Data-driven CSF biomarker profiling: imaging and clinical outcomes in a cohort at risk of Alzheimer's disease

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• dc.contributor.author Argiris, Georgette
• dc.contributor.author Akinci, Muge
• dc.contributor.author Peña-Gómez, Cleofé
• dc.contributor.author Palpatzis, Eleni
• dc.contributor.author Garcia Prat, Marina
• dc.contributor.author Shekari, Mahnaz
• dc.contributor.author Blennow, Kaj
• dc.contributor.author Zetterberg, Henrik
• dc.contributor.author Kollmorgen, Gwendlyn
• dc.contributor.author Quijano Rubio, Clara
• dc.contributor.author Ashton, Nicholas J.
• dc.contributor.author Karikari, Thomas K.
• dc.contributor.author Brinkmalm-Westman, Ann
• dc.contributor.author Lantero Rodriguez, Juan
• dc.contributor.author Fauria, Karine
• dc.contributor.author Sánchez Benavides, Gonzalo
• dc.contributor.author Grau-Rivera, Oriol
• dc.contributor.author Suárez-Calvet, Marc
• dc.contributor.author Arenaza Urquijo, Eider M.
• dc.contributor.author ALFA Study
• dc.contributor.other Argiris, Georgette; Akinci, Muge; Peña-Gómez, Cleofé; Palpatzis, Eleni; Garcia Prat, Marina; Shekari, Mahnaz; Blennow, Kaj; Zetterberg, Henrik; Kollmorgen, Gwendlyn; Quijano Rubio, Clara; Ashton, Nicholas J.; Karikari, Thomas K.; Brinkmalm-Westman, Ann; Lantero Rodriguez, Juan; Fauria, Karine; Sánchez Benavides, Gonzalo; Grau-Rivera, Oriol; Suárez-Calvet, Marc; Arenaza Urquijo, Eider M.; ALFA Study
• dc.date.accessioned 2025-02-10T07:20:45Z
• dc.date.available 2025-02-10T07:20:45Z
• dc.date.issued 2024
• dc.description.abstract Background: Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet. Methods: Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ42, Aβ40, p-tau181, p-tau217, p-tau231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated. Results: Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ42/40 + compared with Aβ42/40 - . Furthermore, Aβ42/40 - participants in C1 showed GM reduction in inferior temporal areas compared with Aβ42/40 + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ42/40 + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time. Conclusions: Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts.
• dc.description.sponsorship The research leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004, the Alzheimer’s Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17–519007). Support has also been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under grant no. 2021 SGR 00913. The research leading to these results has received funding by the Ministry of Science and Innovation (PID2019-111514RA-I00) and the Alzheimer’s Association research grants (AARG 2019-AARG-644641, AARG 2019-AARG-644641-RAPID), to EMA-U. EMA-U is supported by the Spanish Ministry of Science and Innovation—State Research Agency (RYC2018-026053-I), co-funded by the European Social Fund (ESF). EMA-U receives support from EU Joint Programme-Neurodegenerative Disease Research (JPND2022-138). E.P is funded by the Spanish Ministry of Science and Innovation (PRE2020-095827). GA receives support from the Alzheimer’s Association research fellowship (23AARF-1028873). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022–01018 and #2019–02397), the European Union’s Horizon Europe research and innovation program under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201,809–2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21–831,376-C, #ADSF-21–831,381-C, and #ADSF-21–831,377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Program – 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). MSC receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 948677), Project "PI19/00155″, 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 program under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004).
• dc.format.mimetype application/pdf
• dc.identifier.citation Argiris G, Akinci M, Peña-Gómez C, Palpatzis E, Garcia-Prat M, Shekari M, et al. Data-driven CSF biomarker profiling: imaging and clinical outcomes in a cohort at risk of Alzheimer's disease. Alzheimers Res Ther. 2024 Dec 23;16(1):274. DOI: 10.1186/s13195-024-01629-y
• dc.identifier.doi http://dx.doi.org/10.1186/s13195-024-01629-y
• dc.identifier.issn 1758-9193
• dc.identifier.uri http://hdl.handle.net/10230/69532
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Alzheimers Res Ther. 2024 Dec 23;16(1):274
• dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101053962
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-111514RA-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RYC2018-026053-I
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/860197
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/847648
• dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword ALFA cohort
• dc.subject.keyword ATN
• dc.subject.keyword CSF biomarkers
• dc.subject.keyword Hierarchical clustering
• dc.subject.keyword Sporadic Alzheimer’s disease
• dc.subject.keyword β-amyloid
• dc.title Data-driven CSF biomarker profiling: imaging and clinical outcomes in a cohort at risk of Alzheimer's disease
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion