Multimodal-Conditioned Latent Diffusion Models for Spatiotemporal Brain MRI Forecasting

Spatiotemporal forecasting of 3D anatomical changes is a critical generative vision challenge for modeling Alzheimer's Disease (AD) progression. While brain MRI forecasting from single-modality data has advanced, other key complementary multimodal biomarkers remain underutilized. In this work, we propose the Multimodal-Conditioned Latent Diffusion Model (MC-LDM), a novel framework for patient-specific brain MRI synthesis. MC-LDM leverages multimodal biomarkers---MRI, tau-PET, Clinical Dementia Rating (CDR), and APOE4---during training, but relies only on baseline MRI, APOE4, and patient metadata at inference, reflecting realistic clinical availability. Our contributions are threefold: (1) a Latent Diffusion Model (LDM) fine-tuned via Low-Rank Adaptation (LoRA) for data-efficient learning; (2) a multimodal conditioning that integrates molecular and clinical signals to model heterogeneous disease trajectories; and (3) auxiliary predictors estimating unobserved multimodal biomarkers from MRI features and patient covariates to condition the diffusion model, removing the need for these assessments at inference. Trained on 1,355 visits from 852 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI), MC-LDM reduces average regional volumetric MAE by 18% over the second-best baseline on an independent test set of 664 visits. To our knowledge, MC-LDM represents the first diffusion-based framework to leverage multimodal priors for MRI forecasting. This conceptual advancement enables patient-specific trajectory generation that captures aspects of AD heterogeneity not observable from structural anatomy alone, bridging the gap between rich multimodal supervision and the strict constraints of routine clinical deployment. Code is available at: https://github.com/antonioscardace/MC-LDM.