Social isolation, loneliness, genetic risk, and incident dementia in people with type 2 diabetes mellitus: A population-based cohort study

Background Social isolation and loneliness, two independent constructs of social disengagement, are becoming increasingly recognized factors for dementia risk. Objective We aimed to investigate whether these two constructs also associate with dementia risk in individuals with type 2 diabetes mellitus (T2DM), which is becoming more prevalent. Methods The longitudinal study included 24,986 participants (mean age: 60.0 ± 6.9 years, median follow-up: 12.0 years) with T2DM at baseline from the UK Biobank. Social isolation and loneliness were assessed using self-reported questionnaires. Genetic risk factors for dementia including polygenic risk score (PRS) and APOE genotype were extracted. We identified incident dementia cases by linking hospital records and death registries. Results Social isolation (most versus least: hazard ratio, HR: 1.46 [95% confidence intervals, CI: 1.22–1.75]) and loneliness (yes versus no: 1.56 [1.25–1.95]) were associated with an increased risk of incident dementia after adjusting for demographic factors; however, such associations attenuated when further adjusting for health behaviors, psychological factors, or diabetes-related characteristics. The social isolation-dementia association was predominantly attributable to health behaviors (48% for the most social isolation), while the loneliness-dementia association was largely explained by psychological factors (46%). Significant modification effects of dementia genetic risk were observed in these associations. Conclusions Social isolation and loneliness were associated with a greater risk for incident dementia among T2DM individuals, with differential explanatory factors. The genetic risk for dementia modified these associations. The findings underscore the importance of strengthening social connections to mitigate diabetes-related dementia risk.