Regional brain aging signatures predict mortality through neurovascular immune mechanisms

Brain aging provides an integrative marker of systemic health, but whether regional patterns outperform whole-brain approaches remains unknown. Here, we show that regional brain age signatures achieve superior mortality prediction through identifiable neurovascular-immune mechanisms in 1,240 community-dwelling adults followed for 10 years (120 deaths). While global brain age independently predicts mortality (hazard ratio [HR], 1.044 per year), a data-driven three-region model combining the left precentral gyrus, left parahippocampal gyrus, and right cerebellum achieves superior discrimination (C-index, 0.81 vs. 0.79, p = 0.032). Integration with plasma proteomics (513 proteins) reveals complement activation and adaptive immune dysregulation as convergent mechanisms. Region-specific vulnerabilities emerge: microvascular dysfunction in the motor cortex, proteostasis failure in the medial temporal structures, and iron dysregulation in the cerebellum. Longitudinal imaging (n = 444) identifies accelerated brain aging phenotypes predicting cognitive decline (HR, 1.558; p = 0.042). These findings establish regional neuroimaging-proteomic integration as a precision strategy linking network-specific vulnerabilities to systemic immune processes.