Plasma extracellular vesicles and phosphorylated tau 181 as early biomarkers of cognitive impairment in Alzheimer’s dementia
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Source: Alzheimer s Research & Therapy
Authors: Viviana Brembati, Daniela Crescenti, Andrea Geviti, Elisa Rossini, Federico Angelo Cazzaniga, Fabio Moda, Elisa R. Zanier, Gisella Guerrera, Luca Battistini, Simone Baiardi, Alessandra Mandelli, Roberto Furlan, Federico Verde, Benedetta Nacmias, Chiara Adriana Elia, Maria Luisa Malosio, Alberto Imarisio, Franca Rosa Guerini, Chiara Fenoglio, Alessio Di Fonzo, Leonardo Biscetti, Margherita Squillario, Silvia Berra, Francesca Miraglia, Paolo Maria Rossini, Camillo Marra, Nicola Vanacore, Alberto Redolfi, Daniela Perani, Patrizia Spadin, Maria Cotelli, Stefano Cappa, Naike Caraglia, Fabrizio Vecchio, Pietro Tiraboschi, Federica Piras, Giovanni B. Frisoni, Cristina Muscio, Raffaele Lodi, Piero Parchi, Fabrizio Tagliavini, Enza Maria Valente, Gianluigi Forloni, Roberta Ghidoni, INTERCEPTOR Network, /, Maurizio Belfiglio, Giacomina Rossi, Emanuela Maderna, Marcella Catania, Giuseppe Di Fede, Davide Quaranta, Emanuele Cassetta, Mario Barbagallo, Carlo Gabelli, Simona Luzzi, Fulvio Lauretani, Innocenzo Rainero, Carlo Ferrarese, Orazio Zanetti, Michela Marcon, Flavio Mariano Nobili, Matteo Pardini, Giuseppe Pelliccioni, Sabina Capellari, Elena Sinforiani, Alfredo Costa, Gioacchino Tedeschi, Carmen Gerace, Laura Bonanni, Sandro Sorbi, Lucilla Parnetti, Network-AD project, Ilaria Bizzozero, Paola Caroppo, Valeria Crepaldi, Giuseppe Di Fede, Giorgio Giaccone, Veronica Redaelli, Marcella Catania, Edoardo Bistaffa, Chiara Maria Giulia De Luca, Giacomina Rossi, Chiara Boiocchi, Sara Cimini, Maria Grazia Bruzzone, Luigi Antelmi, Stefania Ferraro, Ruben Gianeri, Jean Paul Medina, Anna Nigri, Cristina Rosazza, Domenico Arenella, Fabrizio Piras, Desiree Estela Porcari, Daniela Vecchio, Roberto Langella, Domenico Mancini, Giovanni Mancini, Marco Bozzali, Giovanni Giulietti, Laura Serr, Orazio Schillaci, Agostino Chiaravalloti, Valentino Bettinardi, Sandro Iannaccone, Federica Alemanno, Valerio Golzi, Anna Parma, Alessandra Marcone, Teresa Sikora, Cristina Festari, Valentino Nicolosi, Jorge Jovicich, Silvia De Francesco, Luisa Benussi, Guido Domingo, Roberta Zanardini, Daniela Galimberti, Elio Scarpini, Barbara Borroni, Elisa Bonomi, Viviana Cristillo, Silvia Pelizzari, Rosanna Turrone, Luca Rozzini, Roberto Gasparotti, Daniela Corbo, Lorella Mascaro, Barbara Paghera, Lucilla Parnetti, Elena Chipi, Chiara Montanucci, Lucia Farotti, Mirella Russo, Massimo Eugenio Dottorini, Cristina Tranfaglia, Roberto Tarducci, Andrea Chiappiniello, Pietro Chiarini, Pietro Floridi, Sandro Sorbi, Cristina Polito, Silvia Bagnoli, Gemma Lombardi, Alberto Pupi, Valentina Berti, Maria Teresa De Cristofaro, Alessandro Passeri, Enrico Fainardi, Andrea Ginestroni, Stefano Chiti, Roberto D’Alessandro, Ambra Fiorani, Simona Linarello, Biomarker Italian Team, Sonia Bellini, Antonio Longobardi, Valentina Bonetto, Ilaria Lisi, Laura Pasetto, Emiliano Giardina, Giulia Sancesario, Antonia Ratti, Vincenzo Silani, Nicola Ticozzi, Silvia Bagnoli, Assunta Ingannato, Michela Matteoli, Micol Avenali, Rosaria Calabrese, Cristina Agliardi, Daniela Galimberti, Michele Piana, Annarita Bentivoglio, Giulia Di Lazzaro, Stefano Gambardella
Institutions: Centro San Giovanni di Dio Fatebenefratelli, Fondazione IRCCS Istituto Neurologico Carlo Besta, University of Milan, Mario Negri Institute for Pharmacological Research, Fondazione Santa Lucia, Istituto delle Scienze Neurologiche di Bologna, University of Bologna, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, IRCCS Istituto Auxologico Italiano, University of Florence, IRCCS Humanitas Research Hospital, University of Pavia, Fondazione Istituto Neurologico Nazionale Casimiro Mondino, Don Carlo Gnocchi Foundation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Istituto Nazionale di Riposo e Cura per Anziani, Ospedale Policlinico San Martino, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Agostino Gemelli University Polyclinic, Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Superiore di Sanità, National Centre for Disease Prevention and Control, Istituto Universitario di Studi Superiori di Pavia, University Hospital of Geneva, Azienda Socio Sanitaria Territoriale di Bergamo Ovest
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,290
Funders: 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
Awards: G16173144, G5937494762
OpenAlex ID: W7118358527