Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer’s disease in which amyloid-β (Aβ) deposits in cerebral and leptomeningeal vessel walls, predisposing to micro- and macro-hemorrhage. The vessel wall has distinct proteins and heparan sulfate (HS), linear polysaccharides that bind Aβ and promote fibril formation in vitro. Yet how vascular proteins and HS jointly associate with Aβ is unknown. Here we conducted a multi-omics study to systematically characterize the proteins as well as the HS abundance, sulfation level, and disaccharide composition of leptomeninges from 23 moderate to severe CAA cases and controls. We then analyzed the associations between Aβ and other proteins, HS, and apolipoprotein E (ApoE) genotype. We found an increase in a minor HS disaccharide, unsubstituted glucosamine, as well as 6-O sulfated disaccharides, and Aβ40 levels positively correlated with unsubstituted glucosamine. Our findings of vascular HS and protein alterations specific to CAA-affected leptomeningeal vessels provide molecular insight into the extracellular remodeling co-occurring with Aβ deposits, and provide a basis for ante-mortem diagnostic assay development and therapeutic strategies to impede Aβ - HS interaction.