AbstractAimsTo evaluate associations of metabolic profiles and biomarkers with brain atrophy, lesions, and iron deposition to understand the early risk factors associated with dementia.Materials and methodsUsing data from 26 239 UK Biobank participants free from dementia and stroke, we assessed the associations of metabolic subgroups, derived using an artificial neural network approach (self‐organizing map), and 39 individual biomarkers with brain MRI measures: total brain volume (TBV), grey matter volume (GMV), white matter volume (WMV), hippocampal volume (HV), white matter hyperintensity (WMH) volume, and caudate iron deposition.ResultsIn metabolic subgroup analyses, participants characterized by high triglycerides and liver enzymes showed the most adverse brain outcomes compared to the healthy reference subgroup with high‐density lipoprotein cholesterol and low body mass index (BMI) including associations with GMV (β_standardized −0.20, 95% confidence interval [CI] −0.24 to −0.16), HV (β_standardized −0.09, 95% CI −0.13 to −0.04), WMH volume (β_standardized 0.22, 95% CI 0.18 to 0.26), and caudate iron deposition (β_standardized 0.30, 95% CI 0.25 to 0.34), with similar adverse associations for the subgroup with high BMI, C‐reactive protein and cystatin C, and the subgroup with high blood pressure (BP) and apolipoprotein B. Among the biomarkers, striking associations were seen between basal metabolic rate (BMR) and caudate iron deposition (β_standardized 0.23, 95% CI 0.22 to 0.24 per 1 SD increase), GMV (β_standardized −0.15, 95% CI −0.16 to −0.14) and HV (β_standardized −0.11, 95% CI −0.12 to −0.10), and between BP and WMH volume (β_standardized 0.13, 95% CI 0.12 to 0.14 for diastolic BP).ConclusionsMetabolic profiles were associated differentially with brain neuroimaging characteristics. Associations of BMR, BP and other individual biomarkers may provide insights into actionable mechanisms driving these brain associations.