Abstract
Cerebrovascular disease frequently co-occurs with amyloid-β (Aβ) plaques and tau tangles, the pathological hallmarks of Alzheimer's disease (AD), compounding cognitive decline. Aβ deposition is also central to cerebral amyloid angiopathy (CAA), yet peripheral biomarkers that specifically reflect CAA-related vascular pathology remain elusive. Here, we integrated proteomic, imaging, clinical, neuropathological, and genomic data from brain and cerebrospinal fluid (CSF) to define molecular signatures distinguishing CAA from plaque pathology. Proteomic profiling of 118 cerebrovascular-enriched brain samples quantified over 11,000 proteins, revealing co-expression modules enriched for extracellular matrix (ECM) components strongly linked to CAA. In CSF proteomes from 1,104 individuals, vascular ECM module proteins (e.g., CRIP1, LTBP1, PRSS23) were associated with CAA, white matter hyperintensities (WMH), microbleeds, and infarcts but not Aβ plaque burden. Integrating AD genome-wide association studies and CSF protein quantitative trait loci (pQTLs) identified CRIP1 as a candidate causal protein for AD. Carriers of the minor allele at the CRIP1 pQTL exhibited reduced CRIP1 levels, less WMH, and lower CSF levels of ECM proteins linked to CAA. In vitro, CRIP1 bound Aβ and accelerated fibril formation, providing a mechanistic link to vascular amyloid pathology. These findings establish overlapping brain and CSF biomarkers for CAA and identify CRIP1 and vascular ECM pathways as candidate targets for precision diagnostics and therapeutic intervention.