Abstract
Brain age, a biomarker reflecting brain health relative to chronological age, is increasingly used in neuroimaging to detect early signs of neurodegenerative diseases and support personalized treatment plans. Two primary approaches for brain age prediction have emerged: morphometric feature extraction from MRI scans and deep learning (DL) applied to raw MRI data. However, a systematic comparison of these methods regarding performance, interpretability, and clinical utility has been limited. In this study, we present a comparative evaluation of two pipelines: one using morphometric features from FreeSurfer and the other employing 3D convolutional neural networks (CNNs). Using a multisite neuroimaging dataset, we assessed both model performance and the interpretability of predictions through eXplainable Artificial Intelligence (XAI) methods, applying SHAP to the feature-based pipeline and Grad-CAM and DeepSHAP to the CNN-based pipeline. Our results show comparable performance between the two pipelines in Leave-One-Site-Out (LOSO) validation, achieving state-of-the-art performance on the independent test set ( MAE = 3.21 with DNN and morphometric features and MAE = 3.08 with a DenseNet-121 architecture). SHAP provided the most consistent and interpretable results, while DeepSHAP exhibited greater variability. Further work is needed to assess the clinical utility of Grad-CAM. This study addresses a critical gap by systematically comparing the interpretability of multiple XAI methods across distinct brain age prediction pipelines. Our findings underscore the importance of integrating XAI into clinical practice, offering insights into how XAI outputs vary and their potential utility for clinicians.