Circulating AGRN and ADAMTS8 are associated with carotid plaque presence versus healthy controls but do not independently discriminate plaque presence or instability after multivariable adjustment, and clinical covariates alone provided near-perfect discrimination, indicating substantial spectrum bias in the study design.
Key Findings
Results
Serum AGRN concentrations were significantly elevated in patients with carotid plaques compared to healthy controls.
Differences in baseline characteristics included established cardiovascular risk factors
These differences confound interpretation of biomarker associations, as the groups were not matched on age or risk factor burden
What This Means
This research suggests that two blood proteins — AGRN (agrin) and ADAMTS8 — along with five related proteins were measured in the blood of 128 people to see if they could help identify whether someone has carotid artery plaque (fatty buildup in neck arteries) or whether that plaque is unstable and dangerous. People with carotid plaque had higher levels of AGRN compared to healthy individuals, but ADAMTS8 levels were similar across all groups. When these proteins were combined into a prediction model, they showed moderate ability to distinguish plaque patients from healthy controls, but essentially no ability to tell whether a plaque was stable or unstable — a clinically more important question since unstable plaques are more likely to cause strokes.
However, a critical finding was that simply knowing a person's age and standard risk factors (like high blood pressure, diabetes, and smoking history) was nearly enough on its own to predict who had carotid plaque — meaning the healthy control group was so different from the plaque patients that the biomarkers' apparent usefulness was likely inflated. This is a form of bias called "spectrum bias," where comparing very different groups makes a test look more useful than it would be in real-world screening.
This research suggests that future studies testing blood biomarkers for carotid plaque should compare plaque patients against people of similar age who also have cardiovascular risk factors but no plaque, rather than against young, healthy individuals. Without this type of matched comparison, it is difficult to know whether biomarkers like AGRN truly add value beyond what doctors can already determine from a patient's medical history and standard risk assessment.
Guo S, Cui S, Zhang X, Xing Z, Sun Y, Qin M, et al.. (2026). Circulating Serum AGRN and ADAMTS8 With Related Candidates as Potential Biomarkers for Carotid Plaque Presence and Vulnerability.. CNS neuroscience & therapeutics. https://doi.org/10.1002/cns.71130