Associations of novel visceral obesity indices (METS-VF and BRI) with dementia: the role of metabolic mediators and genetic susceptibility

Background Visceral obesity-related indices may capture metabolically adverse adiposity more effectively than conventional obesity measures, but their comparative associations with dementia risk and the potential roles of metabolic dysfunction and genetic susceptibility remain insufficiently characterized. Methods In this prospective cohort study, 327,368 dementia-free participants from the UK Biobank were included. Body roundness index (BRI) and metabolic score for visceral fat (METS-VF) were first validated against imaging-derived visceral fat measures and then examined for their associations with incident all-cause dementia, Alzheimer’s disease (AD), and vascular dementia using Cox proportional hazards models and restricted cubic spline analyses. Additional analyses assessed subgroup effects, sensitivity, multicollinearity, incremental explanatory value beyond BMI and waist circumference (WC), metabolomic mediation, genetic susceptibility, and longitudinal changes in anthropometric and metabolic markers before dementia diagnosis. Results During follow-up, 8,768 participants developed dementia. METS-VF and BRI showed the strongest correlations with imaging-derived visceral adiposity among the tested obesity indices. Higher METS-VF levels were associated with increased risks of all-cause dementia, vascular dementia, and AD, with significant nonlinear threshold effects. BRI was also positively associated with all three dementia outcomes, although its association with AD was attenuated after full adjustment but remained statistically significant. The association between METS-VF and AD was particularly evident among individuals with low to intermediate genetic risk. Exploratory mediation analyses suggested that metabolic dysfunction may partly explain the observed associations between visceral obesity indices and dementia-free survival time. Among participants who subsequently developed dementia, WC and fasting blood glucose increased before diagnosis, whereas BMI remained relatively stable. Conclusion Visceral obesity, particularly as captured by METS-VF, was independently associated with increased dementia risk. These findings support moving beyond BMI-centric obesity definitions and highlight visceral adiposity-related metabolic dysfunction as a potential focus for dementia risk stratification and prevention research.