UNICAL: Uncertainty-Aware Multimodal Learning with MRI-Derived Synthetic Amyloid PET for Alzheimer's Disease Classification

Limited availability of amyloid positron emission tomography (PET) motivates imaging-informatics methods that derive complementary molecular-imaging representations from routinely acquired magnetic resonance imaging (MRI). We developed UNICAL, an uncertainty-aware multimodal framework for Alzheimer's disease-spectrum versus cognitively normal classification that combines a self-supervised three-dimensional MRI encoder, Contourlet Wavelet Stationary Radiomics (CoWS-Rad) engineered MRI features, and MRI-derived synthetic 18F-florbetapir (AV45) PET. CoCoLIT generated four stochastic PET realizations per MRI; their mean and voxelwise variance were used for uncertainty gating before probability-anchored transformer fusion. Synthetic PET was validated in 228 paired OASIS-3 MRI-AV45 examinations, achieving a mean per-examination voxelwise Pearson correlation of r = 0.864 and strong cortical-composite SUVR agreement with acquired PET (Pearson r = 0.954). In the OASIS-3 development cohort (813 sessions from 811 participants), participant-grouped five-fold cross-validation repeated across 20 seeds yielded AUROC 0.868 and expected calibration error (ECE) 0.061. The OASIS-3 development endpoint used the manuscript's AD-spectrum reference standard, whereas ADNI3 used AD-versus-CN research-group labels, providing cross-dataset evaluation on a related but non-identical prediction endpoint. Without retraining, feature refitting, threshold optimization, or recalibration, the frozen framework was evaluated in an independent matched ADNI3 cohort of 261 participants (87 AD, 174 CN), achieving AUROC 0.836 (95% CI 0.791-0.876). ECE increased to 0.089 under external transfer, indicating that calibration was more sensitive to domain shift than rank discrimination. Ablation analysis and K-sample sensitivity supported the contributions of uncertainty gating, adaptive weighting, modality dropout, residual correction, and the K = 4 synthesis configuration. UNICAL therefore provides an uncertainty-aware MRI-derived multimodal representation for AD-spectrum classification that retains substantial cross-dataset discrimination while remaining distinct from acquired molecular imaging and not replacing amyloid PET as a clinical biomarker.