Amalgamation of plasma complement proteins with classical biomarkers significantly improved the stratification of Alzheimer's disease

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Identifying specific composite plasma markers is crucial for early detection and intervention.
Method: We analyzed 133 plasma samples from patients at various stages of AD. Classic AD biomarkers were measured using the Single Molecule Array (Simoa), and targeted proteomics with multiple reaction monitoring (MRM) was applied to assess the diagnostic potential of integrating these biomarkers with complement and coagulation-related proteins.
Results: Simoa-based ROC analysis identified the p-tau217/Aβ42 ratio as the most valuable biomarker of AD. MRM detected 12 dysregulated proteins, with C1r and CR2 overlapping across different stages of AD. The combination of CR2, GFAP, and p-tau217/Aβ42 achieved an AUC of 0.913 for subjective cognitive decline (SCD) and 1.0 for mild cognitive impairment (MCI), accurately predicting transitions from SCD to MCI and then to AD. The combination of C1RL and p-tau217 achieved an AUC of 1 for both MCI and AD diagnoses, as did the combination of SERPINA5 and p-tau217 for AD.
Conclusion: The study confirms the diagnostic potential of classic AD biomarkers and shows that incorporating complement and coagulation-related proteins enhances their effectiveness. The combination of Ab, tau, and inflammatory markers with those complements improves diagnostic accuracy of AD and supports monitoring early intervention.