<p>Mild cognitive impairment (MCI), the prodromal stage of dementia, is characterized by cognitive dysfunction and white matter (WM) disruption. To investigate the WM microstructure degeneration at different scales in MCI, the orientation-sensitive fixel-based analysis was performed with fixelwise, fiberwise fiber-specific measures in 50 patients with MCI compared to 75 healthy controls. Moreover, to clarify the patterns of the organization operating at different scales in MCI, the potential mediated effects of structural connectome in networkwise on the associations between microstructure alterations of 24 anatomical tracts and cognitive dysfunction were analyzed. Compared to healthy controls, specific tracts were widely disrupted in fiberwise in patients with MCI, represented by the decrease of fiber density and cross-section in most commissural fibers and many association fibers, which was consistent with previous findings. The associations between WM microstructural degeneration and multi-domain cognitive dysfunction were also observed. Interestingly, the structural connectome between visual and salience networks played a potential mediating role in the relationship between disruption of WM microstructure and worse language performance, and we also found a similar situation in the memory domain. The present study provides mechanistic insight into the relationship between microstructure damage and cognitive dysfunction in prodromal dementia under a multilevel WM hierarchy.</p>