Disentangling brain atrophy heterogeneity in Alzheimer's disease: A deep self-supervised approach with interpretable latent space.

Alzheimer's disease (AD) is heterogeneous, but existing methods for capturing this heterogeneity through dimensionality reduction and unsupervised clustering have limitations when it comes to extracting intricate atrophy patterns. In this study, we propose a deep learning based self-supervised framework that characterizes complex atrophy features using latent space representation. It integrates feature engineering, classification, and clustering to synergistically disentangle heterogeneity in Alzheimer's disease. Through this representation learning, we trained a clustered latent space with distinct atrophy patterns and clinical characteristics in AD, and replicated the findings in prodromal Alzheimer's disease. Moreover, we discovered that these clusters are not solely attributed to subtypes but also reflect disease progression in the latent space, representing the core dimensions of heterogeneity, namely progression and subtypes. Furthermore, longitudinal latent space analysis revealed two distinct disease progression pathways: medial temporal and parietotemporal pathways. The proposed approach enables effective latent representations that can be integrated with individual-level cognitive profiles, thereby facilitating a comprehensive understanding of AD heterogeneity.