhD, Amsterdam UMC, The Netherlands
    Submitted July 01, 2022
  • Author response: Associations of Social Isolation and Loneliness With Later Dementia
    • Chun Shen, Postdoctoral research fellow, Fudan University
    • Barbara J. Sahakian, Professor, University of Cambridge
    • Jianfeng Feng, Professor, Fudan Univerisity
    Submitted June 30, 2022
  • Reader Response: Associations of Social Isolation and Loneliness With Later Dementia
    • Tomoyuki Kawada, Professor, Nippon Medical School
    Submitted June 09, 2022
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