Comparison of plasma soluble and extracellular vesicles-associated biomarkers in Alzheimer's disease patients and cognitively normal individuals

Background Amyloid-beta (A beta) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs. Methods Single-molecule enzyme-linked assays were used to quantify A beta 42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE epsilon 4- (n = 168) and APOE epsilon 4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples. Results The soluble plasma A beta 42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (A beta 40, A beta 42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions. Conclusion Soluble plasma A beta 42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of A beta release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma A beta and tau need correction by NDEVs for better AD risk identification in CN populations.