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Sleep disturbance is a recognized risk factor for Alzheimer's disease (AD), but the underlying micro-pathological evidence remains limited. To bridge this gap, we established an amyloid-β oligomers (AβO)-induced rat model of AD and subjected it to intermittent sleep deprivation (SD). Diffusion tensor imaging (DTI) and transmission electron microscopy were employed to assess white matter (WM) integrity and ultrastructural changes in myelin sheaths. Our findings demonstrated that SD exacerbated AβO-induced cognitive decline. Furthermore, we found SD aggravated AβO-induced asymmetrical impairments in WM, presenting with reductions in tract integrity observed in commissural fibers and association fasciculi, particularly the right anterior commissure, right corpus callosum, and left cingulum. Ultrastructural changes in myelin sheaths within the hippocampus and corpus callosum further confirmed a lateralized effect. Moreover, SD worsened AβO-induced lateralized disruption of the brain structural network, with impairments in critical nodes of the left hemisphere strongly correlated with cognitive dysfunction. This work represents the first identification of a lateralized impact of SD on the mesoscopic network and cognitive deficits in an AD rat model. These findings could deepen our understanding of the complex interplay between sleep disturbance and AD pathology, providing valuable insights into the early progression of the disease, as well as the development of neuroimaging biomarkers for screening early AD patients with self-reported sleep disturbances. Enhanced understanding of these mechanisms may pave the way for targeted interventions to alleviate cognitive decline and improve the quality of life for individuals at risk of or affected by AD. a AβO injection and sleep deprivation were conducted on adult rats. b Sleep deprivation and AβO-induced neurotoxicity aggravated cognitive disability with a synergistic effect. c Sleep deprivation and AβO-induced neurotoxicity reduced the integrity of specific association fasciculi and commissural fibers with ultrastructural demyelination. d On the basis of white matter integrity destruction, the structural connection was disrupted. The exacerbated topological properties with lateralized effects were correlated with cognitive decline. [ABSTRACT FROM AUTHOR]