Altered hemispheres lateralization of brain functional gradients in Alzheimer's disease

Background The human brain demonstrates intrinsic hemispheric asymmetry across structural, functional, and biochemical domains. While cortical gradients provide a multiscale framework for understanding brain network organization, their hemispheric divergence in Alzheimer's disease (AD) remains unexplored. Objective To characterize interhemispheric gradient lateralization patterns across the AD continuum and evaluate their clinical correlates. Methods Resting-state fMRI data of 45 normal controls (NC), 45 patients with mild cognitive impairment (MCI), and 45 patients with AD underwent gradient networks processing. Interhemispheric comparisons of mean gradient values were conducted across these groups. A lateralization index (L value) was defined for 17 networks, and differences among the three groups were analyzed using one-way ANOVA. Additionally, correlations between network L values and cognitive scores were examined. Results NC and MCI participants exhibited left lateralization of gradient values in the second gradient. In contrast, AD patients showed a loss of interhemispheric lateralization. Notably, AD patients demonstrated reduced lateralization in default mode network (DMN) and control network. The degree of lateralization in DMN was significantly positively correlated with cognitive function. Conclusions Our findings indicated that patients with AD demonstrated a diminished lateralization in gradient networks. Quantifying gradient laterality may serve as a multimodal biomarker for early AD detection and therapeutic monitoring.