Hippocampus-centered structural covariance network reorganization in Alzheimer’s disease: An individualized graph-based biomarker validated by machine learning

Alzheimer's disease (AD) is characterized by progressive brain network disintegration, yet quantifying this process at an individual level remains challenging. This study explores the potential of an individualized differential structural covariance network (IDSCN) as a graph theory-based biomarker to capture disease-specific network reorganization. We found that throughout the AD spectrum, significant progressive atrophy occurred in multiple brain regions, especially the hippocampus. At the same time, the brain underwent a profound structural covariant reorganization, and this reorganization was significantly centered on the hippocampus. Graph theory analysis revealed a significant enhancement in nodal strength and nodal efficiency across widespread brain regions, with the hippocampus, amygdala, middle temporal gyrus, and entorhinal cortex emerging as core hubs of pathological impact. Importantly, betweenness centrality selectively increased only in the bilateral hippocampus, highlighting their critical role as bridges in the pathological propagation network. Machine learning validation confirmed that this individualized network biomarker performs excellently in distinguishing AD patients from cognitively normal individuals, demonstrates comparable efficacy to traditional morphological models in capturing early disease-related changes, and shows potential in differentiating between mild cognitive impairment converters and non-converters. Our study establishes the hippocampus-centered IDSCN as an effective, individualized graph theory-based biomarker, providing new insights into the network pathophysiology of AD and holding significant potential for early diagnosis and prognostic stratification.