Abstract
Comorbid cardiovascular and metabolic risk factors (CVM) differentially impact brain structure and increase dementia risk, but their specific magnetic resonance imaging signatures (MRI) remain poorly characterized. To address this, we developed and validated machine learning models to quantify the distinct spatial patterns of atrophy and white matter hyperintensities related to hypertension, hyperlipidemia, smoking, obesity, and type-2 diabetes mellitus at the patient level. Using harmonized MRI data from 37,096 participants (45-85 years) in a large multinational dataset of 10 cohort studies, we generated five in silico severity markers that: i) outperformed conventional structural MRI markers with a ten-fold increase in effect sizes, ii) captured subtle patterns at sub-clinical CVM stages, iii) were most sensitive in mid-life (45-64 years), iv) were associated with brain beta-amyloid status, and v) showed stronger associations with cognitive performance than diagnostic CVM status. Integrating personalized measurements of CVM-specific brain signatures into phenotypic frameworks could guide early risk detection and stratification in clinical studies.