Title : A study of plasma extracellular vesicle biomarkers for Alzheimer's disease: Discovery and targeted validation
Abstract:
Background: Alzheimer's disease (AD) poses a significant global health challenge, demanding accessible and non-invasive biomarkers for early detection. Plasma-derived extracellular vesicles (EVs), carrying central nervous system cargo across the blood-brain barrier, offer a promising avenue for biomarker discovery.
Objective: This study aimed to identify and validate a panel of plasma EV protein biomarkers with high diagnostic accuracy for AD.
Methods: We employed a rigorous, two-phase nested case-control study. In the discovery phase, untargeted proteomics (LC-MS/MS) was performed on plasma-derived EVs from 25 patients with probable AD and 25 age- and gender-matched healthy controls (HC). In the validation phase, a candidate protein panel was quantified using targeted mass spectrometry (Selected Reaction Monitoring, SRM) in an independent cohort comprising 30 AD patients, 25 individuals with Mild Cognitive Impairment (MCI), and 30 HC. Statistical models were rigorously adjusted for key confounding factors, including age and systolic blood pressure. Machine learning algorithms were used to construct and evaluate a multi-marker diagnostic model.
Results: The discovery phase identified several differentially expressed proteins. Targeted validation confirmed that PRKCSH was significantly upregulated in AD, while ANGPT1, NCKAP1, and FLJ78516 were significantly downregulated compared to controls (all adjusted p < 0.001). The levels of these proteins in the MCI group were intermediate between AD and HC, suggesting a progressive change along the disease continuum. A diagnostic model combining these four biomarkers demonstrated excellent performance, achieving an Area Under the Curve (AUC) of 0.95 (95% CI: 0.91-0.99) using a Random Forest algorithm, with 92% sensitivity and 91% specificity for distinguishing AD from controls.
Conclusion: We have identified and validated a four-protein plasma EV panel (PRKCSH, ANGPT1, NCKAP1, FLJ78516) that demonstrates high diagnostic potential for AD. This robustly validated, non-invasive biomarker panel represents a significant step towards a clinically applicable blood test to complement existing diagnostic strategies for Alzheimer's disease. The panel's performance, coupled with its non-invasive nature, makes it a promising tool for early detection, patient stratification, and monitoring disease progression in AD. Further validation in larger, longitudinal cohorts is warranted to confirm its clinical utility.
