Regional patch-based MRI brain age modeling with an interpretable cognitive reserve proxy

Accurate brain age prediction from MRI is a promising biomarker for brain health and neurodegenerative disease risk, but current deep learning models often lack anatomical specificity and clinical insight. We present a regional patch-based ensemble framework that uses 3D Convolutional Neural Networks (CNNs) trained on bilateral patches from ten subcortical structures, enhancing anatomical sensitivity. Ensemble predictions are combined with cognitive assessments to derive a cognitively informed proxy for cognitive reserve (CR-Proxy), quantifying resilience to age-related brain changes. We train our framework on a large, multi-cohort dataset of healthy controls and test it on independent samples that include individuals with Alzheimer’s disease and mild cognitive impairment. The results demonstrate that our method achieves robust brain age prediction and provides a practical, interpretable CR-Proxy capable of distinguishing diagnostic groups and identifying individuals with high or low cognitive reserve. This pipeline offers a scalable, clinically accessible tool for early risk assessment and personalized brain health monitoring.