Preclinical Cerebral Network Connectivity Evidence of Deficits in Mild White Matter Lesions

White matter lesions (WMLs) are notable for their high prevalence and have been demonstrated to be a potential neuroimaging biomarker of early diagnosis of Alzheimer’s disease. This study aimed to identify the brain functional and structural mechanisms underlying cognitive decline observed in mild WMLs. Multi-domain cognitive tests, as well as resting-state, diffusion tensor and structural images were obtained on 42 mild WMLs and 42 age/sex-matched healthy controls. For each participant, we examined the functional connectivity (FC) of three resting-state networks (RSNs) related to the changed cognitive domains: the default mode network (DMN) and the bilateral fronto-parietal network (FPN). We also performed voxel-based morphometry analysis to compare whole-brain gray matter (GM) volume, atlas-based quantification of the white matter tracts interconnecting the RSNs, and the relationship between FC and structural connectivity. We observed FC alterations in the DMN and the right FPN combined with related white matter integrity disruption in mild WMLs. However, no significant GM atrophy difference was found. Furthermore, the right precuneus FC in the DMN exhibited a significantly negative correlation with the memory test scores. Our study suggests that in mild WMLs, dysfunction of RSNs might be a consequence of decreased white matter structural connectivity, which further affects cognitive performance.