Hierarchical Reconfiguration of Interhemispheric Dialogue in Alzheimer’s Disease: A Multicenter Analysis

Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Homotopic functional connectivity (HFC) reflects direct communication between corresponding brain hemispheres, enabling seamless information integration. Previous studies have highlighted the potential role of hemispheric asymmetry in AD, yet the specific alterations in HFC and its potential as a neuroimage biomarker remain relatively unexplored. Methods The study consists of 799 subjects from 7 sites with 289 AD, 253 mild cognitive impairment (MCI) and 257 normal controls (NC). Structural measures, including gray matter volume (GMV), fraction dimension (FD), cortical thickness (CT), sulci Depth (SD) and gyral index (GI), and HFC were measured for all participants, along with the clinical symptoms, Mini-Mental State Examination (MMSE). Results AD exhibited an anterior-posterior hierarchical reconfiguration of HFC with the systematic reduced HFC in the posterior and subcortical regions, but a focal increased HFC exclusively within the prefrontal cortex. Genetic association analyses linked pathways of neurodegeneration multiple diseases to the hierarchical reconfiguration of HFC of AD. Moreover, the hierarchical reconfiguration of HFC was a robust AD neuroimaging biomarker with an averaged ACC of 74.5% and with performance significantly enhanced the most 12.9% with structural measures. Conclusions HFC exhibits widespread reduction in AD, and this alteration demonstrates significant associations with underlying genetic correlates and clinical measures. The potential of HFC as a biomarker for AD is furtherly showcased across multi-modal classification and prediction models, opening new avenues for further research and clinical applications.