Causal roles of phenotypic age and metabolic health on dementia: a Mendelian randomisation and structure learning study

Background Phenotypic age acceleration (PhenoAgeAccel), derived from PhenoAge, and MetaboHealth are composite exposures of biological ageing and metabolic health associated with dementia-related outcomes. Whether these associations are causal and reflect the exposures, constituent biomarkers, or both remains unclear. Methods This study included UK Biobank participants of White British genetic ancestry. MetaboHealth was derived from nuclear magnetic resonance (NMR) metabolomics and PhenoAgeAccel from clinical biomarkers and chronological age. Genome-wide association studies (GWAS) were conducted for MetaboHealth (n=272,568) and PhenoAgeAccel (n=274,077). Independent genome-wide significant variants were used as genetic instruments in two-sample Mendelian randomisation (MR) with FinnGen all-cause dementia summary statistics. Inverse-variance weighting was the primary MR method. Causal network analysis estimated relationships among constituent biomarkers and dementia. Findings GWAS identified 126 and 141 independent genome-wide significant variants for MetaboHealth and PhenoAgeAccel, of which 109 and 141 were retained as genetic instruments. MR found no evidence of a causal effect of genetically predicted MetaboHealth (per unit: OR 0.83, 95% CI 0.49-1.42; p=0.51) or PhenoAgeAccel (per year: OR 0.99, 95% CI 0.95-1.02; p=0.44) on all-cause dementia, with consistent findings across sensitivity analyses and robust MR methods. Lower lymphocyte percentage and higher NMR-derived glucose had direct relationships with dementia in the joint constituent-biomarker network. Interpretation MR provided no evidence that either composite exposure causally influenced dementia. The network prioritised lymphocyte percentage and NMR-derived glucose, supporting examination of composite exposures alongside their constituent biomarkers. Funding NIHR, UKRI, MRC, UK Dementia Research Institute, Innovate UK, and European Union. Full funding details are provided in the acknowledgements.