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However, its non\u2010invasive detection using neuron\u2010derived extracellular vesicles (NDEVs) from plasma remains unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We included 139 adults with DS (45 asymptomatic [aDS], 94 symptomatic for AD [sDS]) and 37 healthy controls. NDEVs were isolated from plasma. ProNGF and tetraspanin (CD81) were quantified by enzyme\u2010linked immunosorbent assay. We assessed proNGF\/CD81 changes with age, along the AD continuum (aDS and sDS), and associations with cerebrospinal fluid (CSF), plasma biomarkers, episodic memory, and basal forebrain volume.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In DS, proNGF\/CD81 levels increased with age and were higher in NDEVs from asymptomatic and symptomatic individuals compared to controls, with the highest levels in the symptomatic group. ProNGF correlated with CSF phosphorylated tau (p\u2010tau)181, plasma p\u2010tau217, neurofilament light chain, and episodic memory.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>ProNGF\/CD81 levels in NDEVs increase along the AD continuum in DS and parallel tau pathology, indicating the potential as a promising biomarker for monitoring disease progression in plasma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Nerve growth factor precursor protein (ProNGF)\/tetraspanin (CD81) ratio increased in the third decade of life, 20 years before Alzheimer's disease (AD) symptom onset in Down syndrome (DS).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>proNGF\/CD81 concentrations were significantly higher in individuals with DS compared to controls and were notably elevated in individuals with DS and symptomatic AD compared to asymptomatic AD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>proNGF\/CD81 concentrations were associated with tau pathology and neuronal injury.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70137","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T07:15:41Z","timestamp":1745219741000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Nerve growth factor precursor alterations in neuron\u2010derived extracellular vesicles from individuals with Down syndrome along the Alzheimer's disease continuum"],"prefix":"10.1002","volume":"21","author":[{"given":"Natalia","family":"Valle\u2010Tamayo","sequence":"first","affiliation":[{"name":"Sant Pau Memory Unit Hospital de la Santa Creu i Sant Pau \u2013 Biomedical Research Institute Sant Pau\u2010 Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED) Instituto de Salud Carlos III (ISCIII)  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mateus Rozalem","family":"Aranha","sequence":"additional","affiliation":[{"name":"Sant Pau Memory Unit Hospital de la Santa Creu i Sant Pau \u2013 Biomedical Research Institute Sant Pau\u2010 Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED) Instituto de Salud Carlos III (ISCIII)  Madrid Spain"},{"name":"Neuroradiology Section Department of Radiology \u2013 Memory Unit Department of Neurology Institut de Recerca Sant Pau. 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