Hierarchical reconfiguration of interhemispheric dialogue in Alzheimer’s disease: a multicenter analysis

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 information integration. Prior studies examining AD-related HFC alterations have largely been limited to small cohorts and basic statistical comparisons, yielding inconsistent findings. Here, we systematically validated in a large-scale, multi-center setting to delineate the spatial pattern of HFC alterations in AD and evaluate its potential as a neuroimaging biomarker. The study consisted of 799 subjects from 7 sites with 289 AD, 253 mild cognitive impairment (MCI) and 257 normal controls (NC). HFC was computed for all participants, along with structural asymmetry measures, including gray matter volume (GMV), fractal dimension (FD), cortical thickness (CT), sulcal depth (SD) and gyral index (GI). To investigate abnormal HFC patterns in AD, we conducted the linear regression models with diagnosis as the main effect, age and sex as covariates for each site, followed by random-effects meta-analysis to pool effect sizes across sites. To evaluate the potential of HFC as a biomarker of AD, support vector machines with leave-one-site-out cross-validation were employed for classification tasks using HFC with and without structural asymmetry measures. Support vector regression (SVR) was similarly applied to predict Mini-Mental State Examination (MMSE) scores. AD exhibited an anterior-posterior hierarchical reconfiguration of HFC, characterized by systematically reduced HFC in the posterior and subcortical regions (e.g., rHipp: Cohen’s d = − 0.541, p -FDR = 0.014; mAmyg: Cohen’s d = − 0.330, p -FDR = 0.009), and focally increased in the prefrontal cortex (e.g., A9m: Cohen’s d = 0.391, p -FDR < 0.001). Moreover, this hierarchical reconfiguration of HFC demonstrated the potential as a neuroimaging biomarker, achieving a mean ACC of 0.745 across sites (AUC = 0.815; F1 score = 0.774), with integration of structural measures further improving performance by up to 0.129 in ACC. These findings suggest that interhemispheric dialogue is hierarchically reconfigured in AD from the perspective of homotopic functional connectivity, deepening our understanding of the neural mechanisms underlying the disease. Moreover, HFC holds promise as a complementary biomarker for future therapeutic investigations and individualized assessment.