Predicting Alzheimer's disease progression using rs-fMRI and a history-aware graph neural network

Dementia affects over 55 million people worldwide, projected to reach 139 million by 2050, with Alzheimer's disease (AD) accounting for 60-70% of cases. AD is associated with disruptions in metabolic brain connectivity. Detecting these disruptions early is crucial for AD management. FDG-PET is a useful tool for identifying such impairments. However, most studies rely on group-level analyses or thresholding, potentially masking individual differences and overlooking weaker yet biologically critical brain connections. Moreover, AD prediction largely focuses on univariate rather than multivariate outcomes. To address this, we introduce explainable graph-theoretical machine learning (XGML), a framework for constructing individual metabolic brain graphs and identifying subgraphs most predictive of multivariate disease-related outcomes. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) FDG-PET data, we compared six graph representations against three non-graph baselines, each with six machine learning models using repeated stratified 3-fold cross-validation (10 repeats). The best configuration combined kernel density estimation with Hellinger distance and random forest. Across eight cognitive scores, it reached an overall Fisher-z-averaged Pearson correlation of r=0.595, with strongest performance for ADAS13 (r=0.67), ADAS11 (r=0.65), and ADASQ4 (r=0.62). We identified key edges that were jointly but differentially predictive across outcomes, suggesting their potential as network biomarkers of cognitive decline. Preliminary external feasibility validation on an OASIS3 cohort yielded weak predictive performance for CDRSB (r=0.26) and MMSE (r=0.18), likely reflecting cohort, protocol, and diagnostic differences. Overall, our results suggest the promise of graph-theoretical machine learning for biomarker discovery, disease prediction, and understanding the neural mechanisms underlying AD.

Longitudinal neuroimaging is essential for modeling disease progression in Alzheimer's disease (AD), yet irregular sampling and missing visits pose substantial challenges for learning reliable temporal representations. To address this challenge, we propose SDE-HGNN, a stochastic differential equation (SDE)-driven spatio-temporal hypergraph neural network for irregular longitudinal fMRI connectome modeling. The framework first employs an SDE-based reconstruction module to recover continuous latent trajectories from irregular observations. Based on these reconstructed representations, dynamic hypergraphs are constructed to capture higher-order interactions among brain regions over time. To further model temporal evolution, hypergraph convolution parameters evolve through SDE-controlled recurrent dynamics conditioned on inter-visit intervals, enabling disease-stage-adaptive connectivity modeling. We also incorporate a sparsity-based importance learning mechanism to identify salient brain regions and discriminative connectivity patterns. Extensive experiments on the OASIS-3 and ADNI cohorts demonstrate consistent improvements over state-of-the-art graph and hypergraph baselines in AD progression prediction. The source code is available at https://anonymous.4open.science/r/SDE-HGNN-017F.

Predicting which people with mild cognitive impairment (MCI) will develop dementia matters for starting treatment early, yet computational work on structural brain imaging has relied almost entirely on a single scan. We propose TAFNet, a temporal attention fusion network that combines a baseline and a follow-up T1-weighted scan. A pretrained Siamese encoder represents each scan, and a fusion module combines the two through anatomical difference, cross-temporal attention and joint context, mixed by a learned per-patient gate. We evaluate it on paired scans from participants with MCI in the Alzheimer's Disease Neuroimaging Initiative, taken up to two years apart, with a dementia diagnosis within three years of the first scan as the outcome. The evaluation is designed to hold up under scrutiny: conversion is defined from recorded diagnoses, the pretraining pool shares no participants with the evaluation cohort, a held-out test partition is kept apart from model development, and uncertainty is estimated by resampling participants. TAFNet discriminates converters from non-converters well on the held-out partition. It outperforms conventional single-scan networks and a model that subtracts the two scans; both differences are significant in cross-validation and have the same direction on the smaller held-out partition. With everything else held fixed, adding the follow-up scan gives a significant gain in cross-validation. Against a recurrent CNN-LSTM baseline built on the same encoder, TAFNet performs comparably, with neither model consistently ahead. Operating points chosen on validation data, in place of the default threshold, give high sensitivity at a clinically reasonable specificity.