A plasma biomarker panel for detecting early amyloid-β accumulation and its changes in middle-aged cognitively unimpaired individuals at risk for Alzheimer's disease

González Escalante, Armand; Milà Alomà, Marta; Brum, Wagner S.; Ashton, Nicholas J.; Ortiz-Romero, Paula; Shekari, Mahnaz; Campo, Marta del; Anastasi, Federica; Quijano Rubio, Clara; Kollmorgen, Gwendlyn; Minguillón, Carolina; Sánchez Benavides, Gonzalo; Grau-Rivera, Oriol; Gispert López, Juan Domingo; Zetterberg, Henrik; Vilor Tejedor, Natàlia, 1988-; Blennow, Kaj; Suárez-Calvet, Marc

A plasma biomarker panel for detecting early amyloid-β accumulation and its changes in middle-aged cognitively unimpaired individuals at risk for Alzheimer's disease

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dc.contributor.author González Escalante, Armand
dc.contributor.author Milà Alomà, Marta
dc.contributor.author Brum, Wagner S.
dc.contributor.author Ashton, Nicholas J.
dc.contributor.author Ortiz-Romero, Paula
dc.contributor.author Shekari, Mahnaz
dc.contributor.author Campo, Marta del
dc.contributor.author Anastasi, Federica
dc.contributor.author Quijano Rubio, Clara
dc.contributor.author Kollmorgen, Gwendlyn
dc.contributor.author Minguillón, Carolina
dc.contributor.author Sánchez Benavides, Gonzalo
dc.contributor.author Grau-Rivera, Oriol
dc.contributor.author Gispert López, Juan Domingo
dc.contributor.author Zetterberg, Henrik
dc.contributor.author Vilor Tejedor, Natàlia, 1988-
dc.contributor.author Blennow, Kaj
dc.contributor.author Suárez-Calvet, Marc
dc.date.accessioned 2025-09-04T06:39:40Z
dc.date.available 2025-09-04T06:39:40Z
dc.date.issued 2025
dc.description.abstract Background: Plasma biomarkers of Alzheimer's disease (AD) change during preclinical stages, indicating potential for detecting amyloid-β (Aβ) pathology in cognitively unimpaired (CU) individuals. Given the need for accurate, scalable biomarkers, we evaluated a fully automated plasma panel to detect and monitor longitudinal Aβ accumulation in CU individuals. Methods: In this longitudinal study, we examined a plasma panel (Aβ42/40, p-tau181, GFAP, NfL, p-tau217 and ApoE4) in CU participants at risk for AD. We assessed the biomarkers' performance to detect Aβ pathology and the cross-sectional and longitudinal relationships between the biomarkers and Aβ accumulation, neurodegeneration and cognition. Findings: We included 400 middle-aged CU participants, of whom 135 (33.8%) were CSF Aβ-positive. All plasma biomarkers differed between Aβ-positive and -negative individuals, with plasma Aβ42/40, p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 showing the best performance in detecting A+ CU individuals. However, plasma Aβ42/40 was sensitive to random variability. Plasma p-tau217/Aβ42 had the highest performance in detecting PET A+ individuals (AUC = 0.94). All baseline plasma biomarkers were associated with longitudinal increases in Aβ deposition (mean follow-up [SD]: 3.27 ± 0.5). Longitudinal changes in plasma p-tau217 and p-tau217/Aβ42 were associated with concurrent changes in Aβ (both CSF and PET) and soluble tau pathology. Interpretation: In CU individuals, several plasma biomarkers at baseline detect Aβ accumulation and are associated with its short-term change. Plasma p-tau217, and p-tau217/Aβ42 longitudinal changes reflect concurrent Aβ accumulation during this period. These findings help enrich studies in CU individuals at risk of progressing to AD. Funding: ERC-2020-STG (Grant agreement No. 948677); ERA PerMed-ERA NET and the Generalitat de Catalunya (SLD077/21/000001); PI19/00155; PI22/00456, LCF/BQ/PR21/11840004.
dc.description.sponsorship This publication is part of the ALFA study (ALzheimers and Families). The authors would like to express their most sincere gratitude to the ALFA project participants and relatives without whom this research would not have been possible. The authors thank Roche Diagnostics International Ltd for providing the kits to measure Plasma and CSF biomarkers and GE Healthcare for providing the doses of [18F]flutemetamol PET. The NeuroToolKit is a panel of exploratory prototype assays designed to robustly evaluate biomarkers associated with key pathologic events characteristic of AD and other neurological disorders, used for research purposes only and not approved for clinical use (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Elecsys Phospho-Tau (181P) CSF and Elecsys Total-Tau CSF assays are approved for clinical use. COBAS and ELECSYS are trademarks of Roche. All other product names and trademarks are the property of their respective owners. We thank the collaborators of the ALFA Study: Alba Cañas, Albina Polo, Ana Fernández-Arcos, Annabella Beteta, Anna Brugulat-Serrat, Anna Soteras, Blanca Rodríguez-Fernández, Carme Deulofeu, Ferran Lugo, Irene Cumplido-Mayoral, Jordi Huguet, Laura Hernández, Maria Emilio, Patricia Genius, Paula Marne, Sandra Pradas, Sherezade Fuentes, and Wiesje Pelkmans. MMA receives funding from the Alzheimer’s Association Research Fellowship Program (AARF-23-1141384). FA receives funding from the JDC2022-049347-I grant, funded by the MCIU/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR. GSB is supported by the Agencia Estatal de Investigación AEI/10.13039/501100011033 through the project PID2020-119556RA-I00 and by Instituto de Salud Carlos III (ISCIII) through the project CP23/00039 (Miguel Servet contract), co-funded by the European Union (FSE+). OGR’s institution is supported by Roche Pharmaceuticals and Spanish Ministry of Science, Innovation and Universities (IJC2020-043417-I). HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer’s Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the European Partnership on Metrology, co-financed from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States (NEuroBioStand, #22HLT07), the Bluefield Project, Cure Alzheimer’s Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). NVT is supported by the Spanish Ministry of Science and Innovation - State Research Agency (grant RYC2022-038136-I, cofunded by the European Union FSE+ and grant PID2022-143106OA-I00 cofunded by the European Union FEDER). Additionally, NVT is supported by the William H. Gates Sr. Fellowship from the Alzheimer’s Disease Data Initiative. KB is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270, and #AF-994551), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), the Alzheimer’s Association 2022–2025 Grant (SG-23-1038904 QC), La Fondation Recherche Alzheimer (FRA), Paris, France, the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark, and Familjen Rönströms Stiftelse, Stockholm, Sweden. MSC receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 948677); ERA PerMed-ERA NET and the Generalitat de Catalunya (Departament de Salut) through the project SLD077/21/000001; Project “PI19/00155” and “PI22/00456”, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union; and from a fellowship from ‘la Caixa’ Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004).
dc.format.mimetype application/pdf
dc.identifier.citation González-Escalante A, Milà-Alomà M, Brum WS, Ashton NJ, Ortiz-Romero P, Shekari M, et al. A plasma biomarker panel for detecting early amyloid-β accumulation and its changes in middle-aged cognitively unimpaired individuals at risk for Alzheimer's disease. EBioMedicine. 2025 Jun;116:105741. DOI: 10.1016/j.ebiom.2025.105741
dc.identifier.doi http://dx.doi.org/10.1016/j.ebiom.2025.105741
dc.identifier.issn 2352-3964
dc.identifier.uri http://hdl.handle.net/10230/71105
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof EBioMedicine. 2025 Jun;116:105741
dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101053962
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/860197
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-143106OA-I00
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/847648
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword Alzheimer
dc.subject.keyword Biomarkers
dc.subject.keyword Dementia
dc.subject.keyword Diagnosis
dc.subject.keyword Modelling
dc.subject.keyword Plasma
dc.title A plasma biomarker panel for detecting early amyloid-β accumulation and its changes in middle-aged cognitively unimpaired individuals at risk for Alzheimer's disease
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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