BackgroundCognitive impairment is commonly observed in hydrocephalus patients. Ventricular enlargement compresses brain parenchyma, especially the white matter (WM).PurposeTo investigate whether the relationship between ventricular dilation and cognitive decline in hydrocephalus patients is mediated by WM alterations.Study TypeRetrospective.Population51 communicating hydrocephalus patients (median age, 54 years), 50 obstructive hydrocephalus patients (median age, 49 years), and 53 control subjects (median age, 50 years).Field Strength/SequenceDiffusion tensors imaging, 3D T1 BRAVO, 3D FIESTA, CUBE T2, and FLAIR sequences at 3T.AssessmentDTI parameters (skeletonized fractional anisotropy (FA), skeletonized mean diffusivity (MD), and peak width of skeletonized mean diffusivity p(PSMD)) were extracted using FSL software. Global, periventricular, and deep white matter hyperintensity (WMH) volumes, degree of ventricular enlargement (Evans index), and other conventional imaging markers (number of lacunes and perivascular spaces, intracranial and brain volume) were extracted using united imaging intelligence. Cognitive tests included Montreal cognitive assessment (MoCA), clock drawing test (CDT), and vocabulary fluency test (VFT).Statistical TestsMultivariable linear regression analysis, mediation analyses, and dominance analysis. P‐value <0.05 was considered significant.ResultsThe degree of ventricular dilation, DTI parameters, and cognitive function scores were interrelated. The skeletonized FA values (β = −0.0917, 95% confidence interval (CI): −0.205, −0.024) and normalized global WMH volume (β = −0.0635, 95% CI: −0.13, −0.0005) together mediated 37.2% of the association between Evans index and MoCA. A comparable causal pathway was found for periventricular WMHs but not for deep WMHs. Dominance analysis indicated skeletonized FA values had a greater impact on cognition than WMH volume. The skeletonized FA values also mediated the association between Evans index and CDT (β = −0.0897, 95% CI: −0.165, −0.026) and VFT (β = −0.1589, 95% CI: −0.27, −0.083).ConclusionWM alterations were causal mediators between ventricular dilation and cognitive decline in hydrocephalus patients.Evidence Level3.Technical EfficacyStage 3.