Serum Amyloid A 4 as a Common Marker of Persistent Inflammation in Patients with Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

**Background:** Neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) are common choroidal vasculopathies that share clinical features and treatment strategies, but their common pathomechanisms are not fully understood. Inflammation plays a key role in both conditions. Serum amyloid A 4 (SAA4) is a constitutive acute-phase protein associated with chronic inflammatory diseases, but its role in nAMD and PCV is unknown. This study aimed to characterize aqueous humor (AH) proteome alterations and identify a common biomarker for both diseases.

**Methods:** A total of 30 subjects were recruited for LC-MS/MS analysis: 10 cataract controls, 10 treatment-naive nAMD patients, and 10 treatment-naive PCV patients. AH samples (mean 100 μL) were collected during cataract surgery or intravitreal injection. Proteins were digested using filter-aided sample preparation, and LC-MS/MS was performed on a Q Exactive mass spectrometer. Differentially expressed proteins (DEPs) were defined as |log2(fold change)| > 0.58 and p < 0.05. Bioinformatics analysis included GO and KEGG pathway enrichment, and protein-protein interaction networks were constructed using STRING and Cytoscape. SAA4 was validated by ELISA in an independent cohort of 10 controls, 10 nAMD, and 10 PCV patients. ROC analysis assessed diagnostic performance.

**Key Results:** A total of 737 proteins were identified, of which 544 were quantifiable. Between control and nAMD, 75 DEPs were found (56 upregulated, 19 downregulated); between control and PCV, 48 DEPs (37 upregulated, 11 downregulated); between nAMD and PCV, only 7 DEPs (1 upregulated, 6 downregulated). The most upregulated proteins in both nAMD and PCV included complement components (C8A, C8G), CD14, immunoglobulins, and SAA4. SAA4 was enriched as a hub protein in both conditions. ELISA confirmed significantly higher SAA4 levels in nAMD (1.058 ± 0.176 ng/mL) and PCV (1.174 ± 0.270 ng/mL) compared to controls (0.750 ± 0.142 ng/mL) (p = 0.006 and p = 0.0002, respectively). ROC analysis showed strong discriminatory power: control vs nAMD AUC = 0.9200 (p = 0.0015, 95% CI 0.8033–1.000); control vs PCV AUC = 0.9500 (p = 0.0007, 95% CI 0.8584–1.000). KEGG pathway analysis revealed enrichment in complement and coagulation cascades, COVID-19, and Staphylococcus aureus infection pathways in both nAMD and PCV.

**Clinical Implications:** SAA4 is a promising common biomarker for nAMD and PCV, reflecting persistent inflammation and potential links to lipid abnormalities. Its elevation in AH may aid in diagnosis and risk stratification. The study highlights immune dysregulation as a shared mechanism, suggesting that targeting SAA4 or related inflammatory pathways could complement anti-VEGF therapy. Limitations include small sample size and need for validation in larger cohorts. Future research should correlate SAA4 with clinical features and OCT findings.