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.