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Eitan et al. Extracell Vesicles Circ Nucleic Acids 2023;4:133-150 Extracellular Vesicles and
DOI: 10.20517/evcna.2023.13
Circulating Nucleic Acids

Original Article Open Access

Synaptic proteins in neuron-derived extracellular
vesicles as biomarkers for Alzheimer’s disease:

novel methodology and clinical proof of concept

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Erez Eitan 1 , Tricia Thornton-Wells , Katya Elgart , Eren Erden , Eve Gershun , Amir Levine , Olga
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Volpert , Mitra Azadeh , Daniel G. Smith , Dimitrios Kapogiannis 3
1
NeuroDex Inc., Natick, MA 01760, USA.
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Alkermes, Inc., Department of Translational Medicine and Early-Stage Clinical Development, Waltham, MA 02451-1420, USA.
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National Institute on Aging (NIA/NIH), Human Neuroscience Section, Intramural Research Program, Baltimore, MD 21224,
USA.
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Columbia University, Division of Child and Adolescent Psychiatry, Department of Psychiatry, College of Physicians and
Surgeons, New York, NY 10032, USA.
Correspondence to: Erez Eitan, PhD., NeuroDex Inc., 27 Strathmore Rd, Natick, MA, 01760, USA. Email: eeitan@neurodex.co.
Dimitrios Kapogiannis, MD, National Institute on Aging (NIA/NIH), Human Neuroscience Section, Intramural Research Program,
251 Bayview Blvd, Baltimore, MD 21224, USA. E-mail: kapogiannisd@mail.nih.gov
How to cite this article: Eitan E, Thornton-Wells T, Elgart K, Erden E, Gershun E, Levine A, Volpert O, Azadeh M, Smith DG,
Kapogiannis D. Synaptic proteins in neuron-derived extracellular vesicles as biomarkers for Alzheimer’s disease: novel
methodology and clinical proof of concept. Extracell Vesicles Circ Nucleic Acids 2023;4:133-150.
https://dx.doi.org/10.20517/evcna.2023.13
Received: 8 Feb 2023 First Decision: 6 Mar 2023 Revised: 20 Mar 2023 Accepted: 23 Mar 2023 Published: 31 Mar 2023
Academic Editor: Shilpa Buch Copy Editor: Ying Han Production Editor: Ying Han

Abstract
Aims: Blood biomarkers can improve drug development for Alzheimer’s disease (AD) and its treatment. Neuron-
derived extracellular vesicles (NDEVs) in plasma offer a minimally invasive platform for developing novel
biomarkers that may be used to monitor the diverse pathogenic processes involved in AD. However, NDEVs
comprise only a minor fraction of circulating extracellular vesicles (EVs). Most published studies have leveraged
the L1 cell adhesion molecule (L1CAM) for NDEV immunocapture. We aimed to develop and optimize an
alternative, highly specific immunoaffinity method to enrich blood NDEVs for biomarker development.

Methods: After screening multiple neuronal antigens, we achieved NDEV capture with high affinity and specificity
using antibodies against Growth-Associated Protein (GAP) 43 and Neuroligin 3 (NLGN3). The EV identity of the
captured material was confirmed by electron microscopy, western blotting, and proteomics. The specificity for

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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