Understanding Alzheimer’s Disease (AD) progression using resting-state functional Magnetic Resonance Imaging (rs-fMRI) remains an open challenge. Variational Autoencoders (VAEs) provide compact representations of high-dimensional neuroimaging data but lack mechanisms to highlight disease-relevant features. We propose KS-VAE, a novel framework that integrates the Kolmogorov–Smirnov test into the latent space of VAEs to identify statistically significant variables discriminating healthy from pathological brain states. This integration enables measurement of latent space shifts associated with cognitive decline, offering a quantitative approach to neurodegenerative processes. By modifying the most relevant variables, KS-VAE generates synthetic samples that simulate transitions between clinical conditions while preserving anatomical plausibility. The method enhances the modeling of temporal and distributional dynamics underlying disease progression and provides interpretable analysis of class-relevant features. Applied to rs-fMRI scans of 220 subjects from the ADNI cohort, KS-VAE demonstrated robust class separation between cognitively normal and Alzheimer’s disease subjects, achieving a classification accuracy of 84.5% and an F1-score of 84.5%, and clinically consistent synthetic transitions. KS-VAE thus offers a statistically grounded and clinically interpretable framework for understanding Alzheimer’s disease progression.
Martínez et al. (Fri,) studied this question.