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

BackgroundIdentifying individuals at risk of dementia is essential for prevention and targeted disease-modifying strategies. We investigated whether metabolomic ageing in mid-life is associated with incident dementia and dementia age of onset. We also explored joint associations and interactions with genetic risk, including APOE genotype and dementia polygenic scores. MethodsThe UK Biobank is a community-based observational study of middle-aged and older adults. The Nightingale Health platform was used to quantify plasma metabolites at baseline. Metabolomic age (MileAge) delta represents the difference between metabolite-predicted and chronological age. Dementia cases were identified from primary care, hospital inpatient, death registry and self-reported physician diagnosis data. Associations between MileAge delta and incident dementia were estimated using Cox proportional hazards models. ResultsAmongst 223,496 participants, 3976 developed dementia. A metabolite-predicted age exceeding chronological age was associated with higher hazards of all-cause, unspecified and vascular dementia (HR = 1.61, 95% CI 1.28-2.02, p = 0.001). A higher MileAge delta was also associated with an earlier dementia onset. Key contributors to the MileAge clock included lipids, lipoproteins and amino acids, which were also associated with dementia. Genetic risk and MileAge delta were jointly associated with incident dementia. For example, individuals with a MileAge exceeding chronological age and two copies of the APOE {varepsilon}4 allele had 10.27-fold higher hazards of all-cause dementia (95% CI 7.93-13.30, p < 0.001). ConclusionsMetabolomic ageing in mid-life was associated with incident vascular, unspecified and all-cause dementia, as well as an earlier onset, including of Alzheimers disease. Genetic risk and MileAge delta were jointly associated with incident dementia, likely representing independent pathways.