Metabolomic ageing (MileAge) in mid-life predicts incident vascular, unspecified and all-cause dementia

Introduction: Identifying individuals at risk of dementia is essential for prevention and targeted disease-modifying strategies. We investigated whether mid-life metabolomic ageing is associated with incident dementia and its age of onset and assessed joint associations and interactions with APOE genotype and dementia polygenic scores. Methods: In the UK Biobank, plasma metabolites were quantified at baseline. Metabolomic age (MileAge) delta reflects the difference between metabolite-predicted and chronological age. Dementia was identified via health records. Results: Amongst 223,496 participants, 3976 developed dementia. A higher MileAge delta was associated with higher hazards of all-cause, unspecified and vascular dementia (HR = 1.61, 95% CI 1.28-2.02, p = 0.001) and earlier onset. Key metabolites were lipids, lipoproteins and amino acids. MileAge delta and genetic risk were jointly associated with dementia. Individuals with a high MileAge delta and two APOE ε4 alleles had a 10.30-fold higher all-cause dementia risk (95% CI 7.95-13.34, p < 0.001). Discussion: Metabolomic ageing and genetic risk likely represent independent biological pathways contributing to dementia risk.