Abstract Body: Introduction: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease (SVD) caused by amyloid β deposition. It is closely linked to Alzheimer's disease (AD) and predisposes elderly patients to intracerebral hemorrhage and cognitive impairment. However, no effective serum biomarker has been established for early diagnosis or prediction of the disease progression. We discovered that a protein, “alpha1-Acid glycoprotein (α1-AGP),” is a potential serum biomarker for CAA. Methods: Proteins in serum samples from CAA patients (n = 10) who meet the modified Boston criteria by a classification of probable or possible and age-matched controls (n = 10) were analyzed exhaustively using two-dimensional differential gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF/MS). Afterward, each candidate was evaluated quantitatively using the ELISA (Enzyme-Linked Immunosorbent Assay) method. Results: Compared with the control group, the expression levels of 4 proteins (Hemopexin, Complement C9, C3, α1-AGP) were increased, and 1 protein (Apolipoprotein A-I) was decreased in the CAA group. We evaluated the expression levels of those 5 proteins by ELISA method and confirmed that the concentration of α1-AGP is significantly increased in the serum samples from the CAA group. Receiver Operatorating Characteristic curve analysis showed that the concentration of α1-AGP could clearly distinguish CAA or not. Moreover, we examined the association between the expression levels of those proteins and the MRI SVD burden (CAA-SVD score) in the same patient group and found a good correlation with α1-AGP (R squared is 0.779). Conclusion: Our results suggest that α1-AGP could be a novel serum protein biomarker for diagnosing CAA.