Altered Intersubject Variability of Morphological Connectivity in Cerebral Small Vessel Disease and Its Associations With Gene Expression and Cell Types

Background Cerebral small vessel disease (CSVD) is a heterogeneous disorder; however, interindividual variability in morphometric brain connectivity remains unclear, as does its association with gene expression. Methods We enrolled 65 patients with CSVD and 35 healthy controls. Individual‐level morphometric brain networks were constructed from T1‐weighted magnetic resonance imaging, and intersubject variability of morphometric connectivity (IVMC) was quantified using a Kullback–Leibler divergence–based gray matter similarity measure. Group differences in IVMC and its associations with cognitive and clinical measures were examined. Partial least squares regression was applied to Allen Human Brain Atlas data to relate IVMC to gene expression, cell‐type specificity, and biological functions. Results Compared with healthy controls, patients with CSVD showed globally increased IVMC ( P False Discovery Rate Conclusions CSVD is associated with elevated IVMC across multiple functional networks, with changes in specific networks linked to memory impairment. These alterations may be associated with genes involved in neurodevelopment, synaptic function, and diverse neuronal and glial cell types, providing new insights into the interindividual variability of brain networks and the neurophysiological mechanisms underlying CSVD.