Associations of general and specific psychopathology factors by age 35 with dementia after age 50: a Swedish population-based sibling comparison study

Abstract Multiple psychiatric disorders are associated with later dementia, but it remains unclear whether these associations reflect a shared liability toward all psychiatric conditions (general psychopathology factor) or diagnosis-specific effects (specific psychopathology factors). In this Swedish register-based cohort study, we investigated these questions while adjusting for familial confounding shared by siblings ( N = 2 543 621 individuals, 1 485 880 full-sibling pairs). Exposures were (i) six psychiatric diagnoses recorded by age 35 and (ii) a latent bifactor model fit to these diagnoses that identified one general and three specific (internalizing, externalizing, and psychotic) psychopathology factors. Outcomes were all-cause dementia and Alzheimer’s disease recorded after age 50. For observed psychiatric diagnoses, we estimated between-individual (HR) and within-sibling hazard ratios (HR wn ) using Cox regression; for latent factors, we estimated between-individual (OR) and within-sibling odds ratios (OR wn ) using exploratory structural equation modelling. All psychiatric diagnoses were significantly associated with increased risk of all-cause dementia (HR range 2.03–3.59; HR wn range 1.72–2.94) and Alzheimer’s disease (HR range 1.89–3.47; HR wn range 1.77–3.22). These associations were largely attributable to the general psychopathology factor, even after adjusting for familial confounding (OR wn with 95% CI: 1.25 [1.17–1.32] for dementia; 1.24 [1.16–1.32] for Alzheimer’s disease). After accounting for the general factor, only the psychotic-specific factor remained associated (OR wn with 95% CI: 1.20 [1.07–1.36] for dementia; 1.20 [1.06–1.37] for Alzheimer’s disease). These results suggest that liability toward general psychopathology and, independently, psychotic conditions, by early adulthood might be early markers of increased dementia risk and targets for timely identification and prevention.