Calibration-Aware and Interpretable Graph Learning for Multi-Cohort Diffusion Connectome Brain-Age Modeling

Brain-age models derived from diffusion MRI-based structural connectomes may provide imaging biomarkers of accelerated brain aging, but their biological interpretation and transportability across heterogeneous populations remain uncertain. We developed a calibration-aware and hierarchically interpretable graph-learning framework and evaluated it across four independent aging and Alzheimer's disease-related cohorts: ADNI, Duke/UNC ADRC, HABS-HD, and AD-DECODE. The analysis included 1,093 connectome sessions from 789 participants. Cohort-specific graph neural networks were trained using participant-grouped cross-validation across five imaging and multimodal feature configurations. Prediction performance varied more strongly across cohorts than across feature sets, with imaging-only out-of-fold mean absolute error ranging from 4.72 years in ADNI to 9.75 years in AD-DECODE. The imaging-only graph neural network was competitive with ridge, elastic-net, and gradient-boosted regression models trained on matched vectorized connectome features, but was not uniformly superior. Age-bias-corrected brain-age gap was most consistently associated with reduced diffusion-derived microstructural integrity and structural-network organization across cohorts. In longitudinal analyses, corrected brain-age gap showed moderate-to-good within-person preservation in ADNI and HABS-HD, with intraclass correlation coefficients of 0.67 and 0.81, respectively; higher baseline values also predicted subsequent microstructural and network deterioration in ADNI. Multiscale SHAP analysis identified distributed contributions from global graph topology, regional imaging features, edge-derived regional summaries, and individual structural connections involving thalamic, striatal, frontal, parietal, cerebellar, hippocampal, and entorhinal circuitry. External transfer was highly sensitive to cohort shift: across 12 off-diagonal train-test evaluations, median mean absolute error decreased from 17.39 to 8.22 years after target-cohort linear recalibration, whereas median Pearson correlation remained 0.17. Because recalibration used target-cohort chronological age, it was interpreted as a diagnostic sensitivity analysis rather than deployable external validation. Together, these findings support calibration-aware diffusion-connectome brain age as an interpretable imaging biomarker of structural brain aging and prospective microstructural and network vulnerability, while emphasizing the need for cohort-specific calibration before external application.