Plasma extracellular vesicles and phosphorylated tau 181 as early biomarkers of cognitive impairment in Alzheimer’s dementia

Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice is a great challenge, especially during early disease stages with subtle or mild symptoms of cognitive decline. Moreover, robust and more accessible blood-based screening tests for early diagnosis are needed. In this study, we investigated the core AD blood biomarkers — amyloid beta 42 (Aβ42) and 40 (Aβ40) peptides, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-Tau) — and extracellular vesicle (EVs) size and concentration in individuals characterized by different stages of cognitive decline to identify biochemical markers of dementia for early diagnosis. A total of n = 800 human plasma samples were analyzed. Plasma levels of NfL, t-Tau, p-Tau181, Aβ42, Aβ40 and plasma EVs were evaluated in n = 217 elderly healthy subjects (CTRL), in individuals with subjective cognitive complaints (SCC, n = 48), pre-mild cognitive impairment (pre-MCI, n = 58) and mild cognitive impairment (MCI, n = 426), and in n = 51 probable AD dementia patients (AD-dem), using ultrasensitive Single Molecule Array technology (Simoa®) and nanoparticle tracking analysis (NTA). Logistic regression and Receiver Operating Characteristic (ROC) analyses were employed. Plasma NfL displayed increased levels in AD-dem and MCI patients, while p-Tau181, Aβ42/Aβ40 ratio, Aβ42/p-Tau181 ratio, and EVs plasma levels were altered since the early stages of the pathology: in particular, p-Tau181 levels increased as cognitive symptoms worsened, already in the SCC and pre-MCI groups compared to CTRL, while the ratio of EVs concentration and size (EVs ratio) was decreased in all groups compared to CTRL. Plasma p-Tau181 best classified AD-dem patients from CTRL with an area under the curve (AUC) equal to 0.87, while EVs ratio best differentiated SCC from CTRL (AUC = 0.78). Combining p-Tau181 and EVs ratio with Aβ42/Aβ40 ratio and NfL, respectively, significantly improved the classification of pre-MCI and MCI from CTRL (AUCcomb = 0.79 and AUCcomb = 0.85). Combining biomarkers did not improve accuracy in discriminating MCI from SCC, pre-MCI and AD-dem. p-Tau181 and EVs ratio are promising biomarkers for the identification of individuals at risk of degenerative dementia. Combining the core AD plasma biomarkers with EVs ratio can aid in diagnosing the early stages of AD dementia.

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Publication Details

Journal
Alzheimer s Research & Therapy
Published
2026-01-06
DOI
https://doi.org/10.1186/s13195-025-01897-2
Citations
1
Primary Topic
Extracellular vesicles in disease
Type
article
Field-Weighted Citation Impact
22.24

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article

Plasma extracellular vesicles and phosphorylated tau 181 as early biomarkers of cognitive impairment in Alzheimer’s dementia

Maurizio Belfiglio, Lorella Mascaro, Federica Piras, Enza Maria VALENTE et al.
1 citations
Alzheimer s Research & Therapy
Extracellular vesicles in disease
22.24
article

Plasma extracellular vesicles and phosphorylated tau 181 as early biomarkers of cognitive impairment in Alzheimer’s dementia

Maurizio Belfiglio, Lorella Mascaro, Federica Piras, Enza Maria VALENTE, Margherita Squillario, Stefano Chiti, Andrea Ginestroni, A Nigri, Giacomina Rossi, Teresa Sikora, Chiara Maria Giulia De Luca, Chiara Elia, Maria Grazia Bruzzone, Alfredo Costa, Cristina Tranfaglia, Emanuela Maderna, V M Nicolosi, Simona Luzzi, Andrea Chiappiniello, Stefano Francesco Cappa, Antonia Ratti, Cristina Festari, Massimo E. Dottorini, Piero Parchi, P Chiarini, Viviana Brembati, Laura Pasetto, Orazio Zanetti, Andrea Geviti, R. Tarducci, Leonardo Biscetti, Roberto Gasparotti, Giuseppe Pelliccioni, A P Bentivoglio, G L Forloni, Paolo Maria Rossini, Guido Domingo, Giovanni Mancini, D Galimberti, Gemma Lombardi, Alessandra Mandelli, Sonia Bellini, Patrizia Spadin, Luisa Benussi, Marcella Catania, Silvia Pelizzari, Mirella Russo, Daniela Crescenti, Rosaria Calabrese, Desirèè Estela Porcari, Chiara Boiocchi, Michela Matteoli, Roberta Zanardini, Pietro Tiraboschi, Sara Cimini, Ambra Fiorani, Daniela Vecchio, Elena Chipi, Valentino Bettinardi, Jean Paúl Medina, S T Iannaccone, Fabio Moda, Rosanna Turrone, Antonio Longobardi, Carlo Ferrarese, Cristina Polito, Emanuele Cassetta, Alessio Di Fonzo, G. Frisoni, Chiara Montanucci, Cristina Agliardi, Silvia Berra, L. Rozzini, DAVIDE QUARANTA, Alberto Imarisio, Viviana Cristillo, Matteo Pardini, Simona Linarello, Flavio Nobili, Alberto Pupi, Federica Alemanno, Silvia Bagnoli, Lucia Farotti, Gisella Guerrera, Ruben Gianeri, Valeria Crepaldi, Franca Rosa Guerini, Emiliano Giardina, Carlo Gabelli, Fulvio Lauretani, Giulia Maria Sancesario, Cristina Muscio, Innocenzo Rainero, Alessandra Marcone, R Furlan, Edoardo Bistaffa, Domenico Arenella, D Mancini, Alessandro Passeri, Luigi Antelmi, Giuseppe Di Fede, P. Floridi, Barbara Borroni, Michele Piana, I. Bizzozero, Impacc Network, Elena Sinforiani, Roberto D’Alessandro, Maria Cotelli, Ilaria Lisi, Gioacchino Tedeschi, Giorgio Giaccone, Roberta Ghidoni, Federico Verde, Simone Baiardi, Nicola Vanacore, Fabrizio Tagliavini, Barbara Paghera, Valentina Berti, C A Gerace, M L Marcon, L Battistini, Barbagallo Mario, Lucilla Parnetti, Marra Camillo, Sabina Capellari, Laura Bonanni, Cristina Rosazza, Raffaele Lodi, Chiara Fenoglio, Jorge Jovicich, Daniela Perani, Stefano Gambardella, Benedetta Nacmias, Vincenzo Silani, Roberto Langella, Stefania Ferraro, Biomarker Italian Team, Naike Caraglia, Valerio Golzi, Anna Parma, Laura Serr, Paola Caroppo, Fabrizio Piras, Marco Bozzali, Giulia Di Lazzaro, Network-AD project, Alberto Redolfi, Fabrizio Vecchio, Giovanni Giulietti, Valentina Bonetto, Agostino Chiaravalloti, Micol Avenali, Sandro Sorbi, Veronica Redaelli, Nicola Ticozzi, Maria Luisa Malosio, /, Elisa Rossini, Enrico Fainardi, Federico Angelo Cazzaniga, Orazio Schillaci, Francesca Miraglia, Elio Scarpini, Daniela Corbo, Maria Teresa De Cristofaro, Elisa Bonomi, Assunta Ingannato, Elisa R. Zanier, Silvia De Francesco
article en
1 citations

Abstract

Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice is a great challenge, especially during early disease stages with subtle or mild symptoms of cognitive decline. Moreover, robust and more accessible blood-based screening tests for early diagnosis are needed. In this study, we investigated the core AD blood biomarkers — amyloid beta 42 (Aβ42) and 40 (Aβ40) peptides, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-Tau) — and extracellular vesicle (EVs) size and concentration in individuals characterized by different stages of cognitive decline to identify biochemical markers of dementia for early diagnosis. A total of n = 800 human plasma samples were analyzed. Plasma levels of NfL, t-Tau, p-Tau181, Aβ42, Aβ40 and plasma EVs were evaluated in n = 217 elderly healthy subjects (CTRL), in individuals with subjective cognitive complaints (SCC, n = 48), pre-mild cognitive impairment (pre-MCI, n = 58) and mild cognitive impairment (MCI, n = 426), and in n = 51 probable AD dementia patients (AD-dem), using ultrasensitive Single Molecule Array technology (Simoa®) and nanoparticle tracking analysis (NTA). Logistic regression and Receiver Operating Characteristic (ROC) analyses were employed. Plasma NfL displayed increased levels in AD-dem and MCI patients, while p-Tau181, Aβ42/Aβ40 ratio, Aβ42/p-Tau181 ratio, and EVs plasma levels were altered since the early stages of the pathology: in particular, p-Tau181 levels increased as cognitive symptoms worsened, already in the SCC and pre-MCI groups compared to CTRL, while the ratio of EVs concentration and size (EVs ratio) was decreased in all groups compared to CTRL. Plasma p-Tau181 best classified AD-dem patients from CTRL with an area under the curve (AUC) equal to 0.87, while EVs ratio best differentiated SCC from CTRL (AUC = 0.78). Combining p-Tau181 and EVs ratio with Aβ42/Aβ40 ratio and NfL, respectively, significantly improved the classification of pre-MCI and MCI from CTRL (AUCcomb = 0.79 and AUCcomb = 0.85). Combining biomarkers did not improve accuracy in discriminating MCI from SCC, pre-MCI and AD-dem. p-Tau181 and EVs ratio are promising biomarkers for the identification of individuals at risk of degenerative dementia. Combining the core AD plasma biomarkers with EVs ratio can aid in diagnosing the early stages of AD dementia.

Alzheimer s Research & TherapyVol. 18(1)
University of Bergamo (IT), Vita-Salute San Raffaele University (IT), University of Milan (IT), Mario Negri Institute for Pharmacological Research (IT), University of Pavia (IT), Istituto Universitario di Studi Superiori di Pavia (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), National Centre for Disease Prevention and Control (IT), University Hospital of Geneva (CH), Centro San Giovanni di Dio Fatebenefratelli (IT), Associazione Italiana Di Oncologia Medica (IT), Don Carlo Gnocchi Foundation (IT), Associazione Italiana per l'Agricoltura Biologica (IT), National Institute of Health (AM), Istituto delle Scienze Neurologiche di Bologna (IT), IRCCS Ospedale San Raffaele (IT), IRCCS Istituto Auxologico Italiano (IT), Ospedale Policlinico San Martino (IT), Fondazione Santa Lucia (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Istituto Nazionale di Riposo e Cura per Anziani (IT), IRCCS Humanitas Research Hospital (IT), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Azienda Socio Sanitaria Territoriale di Bergamo Ovest, University of Florence (IT), Geneva College (US), University of Bologna (IT)
Università degli Studi di Milano, Istituto di Ricerche Farmacologiche Mario Negri - IRCCS, Ministero della Salute, Università degli Studi di Trento, Università degli Studi di Firenze, Università degli Studi di Pavia, Università di Bologna, Hôpitaux Universitaires de Genève, Università degli Studi di Brescia, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Humanitas University, Istituto Auxologico Italiano, Humanitas Research Hospital, Agenzia Italiana del Farmaco, Ministero della Salute
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Extracellular vesicles in disease
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