ProMUSE: Progressive Multi-modal Uncertainty-guided Staged Evidential Alzheimer Disease Classification

Missing modalities are prevalent in real-world Alzheimer's disease (AD) assessment and pose a significant challenge to multimodal learning, particularly when the distribution of observed modality subsets differs between training and deployment. Such missingness pattern mismatch induces a conditional representation shift across modality subsets. Existing approaches that rely on implicit imputation or modality synthesis often fail to explicitly model modality availability and uncertainty, leading to overconfident dependence on synthesized features, reduced robustness, and miscalibrated uncertainty estimates. To address these limitations, we propose PRA-PoE, an incomplete multimodal learning framework that is equipped with Prototype-anchored Representation Alignment (PRA) and an Uncertainty-aware Product of Experts (UA-PoE) fusion mechanism. First, PRA uses learnable global prototypes and availability-conditioned tokens to encode modality availability, distinguish observed from missing modalities, re-synthesize features for missing modalities, and adaptively refine observed representations to align latent spaces across modality subsets, with the goal of reducing representation shift under varying missingness patterns. Second, UA-PoE models each modality as a Gaussian expert and performs closed-form Product of Experts fusion, where experts with higher uncertainty are automatically down-weighted via lower precision, improving uncertainty reliability. We evaluate PRA-PoE under a clinically realistic protocol by training with naturally missing data and testing on all non-empty modality combinations. PRA-PoE consistently outperforms the state-of-the-art across datasets, achieving a 5.4% relative improvement in average accuracy on ADNI and a 10.9% relative gain in average F1 on OASIS-3 over the strongest baseline across all non-empty modality subsets.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder and a leading cause of death worldwide. Early diagnosis plays an important part especially at the Mild Cognitive Impairment stage, where timely intervention can help slow its progression before it advances to AD. Neuroimaging data, like Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) scans, can help detect brain changes early by providing structural and functional brain changes related to the disease. Yet, many multimodal models still fuse MRI and PET with static concatenation and apply identical computation to all subjects, which limits robustness to patient/site heterogeneity and can waste computation. To address these limitations, we present the first study of combining 3D convolutional feature extractors with three fusion strategies - concatenation, Gated Multimodal Unit (GMU), and gated self-attention - and a sparsely gated Mixture-of-Experts (MoE) classifier that performs input-adaptive routing, activating only the most informative experts per case. Finally, we utilize Grad-CAM to visualize disease-related regions, ensuring model interpretability. Experiments are performed across three binary classification tasks (NC vs. MCI, MCI vs. AD, and NC vs. AD). Results show that GMU achieves accuracies of 80.46 % (NC vs. MCI) and 95.47 % (NC vs. AD), while gated self-attention attains 82.08 % on MCI vs. AD. Ablations show that removing the MoE consistently degrades accuracy across all tasks. These findings underscore the value of input-adaptive, multimodal modeling for AD diagnosis by leveraging the complementary nature of MRI and PET.

Dementia is a major and growing global health burden, with Alzheimer's disease (AD) accounting for most cases. Timely and accurate diagnosis is central to managing this burden and increasingly depends on integrating complementary clinical and imaging information. Multimodal deep learning can combine these modalities for AD diagnosis, but how its explanations behave across modalities, fusion strategies, and cohorts remains unclear. We developed an explainable multimodal framework pairing a 3D CNN encoder for T1-weighted MRI with a feedforward network for harmonized clinical and demographic data, comparing varied model setups on three-way and pairwise diagnostic tasks using 6,479 internal records from the ADNI and 1,703 independent records from the OASIS-3. On ADNI, the tabular-only model achieved the highest three-class AUC-ROC of 0.879 and best discriminated cognitively normal (CN) versus mild cognitive impairment (MCI; 0.903), while cross-attention performed best for MCI versus AD (0.861); CN versus AD was highly discriminative overall. On OASIS-3, the vision-only model performed best (three-class AUC-ROC 0.910); CN versus MCI remained difficult, and no fusion strategy consistently outperformed single modalities across tasks and cohorts. SHAP and Integrated Gradients identified the MMSE as the dominant tabular feature in both cohorts, with global feature rankings agreeing strongly in ADNI ($\rho=0.94$) and OASIS-3 ($\rho=0.96$); CAM-based explanations, however, changed with model configuration and cohort. These findings show that multimodal performance and explanations are task, modality, fusion, and cohort-dependent: a dominant cognitive signal persisted across cohorts, but feature contributions and CAM explanations did not, underscoring the need to evaluate explainability under cohort shift rather than as a stable, intrinsic property.