Blood extracellular vesicles carrying synaptic function- and brain-related proteins as potential biomarkers for Alzheimer's disease.

INTRODUCTION:Objective and accessible markers for Alzheimer's disease (AD) and other dementias are critically needed. METHODS:We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting such plasma EVs readily. The assay was initially tested in our local cross-sectional study to distinguish AD patients from healthy controls (HCs) or from Parkinson's disease (PD) patients, followed by a validation study using an independent cohort collected from multiple medical centers (the Alzheimer's Disease Neuroimaging Initiative). Cerebrospinal fluid AD molecular signature was used to confirm diagnoses of all AD participants. RESULTS:Likely CNS-derived EVs in plasma were significantly reduced in AD compared to HCs in both cohorts. Integrative models including CNS-derived EV markers and AD markers present on EVs reached area under the curve of 0.915 in discovery cohort and 0.810 in validation cohort. DISCUSSION:This study demonstrated that robust and rapid analysis of individual neuron-derived synaptic function-related EVs in peripheral blood may serve as a helpful marker of synaptic dysfunction in AD and dementia.