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

INTRODUCTION Amyloid-β (Aβ) 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 number and content of EVs. METHODS Single-molecule enzyme-linked assays were used to quantify Aβ42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4– and APOE ε4+ cognitively normal individuals (CN) and AD patients. RESULTS Soluble plasma Aβ42/40 ratio is decreased in AD patients compared to CN individuals. The amount and content (Aβ40, Aβ42, tau) of plasma NDEVs were similar between groups. Quantity of soluble biomarkers were negatively correlated to NDEVs number only in CN individuals. DISCUSSION Soluble Aβ42/40 ratio is the most robust AD plasma biomarker. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aβ release in AD. Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of Clinics Saint-Luc University Hospital, 1200 Brussels, Belgium (UCL-2022-473; UCL-2016-121; UCL-2018-119). HIGHLIGHTS The number of neurally-derived extracellular vesicles (NDEVs) in plasma is not a stand-alone biomarker for Alzheimer’s disease (AD). Plasma levels of Aβ42, Aβ40 and total-tau are strongly negatively correlated with NDEVs concentration in cognitively normal (CN) individuals. In AD patients, this correlation is lost, highlighting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions. The soluble plasma amyloid-β (Aβ) 42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. RESEARCH IN CONTEXT Systematic review: The authors reviewed PubMed for plasma biomarkers and neurally-derived extracellular vesicles (NDEVs) in AD. While many studies focus on soluble plasma AD biomarkers like Aβ42/40 ratio or tau protein variants, less explore NDEVs. This study investigates NDEVs as potential AD biomarkers and their correlation with soluble plasma biomarkers. Interpretation: Our study confirms decreased soluble Aβ42 and increased soluble total-tau in AD patients, with soluble Aβ40 indicating elevated Aβ production in AD versus CN individuals. The Aβ42/40 ratio is a robust AD biomarker. CN individuals with AD risk ( APOE ε4+) show decreased ratios without symptoms. Plasma NDEVs remain consistent across ages and between AD and CN individuals, but correlations with soluble plasma biomarkers suggest altered Aβ processes in AD. Future directions: Further research on independent cohorts can confirm our findings and assess whether plasma Aβ and tau need correction by NDEVs for better AD risk identification in CN populations.