BRIDGE: Learning Brain-Gut Metabolic Evidence for Alzheimer's Disease Diagnosis

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.

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.

Reliable Alzheimer's disease (AD) diagnosis increasingly relies on multimodal assessments combining structural Magnetic Resonance Imaging (MRI) and Electronic Health Records (EHR). However, deploying these models is bottlenecked by modality missingness, as MRI scans are expensive and frequently unavailable in many patient cohorts. Furthermore, synthesizing de novo 3D anatomical scans from sparse, high-dimensional tabular records is technically challenging and poses severe clinical risks. To address this, we introduce MIRAGE, a novel framework that reframes the missing-MRI problem as an anatomy-guided cross-modal latent distillation task. First, MIRAGE leverages a Biomedical Knowledge Graph (KG) and Graph Attention Networks to map heterogeneous EHR variables into a unified embedding space that can be propagated from cohorts with real MRIs to cohorts without them. To bridge the semantic gap and enforce physical spatial awareness, we employ a frozen pre-trained 3D U-Net decoder strictly as an auxiliary regularization engine. Supported by a novel cohort-aggregated skip feature compensation strategy, this decoder acts as a rigorous structural penalty, forcing 1D latent representations to encode biologically plausible, macro-level pathological semantics. By exclusively utilizing this distilled "diagnostic-surrogate" representation during inference, MIRAGE completely bypasses computationally expensive 3D voxel reconstruction. Experiments demonstrate that our framework successfully bridges the missing-modality gap, improving the AD classification rate by 13% compared to unimodal baselines in cohorts without real MRIs.