Biomarker potential of brain‐secreted extracellular vesicles in blood in Alzheimer's disease
Open accessAbstract
INTRODUCTION: Brain cells secrete extracellular microvesicles (EVs) that cross the blood-brain barrier. Involved in cell-to-cell communication, EVs contain surface markers and a biologically active cargo of molecules specific to their tissue (and cell) of origin, reflecting the tissue or cell's physiological state. Isolation of brain-secreted EVs (BEVs) from blood provides a minimally invasive way to sample components of brain tissue in Alzheimer's disease (AD), and is considered a form of "liquid biopsy." METHODS: We performed a comprehensive review of the PubMed literature to assess the biomarker and therapeutic potential of blood-isolated BEVs in AD. RESULTS: We summarize methods used for BEV isolation, validation, and novel biomarker discovery, as well as provide insights from 26 studies in humans on the biomarker potential in AD of four cell-specific BEVs isolated from blood: neuron-, neural precursor-, astrocyte-, and brain vasculature-derived BEVs. Of these, neuron-derived BEVs has been investigated on several fronts, and these include levels of amyloid-β and tau proteins, as well as synaptic proteins. In addition, we provide a synopsis of the current landscape of BEV-based evaluation/monitoring of AD therapeutics based on two published trials and a review of registered clinical trials. DISCUSSION: Blood-isolated BEVs have emerged as a novel player in the study of AD, with enormous potential as a diagnostic, evaluation of therapeutics, and treatment tool. The literature has largely concentrated on neuron-derived BEVs in the blood in AD. Given the multifactorial pathophysiology of AD, additional studies, in neuron-derived and other brain cell-specific BEVs are warranted to establish BEVs as a robust blood-based biomarker of AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Circulating exosomes containing Aβ, tau, and inflammasome components represent a promising avenue for minimally invasive biomarker discovery, as they may mirror central nervous system processes in peripheral fluids.
“Circulating exosomes containing Aβ, tau, and inflammasome components also represent a promising avenue for minimally invasive biomarker discovery, as they may mirror central nervous system processes in peripheral fluids [174].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [174]
The Introduction (page not provided) describes blood-accessible extracellular vesicles as carrying tissue-specific cargo that reflects the originating cells’ physiological state. Section 6, Conclusions (page not provided), discusses Aβ42 and tau in blood-isolated brain-derived vesicles as potential Alzheimer’s biomarkers, while noting inconsistent findings for tau. The copy does not identify inflammasome components as part of this biomarker avenue. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., Antoniou, A., Arab, T., Archer, F., Atkin‐Smith, G. K., et al. (2018) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2018.1535750 · Cited by 11,099 · see citing works
NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.018 · Cited by 10,537 · see citing works
A molecular atlas of cell types and zonation in the brain vasculature
Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., et al. (2018) · Nature · doi:10.1038/nature25739 · Cited by 2,074 · cited 1× · see citing works
“These were as follows: (7) mesenchymal stem cells AND Alzheimer’s disease AND therapy AND extracellular microvesicles; (8) mesenchymal stem cells AND Alzheimer’s disease AND therapy AND exosomes; (9) stem cells AND Alzheimer’s disease AND therapy AND extracellular microvesicles; (10) stem cells AND Alzheimer’s disease…”
MethodFiandaca, M. S., Kapogiannis, D., Mapstone, M., Boxer, A., Eitan, E., Schwartz, J. B., Abner, E. L., Petersen, R. C., Federoff, H. J., Miller, B. L., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.06.008 · Cited by 959 · see citing works
The release and trans-synaptic transmission of Tau via exosomes
Wang, Y., Balaji, V., Kaniyappan, S., Krüger, L., Irsen, S., Tepper, K., Chandupatla, R., Maetzler, W., Schneider, A., Mandelkow, E., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0143-y · Cited by 674 · see citing works
Tau Kinetics in Neurons and the Human Central Nervous System
Sato, C., Barthélemy, N. R., Mawuenyega, K. G., Patterson, B. W., Gordon, B. A., Jockel-Balsarotti, J., Sullivan, M., Crisp, M. J., Kasten, T., Kirmess, K. M., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.015 · Cited by 586 · see citing works
Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers
Sardar Sinha, M., Ansell-Schultz, A., Civitelli, L., Hildesjö, C., Larsson, M., Lannfelt, L., Ingelsson, M., & Hallbeck, M. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1868-1 · Cited by 527 · see citing works
Goetzl, E. J., Abner, E. L., Jicha, G. A., Kapogiannis, D., & Schwartz, J. B. (2018) · The FASEB Journal · doi:10.1096/fj.201700731r · Cited by 219 · see citing works
Shi, M., Kovac, A., Korff, A., Cook, T. J., Ginghina, C., Bullock, K. M., Yang, L., Stewart, T., Zheng, D., Aro, P., et al. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.04.003 · Cited by 206 · see citing works
Flagged first, then by citations
Research works printed but not linked: 51
- Kalra H, Drummen GPC, Mathivanan S. Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci. 2016;17:170.
- Dinkins MB, Wang G, Bieberich E. Sphingolipid-enriched extracellular vesicles and Alzheimer's disease: a decade of research. J Alzheimers Dis. 2017;60:757-768.
- Rajendran L, Honsho M, Zahn TR, et al. Alzheimer's disease beta- amyloid peptides are released in association with exosomes. Proceed- ings of the National Academy of Sciences. 2006;103:11172-11177.
- Musunuri S, Khoonsari PE, Mikus M, et al. Increased levels of extracellular microvesicle markers and decreased levels of endo- cytic/exocytic proteins in the Alzheimer's disease brain. J Alzheimers Dis. 2016;54:1671-1686.
- Lugli G, Cohen AM, Bennett DA, et al. Plasma exosomal miRNAs in persons with and without Alzheimer disease: altered expression and prospects for biomarkers. PLoS One. 2015;10:e0139233.
- Chivet M, Hemming F, Pernet-Gallay K, Fraboulet S, Sadoul R. Emerg- ing role of neuronal exosomes in the central nervous system. Front Physiol. 2012;3:145.
- Peng KY, Pérez-González R, Alldred MJ, et al. Apolipoprotein E4 geno- type compromises brain exosome production. Brain. 2019;142:163- 175.
- Eitan E, Hutchison ER, Marosi K, et al. Extracellular vesicle-associated A𝛽 mediates trans-neuronal bioenergetic and Ca 2+ -handling deficits in Alzheimer's disease models. NPJ Aging Mech Dis. 2016;2. https://doi.org/10.1038/npjamd.2016.19. · DOI · Paper page
- Fiandaca MS, Mapstone ME, Cheema AK, Federoff HJ. The criti- cal need for defining preclinical biomarkers in Alzheimer's disease. Alzheimers Dement. 2014;10:S196-S212.
- Witwer KW, Buzás EI, Bemis LT, et al. Standardization of sample collec- tion, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2. https://doi.org/10.3402/jev.v2i0.20360. · DOI
- Darmanis S, Sloan SA, Zhang Y, et al. A survey of human brain tran- scriptome diversity at the single cell level. Proc Natl Acad Sci U S A. 2015;112:7285-7290.
- Filipe V, Hawe A, Jiskoot W. Critical evaluation of Nanoparticle Track- ing Analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm Res. 2010;27:796-810.
- Yang TT, Liu CG, Gao SC, Zhang Y, Wang PC. The serum exosome derived MicroRNA-135a, -193b, and -384 were potential Alzheimer's disease biomarkers. Biomed Environ Sci. 2018;31:87-96.
- Paterson RW, Heywood WE, Heslegrave AJ, et al. A targeted proteomic multiplex CSF assay identifies increased malate dehy- drogenase and other neurodegenerative biomarkers in individu- als with Alzheimer's disease pathology. Transl Psychiatry. 2016;6: e952.
- Haqqani AS, Delaney CE, Tremblay T-L, Sodja C, Sandhu JK, Stan- imirovic DB. Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells. Fluids Barriers CNS. 2013;10:4.
- Yu L, Petyuk VA, Gaiteri C, et al. Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia. Ann Neurol. 2018;84:78- 88.
- Badhwar A, Brown R, Stanimirovic DB, Haqqani AS, Hamel E. Pro- teomic differences in brain vessels of Alzheimer's disease mice: nor- malization by PPAR𝛾 agonist pioglitazone. J Cereb Blood Flow Metab. 2016. https://doi.org/10.1177/0271678X16655172. · DOI
- Badhwar A, Stanimirovic DB, Hamel E, Haqqani AS. The proteome of mouse cerebral arteries. J Cereb Blood Flow Metab. 2014;34:1033- 1046.
- Nakayasu ES, Nicora CD, Sims AC, et al. MPLEx: A robust and uni- versal protocol for single-sample integrative proteomic, metabolomic, and lipidomic analyses. mSystems. 2016;1. https://doi.org/10.1128/ mSystems.00043-16. · DOI
- Cambiaghi A, Díaz R, Martinez JB, et al. An innovative approach for the integration of proteomics and metabolomics data in severe septic shock patients stratified for mortality. Sci Rep. 2018;8:6681.
- Agliardi C, Guerini FR, Zanzottera M, Bianchi A, Nemni R, Clerici M. SNAP-25 in serum is carried by exosomes of neuronal origin and is a potential biomarker of Alzheimer's disease. Mol Neurobiol. 2019. https://doi.org/10.1007/s12035-019-1501-x. · DOI
- Goetzl EJ, Nogueras-Ortiz C, Mustapic M, et al. Deficient neurotrophic factors of CSPG4-type neural cell exosomes in Alzheimer disease. FASEB J. 2019;33:231-238.
- Jia L, Qiu Q, Zhang H, et al. Concordance between the assessment of A𝛽42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement. 2019;15:1071- 1080.
- Goetzl EJ, Schwartz JB, Abner EL, Jicha GA, Kapogiannis D. High com- plement levels in astrocyte-derived exosomes of Alzheimer disease. Ann Neurol. 2018;83:544-552.
- Guix FX, Corbett GT, Cha DJ, et al. Detection of aggregation- competent tau in neuron-derived extracellular vesicles. Int J Mol Sci. 2018;19. https://doi.org/10.3390/ijms19030663. · DOI
- Wei H, Xu Y, Xu W, et al. Serum exosomal miR-223 serves as a poten- tial diagnostic and prognostic biomarker for dementia. Neuroscience. 2018;379:167-176.
- Winston CN, Goetzl EJ, Baker LD, Vitiello MV, Rissman RA. Growth hormone-releasing hormone modulation of neuronal exosome biomarkers in mild cognitive impairment. J Alzheimers Dis. 2018;66: 971-981.
- Mullins RJ, Mustapic M, Goetzl EJ, Kapogiannis D. Exosomal biomark- ers of brain insulin resistance associated with regional atrophy in Alzheimer's disease. Hum Brain Mapp. 2017;38:1933-1940.
- Goetzl EJ, Kapogiannis D, Schwartz JB, et al. Decreased synap- tic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease. FASEB J. 2016;30:4141-4148.
- Goetzl EJ, Mustapic M, Kapogiannis D, et al. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease. FASEB J. 2016;30:3853-3859.
- Winston CN, Goetzl EJ, Akers JC, et al. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement. 2016;3:63-72.
- Cheng L, Doecke JD, Sharples RA, et al. Prognostic serum miRNA biomarkers associated with Alzheimer's disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry. 2015;20:1188-1196.
- Goetzl EJ, Boxer A, Schwartz JB, et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neu- rology. 2015;85:40-47.
- Kapogiannis D, Boxer A, Schwartz JB, et al. Dysfunctionally phos- phorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB J. 2015;29:589- 596.
- Liu C-G, Song J, Zhang Y-Q, Wang P-C. MicroRNA-193b is a regula- tor of amyloid precursor protein in the blood and cerebrospinal fluid derived exosomal microRNA-193b is a biomarker of Alzheimer's dis- ease. Mol Med Rep. 2014;10:2395-2400.
- Sweeney MD, Montagne A, Sagare AP, et al. Vascular dysfunction- the disregarded partner of Alzheimer's disease. Alzheimers Dement. 2019;15:158-167.
- Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC, Alzheimer's disease neuroimaging initiative. Early role of vascular dys- regulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun. 2016;7:11934.
- Jack CR, Jr, Bennett DA, Blennow K, et al. A/T/N: an unbiased descrip- tive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87:539-547.
- Chen Z, Mengel D, Keshavan A, et al. Learnings about the complex- ity of extracellular tau aid development of a blood-based screen for Alzheimer's disease. Alzheimers Dement. 2019;15:487-496.
- Cicognola C, Brinkmalm G, Wahlgren J, et al. Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease. Acta Neuropathol. 2019;137:279- 296.
- Badhwar A, McFall GP, Sapkota S, et al. Toward discovery of multi- omics biotypes of Alzheimer's disease: a focused review and proposed roadmap. Brain. 2019; awz384, https://doi.org/10.1093/brain/awz384. · DOI
- Kanmert D, Cantlon A, Muratore CR, et al. C-Terminally truncated forms of tau, but not full-length tau or its C-terminal fragments, are released from neurons independently of cell death. J Neurosci. 2015;35:10851-10865.
- Badhwar A, Tam A, Dansereau C, Orban P, Hoffstaedter F, Bel- lec P. Resting-state network dysfunction in Alzheimer's disease: a systematic review and meta-analysis. Alzheimers Dement. 2017;8: 73-85.
- Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclini- cal stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnos- tic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280- 292.
- Mullins RJ, Diehl TC, Chia CW, Kapogiannis D. Insulin resistance as a link between amyloid-Beta and tau pathologies in Alzheimer's disease. Front Aging Neurosci. 2017;9:118.
- Mustapic M, Tran J, Craft S, Kapogiannis D. Extracellular vesicle biomarkers track cognitive changes following intranasal insulin in Alzheimer's disease. J Alzheimers Dis. 2019;69:489-498. https://doi. org/10.3233/JAD-180578. · DOI
- Ashton NJ, Hye A, Leckey CA, et al. Plasma REST: A novel candi- date biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population. Transl Psychiatry. 2017;7:e1148- e1148.
- Elahi FM, Casaletto KB, Altendahl M, et al. "Liquid Biopsy" of white matter hyperintensity in functionally normal elders. Front Aging Neu- rosci. 2018;10:343.
- Lukiw WJ, Andreeva TV, Grigorenko AP, Rogaev EI. Studying micro RNA function and dysfunction in Alzheimer's disease. Front Genet. 2012;3:327.
- Wang L-L, Min L, Guo Q-D, et al. Profiling microRNA from brain by microarray in a transgenic mouse model of Alzheimer's disease. Biomed Res Int. 2017;2017:8030369.
- Liew LC, Katsuda T, Gailhouste L, Nakagama H, Ochiya T. Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating Alzheimer's disease. Int Immunol. 2017;29:11-19.
Cited by
Sorted by citations
Roseborough, A. D., Saad, L., Goodman, M., Cipriano, L. E., Hachinski, V. C., & Whitehead, S. N. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12642 · Cited by 80 · see citing works
Hein, Z. M., Karikalan, B., Gopalakrishna, P. K., Dhevi, K., Alkatiri, A., Hussan, F., Mohd Moklas, M. A., Jagadeesan, S., Che Ramli, M. D., Che Mohd Nassir, C. M. N., et al. (2026) · Molecular Neurobiology · doi:10.1007/s12035-025-05602-0 · Cited by 43 · see citing works
- Authors
- Badhwar, A., & Haqqani, A. S.
- Affiliations
- Institut Universitaire de Gériatrie de Montréal (CA)
- National Research Council Canada (CA)
- Corresponding author
- Badhwar, AmanPreet
- Venue
- Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
- Publisher
- Wiley
- Published
- 2020-01
- Volume
- 12
- Issue
- 1
- Pages
- e12001-e12001
- ISSN
- 2352-8729 (ISSN-L)
- PMC
- PMC7085285
- OpenAlex
- W3009750740
- Cited by
- 87
- References
- 9
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 21 · 2023: 6 · 2022: 11 · 2021: 19 · 2020: 12 · 2019: 2
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Consortium canadien en neurodégénérescence associée au vieillissement
- Courtois Foundation
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, blood-based biomarkers, liquid biopsy, neuron-derived extracellular vesicles, amyloid-beta, tau protein, synaptic proteins, therapeutic monitoring, extracellular vesicle isolation, neural progenitor cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
