A Hierarchical Multi-Modal Fusion Framework for Alzheimer’s Disease Classification Using 3D MRI and Clinical Biomarkers

Accurate and interpretable staging of Alzheimer’s disease (AD) remains challenging due to the heterogeneous progression of neurodegeneration and the complementary nature of imaging and clinical biomarkers. This study implements and evaluates an optimized Hierarchical Multi-Modal Fusion Framework (HMFF) that systematically integrates 3D structural MRI with clinical assessment scales for robust three-class classification of cognitively normal (CN), mild cognitive impairment (MCI), and AD subjects. A standardized preprocessing pipeline, including N4 bias field correction, nonlinear registration to MNI space, ANTsNet-based skull stripping, voxel normalization, and spatial resampling, was employed to ensure anatomically consistent and high-quality MRI inputs. Within the proposed framework, volumetric imaging features were extracted using a 3D DenseNet-121 architecture, while structured clinical information was modeled via an XGBoost classifier to capture nonlinear clinical priors. These heterogeneous representations were hierarchically fused through a lightweight multilayer perceptron, enabling effective cross-modal interaction. To further enhance discriminative capability and model efficiency, a hierarchical feature selection strategy was incorporated to progressively refine high-dimensional imaging features. Experimental results demonstrated that performance consistently improved with feature refinement and reached an optimal balance at approximately 90 selected features. Under this configuration, the proposed HMFF achieved an accuracy of 0.94 (95% Confidence Interval: [0.918, 0.951]), a recall of 0.91, a precision of 0.94, and an F1-score of 0.92, outperforming unimodal and conventional multimodal baselines under comparable settings. Moreover, Grad-CAM visualization confirmed that the model focused on clinically relevant neuroanatomical regions, including the hippocampus and medial temporal lobe, enhancing interpretability and clinical plausibility. These findings indicate that hierarchical multimodal fusion with interpretable feature refinement offers a promising and extensible solution for reliable and explainable automated AD staging.