Proteomic dysregulation associated with cerebral amyloid angiopathy

Abstract INTRODUCTION Cerebral amyloid angiopathy (CAA) is characterized by impaired vascular amyloid‐β clearance, distinct from Alzheimer's disease (AD), underscoring the need to clarify its molecular basis for predicting therapy‐related amyloid‐related imaging abnormalities.

Methods

We analyzed post‐mortem brain proteomics from Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and cerebrospinal fluid (CSF) proteomics from Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify CAA‐associated proteins and network modules, delineate their biological processes and cellular origins, and determine their diagnostic performance.

Results

Proteomics analysis identified 30 proteins as associated with CAA severity, enriched in pathways distinct from AD pathology, with 11 replicated in ADNI. Two CAA‐associated modules were enriched for microglial vesicle transport and astrocytic potassium‐ion homeostasis. Pseudotime analysis demonstrated a molecular trajectory aligned with increasing CAA severity. Three proteins (RCSD1, FRZB, AKAP6) improved CAA classification beyond demographics and APOE ε4.

Discussion

This integrative proteomics analysis identifies distinct, reproducible molecular signatures of CAA, revealing glia‐mediated pathways and promising biomarkers for CAA detection and therapy‐related risk assessment.