Nonlinear associations between animal- and plant-derived fats and dementia: integrating genetic risk and metabolomic profiling

Abstract Background The impact of dietary fat on dementia risk remains controversial due to conflicting findings on fat subtypes, over-reliance on linear models, and limited attention to fat source balance. Methods In a large prospective analysis of 97,765 UK Biobank adults, we examined associations between dietary fat composition and incident dementia, integrating genetic susceptibility and metabolomic profiling. Results Total fat intake, animal fat, and plant fat all showed significant U-shaped associations with dementia risk. Notably, the animal-to-plant fat ratio exhibited a clear U-shaped association ( P FDR for nonlinearity = 0.011), with the lowest risk observed at a ratio of 0.9. A significant interaction with APOE -ε4 carriage was identified ( P for interaction = 0.041), in which carriers in the lowest quartile of the fat ratio had the highest dementia risk (HR = 3.88, 95% CI: 3.00–5.00). A similar nonlinear pattern was observed for executive function. Mediation analyses implicated very-low-density lipoprotein-related metabolites as key intermediates. Conclusions These findings highlight the importance of balanced fat sources and support precision nutrition strategies tailored to genetic risk.