Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts

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• dc.contributor.author Cacciaglia, Raffaele
• dc.contributor.author Salvadó, Gemma
• dc.contributor.author Molinuevo, José Luis
• dc.contributor.author Shekari, Mahnaz
• dc.contributor.author Falcón, Carles
• dc.contributor.author Operto, Grégory
• dc.contributor.author Suárez-Calvet, Marc
• dc.contributor.author Milà Alomà, Marta
• dc.contributor.author Sala, Arianna
• dc.contributor.author Rodriguez-Vieitez, Elena
• dc.contributor.author Kollmorgen, Gwendlyn
• dc.contributor.author Suridjan, Ivonne
• dc.contributor.author Blennow, Kaj
• dc.contributor.author Zetterberg, Henrik
• dc.contributor.author Gispert López, Juan Domingo
• dc.contributor.author Alzheimer’s Disease Neuroimaging Initiative
• dc.contributor.author ALFA Study
• dc.date.accessioned 2022-10-11T06:11:56Z
• dc.date.available 2022-10-11T06:11:56Z
• dc.date.issued 2022
• dc.description.abstract Amyloid (Aβ) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aβ pools, reflecting the clearance of soluble Aβ as opposed to the presence of Aβ fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited Aβ. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aβ deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aβ, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aβ deposition for any given level of CSF Aβ42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aβ aggregation, with APOE-ε4 possibly facilitating a co-localization between Aβ and tau along the disease continuum.
• dc.description.sponsorship The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 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 is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). MSC receives funding from 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). KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017-00915); the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243); and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement. 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), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL.
• dc.format.mimetype application/pdf
• dc.identifier.citation Cacciaglia R, Salvadó G, Molinuevo JL, Shekari M, Falcon C, Operto G, Suárez-Calvet M, Milà-Alomà M, Sala A, Rodriguez-Vieitez E, Kollmorgen G, Suridjan I, Blennow K, Zetterberg H, Gispert JD; Alzheimer’s Disease Neuroimaging Initiative; ALFA study. Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts. Mol Psychiatry. 2022 Apr;27(4):2010-8. DOI: 10.1038/s41380-022-01436-7
• dc.identifier.doi http://dx.doi.org/10.1038/s41380-022-01436-7
• dc.identifier.issn 1359-4184
• dc.identifier.uri http://hdl.handle.net/10230/54335
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Mol Psychiatry. 2022 Apr;27(4):2010-8
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681712
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/860197
• dc.rights © The Author(s) 2022. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Biomarkers
• dc.subject.keyword Genetics
• dc.subject.keyword Neuroscience
• dc.title Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion