Circulating Metabolites are Linked to Dementia and Brain Imaging Phenotypes, and Mediate Modifiable Risk Pathways

Dementia poses an escalating global health burden, yet its underlying mechanisms remain incompletely understood. In this large-scale, targeted metabolomic study of UK Biobank participants, we applied machine learning models to 327 metabolite and lipid particle measures to identify metabolomic signatures predictive of incident all-cause dementia (ACD), Alzheimer’s disease (AD), and vascular dementia (VaD), beyond conventional risk factors. Metabolites within these signatures, including the linoleic acid to total fatty acids percentage (LA_pct), glutamine, branched-chain amino acids (BCAAs), low-density lipoprotein (LDL) size, small LDL phospholipids percentage (S_LDL_PL_pct) exhibited widespread associations with dementia outcomes and with neuroimaging markers, including brain atrophy and white matter hyperintensities (WMHs). Many of these key metabolites were associated with plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), and most were validated in an independent external cohort. Mediation analyses highlighted that several metabolites potentially mediate the effects of modifiable risk factors—such as obesity, diabetes, hypertension, and education—on dementia risk, with the strongest mediating effects observed for LA_pct in the association between obesity and both ACD and VaD. Mendelian randomization (MR) analyses suggested a potential causal relationship between several metabolites and AD, with glutamine emerging as the strongest candidate. Statistical colocalisation and expression quantitative trait loci (eQTL) integration revealed shared genetic loci between glutamine, SPRY domain-containing protein 4 (SPRYD4) gene expression levels and AD, and between LA_pct, fatty acid desaturase 1 (FADS1) gene expression levels and WMHs related brain atrophy (WMHs_atrophy). Mediation MR further highlighted potentially causal mediating roles for these metabolites in the association of gene expression and outcomes. Finally, multivariable MR (MVMR) indicated that glutamine partially mediates the positive relationship between educational attainment and AD. Overall, most MR associations aligned with neuroimaging-based associations, allowing triangulation of evidence and strengthening causal inference. These findings highlight blood metabolites could potentially present as promising biomarkers for early dementia detection and suggest links between modifiable lifestyle factors, metabolic dysfunction, and neurodegeneration, offering potential avenues for targeted prevention in at-risk populations.