Brain age gap as biomarker linking cardiovascular diseases genetic susceptibility and causality

Cardiovascular diseases (CVDs) remain a primary cause of global mortality, underscoring the need for biomarkers that capture systemic aging risks. T1-weighted magnetic resonance imaging (MRI) data from UK Biobank (UKB) participants were utilized to develop a three-dimensional vision transformer (3D-ViT) model for predicting brain age and computing BAG, an imaging-derived indicator of biological aging. Causal BAG-CVD relationships were assessed through bidirectional Mendelian randomization (MR). The results substantiated significant brain-heart interactions, revealing that acute myocardial infarction (AMI) and chronic ischemic heart disease (CIH) were associated with decelerated brain aging (OR = 0.783; OR = 0.847), while an elevated BAG correlated with a reduced risk of AMI and CIH (OR = 0.954; OR = 0.969). These findings highlight BAG as an integrative indicator combining neuroimaging and genetic profiles. The observed bidirectional causality offers a biological framework for defining intervention strategies targeting comorbid brain and cardiovascular health.