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BACKGROUND AND PURPOSE: Whole-brain network connectivity has been shown to be a useful biomarker of cerebral amyloid angiopathy and related cognitive impairment. We evaluated an automated DTI-based method, peak width of skeletonized mean diffusivity, in cerebral amyloid angiopathy, together with its association with conventional MRI markers and cognitive functions. MATERIALS AND METHODS: We included 24 subjects (mean age, 74.7 [SD, 6.0] years) with probable cerebral amyloid angiopathy and mild cognitive impairment and 62 patients with MCI not attributable to cerebral amyloid angiopathy (non-cerebral amyloid angiopathy-mild cognitive impairment). We compared peak width of skeletonized mean diffusivity between subjects with cerebral amyloid angiopathy-mild cognitive impairment and non-cerebral amyloid angiopathy-mild cognitive impairment and explored its associations with cognitive functions and conventional markers of cerebral small-vessel disease, using linear regression models. RESULTS: Subjects with Cerebral amyloid angiopathy-mild cognitive impairment showed increased peak width of skeletonized mean diffusivity in comparison to those with non-cerebral amyloid angiopathy-mild cognitive impairment (P , .001). Peak width of skeletonized mean diffusivity values were correlated with the volume of white matter hyperintensities in both groups. Higher peak width of skeletonized mean diffusivity was associated with worse performance in processing speed among patients with cerebral amyloid angiopathy, after adjusting for other MRI markers of cerebral small vessel disease. The peak width of skeletonized mean diffusivity did not correlate with cognitive functions among those with non-cerebral amyloid angiopathy-mild cognitive impairment. CONCLUSIONS: Peak width of skeletonized mean diffusivity is altered in cerebral amyloid angiopathy and is associated with performance in processing speed. This DTI-based method may reflect the degree of white matter structural disruption in cerebral amyloid angiopathy and could be a useful biomarker for cognition in this population. ABBREVIATIONS: CAA ¼ cerebral amyloid angiopathy; CMB ¼ cerebral microbleeds; CSO-PVS ¼ perivascular spaces in the centrum semiovale; cSS ¼ cortical superficial siderosis; cSVD ¼ cerebral small vessel disease; ICH ¼ intracerebral hemorrhage; IQR ¼ interquartile range; MCI ¼ mild cognitive impairment; MD ¼ mean diffusivity; MMSE ¼ Mini-Mental State Examination; PSMD ¼ peak width of skeletonized mean diffusivity; nTBV ¼ normalized total brain volume; nWMHV ¼ normalized white matter hyperintensity volume; WMH ¼ white matter hyperintensities S poradic cerebral amyloid angiopathy (CAA) is a highly prevalent cerebral small-vessel disease (cSVD) in the elderly. 1 CAA is a well-known cause of lobar intracerebral hemorrhage (ICH) and is also increasingly recognized as a major contributor to vascular cognitive impairment and dementia. 2,3 Although underlying