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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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