Summary

Target

To investigate the independent associations of social isolation and loneliness with the incidence of dementia and to explore possible neurobiological mechanisms.

Method

We used the UK Biobank cohort to establish a Cox proportional hazard model with social isolation and loneliness as separate exposures. Demographics (gender, age, and ethnicity), socioeconomic (education level, household income, and Townsend Deprivation Index), biological (BMI, APOE genotype, diabetes, cancer, cardiovascular disease, and other disabilities), cognitive (processing speed) and vision). Storage).

Behavioral (current smoking, alcohol use, and physical activity) and psychological (social isolation or loneliness, depressive symptoms, and neuroticism) factors measured at baseline were adjusted.

Then, voxel-based whole-brain association analysis was used to identify gray matter volume (GMV) is associated with social isolation and loneliness. Partial least squares regression was performed to examine the spatial correlation of GMV differences and gene expression using the Allen Human Brain Atlas.

Results

including 462,619 participants (mean age at baseline 57.0 years [DE 8,1]). With a median follow-up of 11.7 years (SD 1.7), 4,998 developed dementia from any cause. Social isolation was associated with a 1.26-fold increased risk of dementia (95% CI, 1.15–1.37) regardless of several risk factors, including loneliness and depression (ie, full adjustment).

However, the fully adjusted hazard ratio for loneliness-related dementia was 1.04 (95% CI, 0.94-1.16); and 75% of this association was due to depressive symptoms.

Structural MRI data were obtained from 32,263 participants (mean age 63.5 years). [DE 7,5]). Socially isolated individuals have lower GMV in temporal, frontal, and other areas (eg, hippocampus). Mediation analyzes showed that the identified gray matter volume (GMV) partially mediates the relationship between social isolation at baseline and cognitive function at follow-up.

Lower gray matter volume (GMV) associated with social isolation is associated with insufficient expression of genes that are downregulated in Alzheimer’s disease and with genes involved in mitochondrial dysfunction and oxidative phosphorylation.

conclusion

Social isolation is a risk factor for dementia that is independent of loneliness and many other covariates. Brain structural differences associated with social isolation, along with different molecular functions, also support the association of social isolation with cognition and dementia. Therefore, social isolation can be an early indicator of an increased risk of dementia.