Spatio-Temporal Graph Deep Learning with Stochastic Differential Equations for Uncovering Alzheimer's Disease Progression

Identifying objective neuroimaging biomarkers to forecast Alzheimer's disease (AD) progression is crucial for timely intervention. However, this task remains challenging due to the complex dysfunctions in the spatio-temporal characteristics of underlying brain networks, which are often overlooked by existing methods. To address these limitations, we develop an interpretable spatio-temporal graph neural network framework to predict future AD progression, leveraging dual Stochastic Differential Equations (SDEs) to model the irregularly-sampled longitudinal functional magnetic resonance imaging (fMRI) data. We validate our approach on two independent cohorts, including the Open Access Series of Imaging Studies (OASIS-3) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Our framework effectively learns sparse regional and connective importance probabilities, enabling the identification of key brain circuit abnormalities associated with disease progression. Notably, we detect the parahippocampal cortex, prefrontal cortex, and parietal lobule as salient regions, with significant disruptions in the ventral attention, dorsal attention, and default mode networks. These abnormalities correlate strongly with longitudinal AD-related clinical symptoms. Moreover, our interpretability strategy reveals both established and novel neural systems-level and sex-specific biomarkers, offering new insights into the neurobiological mechanisms underlying AD progression. Our findings highlight the potential of spatio-temporal graph-based learning for early, individualized prediction of AD progression, even in the context of irregularly-sampled longitudinal imaging data.