One of the main hurdles in the study of Alzheimer’s Disease (AD) is the lack of easily accessible and sensitive biomarkers for the diagnosis, the prediction of the disease progression rate and the evaluation of rehabilitative and pharmacological treatments. Extracellular Vesicles (EVs) are nanoscale particles released by body cells, studied as promising biomarkers of AD as they are involved in the onset and progression of the disease. In the strive for a reliable and sensitive method to analyze EVs, we applied our recently developed biosensor based on Surface Plasmon Resonance imaging (SPRi) technology for the identification and profiling of neural EVs populations circulating in the plasma of 10 AD patients and 10 healthy subjects. The SPRi-array was designed to separate simultaneously EVs released by neurons, astrocytes, microglia and oligodendrocytes, and to evaluate the presence and the relative amount of specific surface molecules related to pathological processes including translocator protein (TSPO), β-Amyloid and ganglioside M1. As results, significant variations in the relative amount and cargoes of specific brain-derived populations of EVs were observed comparing EVs coming from AD patients and healthy subjects, finding the main differences in the activation phenotype of microglia EVs, in the lipid moieties on generic EVs and in the β-Amyloid expression on surfaces of neuronal EVs. Besides, the demonstrated correlation of SPRi data with Magnetic Resonance Imaging analysis, provided support for using the SPRi-based biosensor for the evaluation of neurodegeneration detecting and characterizing circulating EVs as peripheral biomarkers for the diagnosis and monitoring of progression and rehabilitation treatments in AD patients.Copyright © 2020 Elsevier B.V. All rights reserved.