Cross-disorder Learning of Imaging-derived Joint Mophometric Markers in Alzheimer's and Parkinson's Diseases

Deep learning models for Alzheimer disease (AD) classification routinely report near-perfect discrimination, yet few are shown to rest on AD-relevant neurobiology rather than on dataset artifacts, subject-level leakage, or non-brain image content. We present a fusion network combining T1 MRI and FDG PET across axial, coronal, and sagittal planes, trained on ADNI consists of 554 paired subjects. The fusion model reaches AUC 0.962, accuracy 0.909, and F1 0.891, competitive with recent 3D CNN and multimodal transformer systems at substantially lower cost. We first quantify how much modality, plane and slice geometry matter. A validation-only search over slice centres and neighbour spacings moves AUC by 0.180 for MRI and 0.078 for PET, selecting narrow spacing for MRI and wide spacing for PET, with the chosen coronal centres falling on the hippocampal body and on the posterior cingulate respectively. The contribution, however, is the evidence layer built around that number. Shortcut controls collapse the model to AUC 0.622 (silhouette), 0.608 (exterior), and 0.500 (blank), and a label-permutation null yields 0.456. Forward region-of-interest (ROI) ablation shows that masking medial temporal cortex in MRI and the posterior default-mode network (DMN) in PET produces the largest shift in the AD logit, while area-matched controls remain indistinguishable from that null. Reverse ROI ablation shows that the medial temporal lobe alone retains 89.2% of above-chance discrimination in MRI and the posterior DMN alone retains 79.0% in PET. A quantitative comparison of attribution methods shows occlusion sensitivity reaching 3.5-5.0* enrichment inside a priori AD regions against 0.10-0.43* in controls. Ablation and attribution independently establish a biologically correct double dissociation: hippocampal evidence is carried by MRI, posterior cingulate evidence by PET.

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.

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.