# Multi-omic analysis of meningeal cerebral amyloid angiopathy reveals enrichment of unsubstituted glucosamine and extracellular proteins

## TL;DR

This study explores how proteins and heparan sulfate in blood vessels relate to amyloid-β deposits in cerebral amyloid angiopathy, a condition linked to Alzheimer's disease.

## Contribution

The first multi-omics analysis of leptomeningeal vessels in CAA reveals novel associations between Aβ, HS disaccharides, and extracellular proteins.

## Key findings

- Unsubstituted glucosamine and 6-O sulfated disaccharides are enriched in CAA-affected vessels.
- Extracellular proteins like olfactomedin-like protein 3 and fibrinogen increase in CAA cases.
- Aβ40 levels correlate with unsubstituted glucosamine in leptomeningeal vessels.

## Abstract

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 vessels to micro- and macro-hemorrhages. The vessel walls contain distinct proteins and heparan sulfate (HS), yet how vascular proteins and HS jointly associate with Aβ is unknown. We conducted the first 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 genotype. We found an increase in a minor HS disaccharide containing unsubstituted glucosamine, as well as 6-O sulfated disaccharides; Aβ40 levels positively correlated with unsubstituted glucosamine. There was also an increase in extracellular proteins derived from brain parenchyma or plasma, including olfactomedin-like protein 3, fibrinogen, serum amyloid protein, apolipoprotein E, and secreted frizzled related protein-3. Our findings of vascular HS and protein alterations specific to CAA-affected leptomeningeal vessels provide molecular insight into the extracellular remodeling that co-occurs with Aβ deposits and may indicate a basis for antemortem diagnostic assay development and therapeutic strategies to impede Aβ-HS interactions.