Development and Validation of a Brain Aging Biomarker in Middle-Aged and Older Adults: Deep Learning Approach

Background Precise assessment of brain aging is crucial for early detection of neurodegenerative disorders and aiding clinical practice. Existing magnetic resonance imaging (MRI)–based methods excel in this task, but they still have room for improvement in capturing local morphological variations across brain regions and preserving the inherent neurobiological topological structures. Objective To develop and validate a deep learning framework incorporating both connectivity and complexity for accurate brain aging estimation, facilitating early identification of neurodegenerative diseases. Methods We used 5889 T1-weighted MRI scans from the Alzheimer’s Disease Neuroimaging Initiative dataset. We proposed a novel brain vision graph neural network (BVGN), incorporating neurobiologically informed feature extraction modules and global association mechanisms to provide a sensitive deep learning–based imaging biomarker. Model performance was evaluated using mean absolute error (MAE) against benchmark models, while generalization capability was further validated on an external UK Biobank dataset. We calculated the brain age gap across distinct cognitive states and conducted multiple logistic regressions to compare its discriminative capacity against conventional cognitive-related variables in distinguishing cognitively normal (CN) and mild cognitive impairment (MCI) states. Longitudinal track, Cox regression, and Kaplan-Meier plots were used to investigate the longitudinal performance of the brain age gap. Results The BVGN model achieved an MAE of 2.39 years, surpassing current state-of-the-art approaches while obtaining an interpretable saliency map and graph theory supported by medical evidence. Furthermore, its performance was validated on the UK Biobank cohort (N=34,352) with an MAE of 2.49 years. The brain age gap derived from BVGN exhibited significant difference across cognitive states (CN vs MCI vs Alzheimer disease; P<.001), and demonstrated the highest discriminative capacity between CN and MCI than general cognitive assessments, brain volume features, and apolipoprotein E4 carriage (area under the receiver operating characteristic curve AUC of 0.885 vs AUC ranging from 0.646 to 0.815). Brain age gap exhibited clinical feasibility combined with Functional Activities Questionnaire, with improved discriminative capacity in models achieving lower MAEs (AUC of 0.945 vs 0.923 and 0.911; AUC of 0.935 vs 0.900 and 0.881). An increasing brain age gap identified by BVGN may indicate underlying pathological changes in the CN to MCI progression, with each unit increase linked to a 55% (hazard ratio=1.55, 95% CI 1.13-2.13; P=.006) higher risk of cognitive decline in individuals who are CN and a 29% (hazard ratio=1.29, 95% CI 1.09-1.51; P=.002) increase in individuals with MCI. Conclusions BVGN offers a precise framework for brain aging assessment, demonstrates strong generalization on an external large-scale dataset, and proposes novel interpretability strategies to elucidate multiregional cooperative aging patterns. The brain age gap derived from BVGN is validated as a sensitive biomarker for early identification of MCI and predicting cognitive decline, offering substantial potential for clinical applications.