PRA-PoE: Robust Multimodal Alzheimer's Diagnosis with Arbitrary Missing Modalities
Authors: Guangqian Yang, Ye Du, Wenlong Hou, Qian Niu, Shujun Wang
Organizations: Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China · Department of Technology Management for Innovation, The University of Tokyo,2026 Japan · Department of Data Science and Artificial Intelligence, The Hong Kong Polytechnic University, Hong Kong SAR, China
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 a fatal disorder that destroys memory and cognitive skills in the elderly population. Most treatments for AD are effective in the early stage, leading to an increasing demand for early AD diagnosis. AD diagnosis increasingly relies on multimodal data such as clinical assessments, structural Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) imaging. However, MRI and PET acquisition remain costly and not universally accessible, making full-modality inference impractical in real-world clinical workflows. We propose ProMUSE, a Progressive Multi-modal Uncertainty Guided Staged Evidential Network that adaptively determines when additional modalities are necessary, helping reduce the overall cost of data acquisition while maintaining accuracy. ProMUSE first performs evidential classification using low-cost clinical data and quantifies uncertainty via a Dirichlet-based subjective logic model. When uncertainty exceeds a learned threshold, ProMUSE progressively incorporates MRI or PET features, fusing modality-wise belief and uncertainty through Dempster-Shafer theory to obtain a calibrated multimodal prediction. This staged acquisition strategy enables accurate diagnosis while minimizing reliance on expensive imaging. Experiments on ADNI, AIBL, and OASIS across CN-AD, CN-MCI, and MCI-AD tasks demonstrate that ProMUSE achieves competitive or superior accuracy compared to full-modality baselines while reducing MRI/PET usage by 50-90%, yielding substantial cost savings. These results highlight ProMUSE as a practical, uncertainty-aware, and resource-efficient solution for real-world AD screening.
Clinical decision making heavily relies on predicting the disease progression trajectory by seeking to understand patient's health status which is characterised by multimodal medical data. AI holds great potential for learning useful representations from multimodal medical data to predict disease progression and aid clinical decision making. However, development of predictive AI models is constrained by missing modalities and incomplete tabular data frequently occurring in medical datasets. In addition, disease labels alone may only provide limited supervisory signals for learning representations from high-dimensional multimodal data. Here, we present MMAP, a novel Multimodal Missing-aware Alignment Pretraining method for learning image-tabular representations from incomplete data. An image encoder is pretrained with efficient sigmoid contrastive learning combined with generative reconstruction. A tabular encoder is built upon a tabular foundation model. A missing token generator enables the two encoders to take incomplete data as input, enabling the model to be robust against missing modalities, either with missing images or missing tabular data. We evaluate the clinical usefulness of the learnt multimodal representations on two challenging longitudinal clinical tasks for Alzheimer's disease: predicting disease stage conversion and predicting amyloid status. The proposed method outperforms strong multimodal and unimodal baselines.
Multimodal clinical learning is increasingly important for integrating diverse patient data, including imaging, text, and personalised health records. However, it faces two fundamental challenges: i) modality missingness, where arbitrary subsets of modalities are unavailable at a given patient visit, ii) longitudinal dynamics, where the diagnostic significance of an observation depends on the patient's evolving disease trajectory over time. Existing methods address these challenges in isolation: missing-modality frameworks treat each visit as an independent static snapshot and discard temporal context, while longitudinal models often assume complete modality availability and degrade under systematic modality incompleteness. We propose LongMoE (Longitudinal Mixture-of-Experts), the unified framework to jointly address both challenges. LongMoE combines a context-aware imputation module with an attentional tokenization module that captures frequency-domain temporal patterns across irregular visit sequences, a trajectory-aware encoder for modeling disease progression, and context-conditioned Sparse MoE routing for patient-specific expert selection. Experiments on ADNI, OASIS-3, and MIMIC-IV show that LongMoE improves robustness under missing or weak contemporaneous modalities and remains competitive in full-modality settings, establishing a strong foundation for longitudinally-aware multimodal clinical learning.
Maxx Richard Rahman, Prakhar Kumar, Wolfgang Maass