Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile

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  • dc.contributor.author Milà Alomà, Marta
  • dc.contributor.author Shekari, Mahnaz
  • dc.contributor.author Salvadó, Gemma
  • dc.contributor.author Gispert López, Juan Domingo
  • dc.contributor.author Arenaza Urquijo, Eider M.
  • dc.contributor.author Operto, Grégory
  • dc.contributor.author Falcón, Carles
  • dc.contributor.author Vilor Tejedor, Natàlia, 1988-
  • dc.contributor.author Grau-Rivera, Oriol
  • dc.contributor.author Sala Vila, Aleix
  • dc.contributor.author Sánchez Benavides, Gonzalo
  • dc.contributor.author González de Echávarri, José Maria
  • dc.contributor.author Minguillón, Carolina
  • dc.contributor.author Suárez-Calvet, Marc
  • dc.contributor.author Molinuevo, José Luis
  • dc.contributor.author ALFA Study
  • dc.date.accessioned 2021-11-29T07:32:49Z
  • dc.date.available 2021-11-29T07:32:49Z
  • dc.date.issued 2021
  • dc.description.abstract Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [18F]-FDG, and [18F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex. Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials. Trial registration: NCT02485730.
  • dc.description.sponsorship The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. JDG holds a “Ramón y Cajal” fellowship (RYC-2013-13054). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation–Spanish State Research Agency. OG-R is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437), and receives funding from the Alzheimer’s Association Research Fellowship Program (2019-AARF-644568). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at UCL. KB is supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). MSC receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant agreement No. 948677). MSC also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Milà-Alomà M, Shekari M, Salvadó G, Gispert JD, Arenaza-Urquijo EM, Operto G et al. Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile. Alzheimers Res Ther. 2021;13(1):134. DOI: 10.1186/s13195-021-00863-y
  • dc.identifier.doi http://dx.doi.org/10.1186/s13195-021-00863-y
  • dc.identifier.issn 1758-9193
  • dc.identifier.uri http://hdl.handle.net/10230/49078
  • dc.language.iso eng
  • dc.publisher BioMed Central
  • dc.relation.ispartof Alzheimers Res Ther. 2021;13(1):134
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681712
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
  • dc.rights © The Author(s). 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Alzheimer’s disease
  • dc.subject.keyword Biomarkers
  • dc.subject.keyword CSF
  • dc.subject.keyword Cognitively unimpaired
  • dc.subject.keyword Preclinical
  • dc.subject.keyword Subthreshold
  • dc.title Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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