Probabilistic Joint and Individual Variation Explained (ProJIVE) for Data Integration

Despite increasing adoption of multimodal approaches in Alzheimer's Disease (AD) research -- aimed at integrating molecular, structural, clinical, and genetic biomarkers to enhance disease characterization -- the relationships among these modalities remain poorly understood. A systematic analysis of their dynamic interaction is essential for improving disease modeling, identifying redundant assessments, and reducing patient burden and acquisition costs. In this paper, we present a quantitative analysis of multimodal AD biomarkers by integrating tau-PET, structural MRI, cognitive scores (MMSE and CDR), and APOE4 data from 789 subjects drawn from the ADNI dataset. In our analyses, we (A) quantify cross-modal mutual information and explained variance to assess redundancy and predictive dependencies; (B) examine associations between tau topologies and structural atrophy across brain regions to select informative ROIs; (C) perform a statistical decomposition of the tau-cognition association into atrophy-related and atrophy-independent components; (D) and identify a dominant neurodegenerative trajectory that aligns with cognitive decline. This study provides a systematic characterization of cross-modal relationships, improving the interpretability and selection of biomarkers in AD. Code is publicly available at: https://github.com/antonioscardace/Multimodal-AD.

The interaction between brain structure and genetic influences is key to understanding neuropsychiatric disorders. However, most large-scale datasets are unimodal, providing either neuroimaging or genetics data. We propose CALM, a framework that learns interpretable associations between brain ROIs and genetic pathways from completely disjoint populations. CALM aligns the two modalities in a shared latent space via linear projections that simultaneously match the class-conditional latent distributions and ensure group separability. These projections provide interpretable pathway--ROI associations. When trained on unimodal imaging and genetics datasets, CALM generalizes to an unseen paired dataset, outperforming several state-of-the-art methods and ablation baselines. We also demonstrate stability of the learned associations against a paired baseline. Our experiments on autism spectrum disorder reveal immune and metabolic pathways linked to specific cortical regions and are consistent with established literature. Thus, CALM opens the door to leveraging large unimodal repositories for studying cross-modal interactions in brain disorders across disparate datasets.

While various multimodal methods combining imaging and tabular data for Alzheimer's disease (AD) diagnosis were proposed, they are often limited in generalization across cohorts. In-context learning (ICL) has demonstrated excellent generalization performances and high flexibility in foundational tabular models such as TabPFN. To extend TabPFN's ICL to multimodal AD analysis, the main obstacle is that TabPFN is meta-trained on synthetic tabular priors that do not naturally match the statistical structure of image-derived features. We propose M$^2$PFN, an end-to-end framework that turns this tabular foundation model into a multimodal AD predictor. M$^2$PFN (i) performs differentiable inference through TabPFN's transformer, back-propagating task gradients into 3D-MRI and tabular encoders; (ii) aligns the two modalities into a shared subspace, via disentanglement and a contrastive objective, matched to the ICL engine's prior; and (iii) folds in a frozen tabular-only prediction through a learnable gated shortcut. Because the ICL engine stays frozen, its in-context mechanism is preserved for test-time generalization, while end-to-end training shapes the encoders into features it can exploit. On ADNI ($n=2240$, three-class CN/MCI/AD), M$^2$PFN attains $65.55\%$ macro-F1 and $82.21\%$ macro-AUC, surpassing a comprehensive set of unimodal and multimodal baselines. By swapping only the head for a TabPFN regressor, the same architecture regresses baseline MMSE on a $1250$-subject sub-cohort to test MAE $1.743$, outperforming every multimodal baseline. On two external cohorts (OASIS-3 and SCAN) with no retraining, M$^2$PFN achieves the best AUC and the lowest MMSE MAE across all baselines, and transfers even when the cognitive instrument changes.