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Genotypic effects of APOE-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation

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dc.contributor.author Cacciaglia, Raffaele
dc.contributor.author Operto, Grégory
dc.contributor.author Falcón, Carles
dc.contributor.author González de Echávarri, José Maria
dc.contributor.author Sánchez Benavides, Gonzalo
dc.contributor.author Brugulat Serrat, Anna, 1986-
dc.contributor.author Milà Alomà, Marta
dc.contributor.author Blennow, Kaj
dc.contributor.author Zetterberg, Henrik
dc.contributor.author Molinuevo, José Luis
dc.contributor.author Suárez-Calvet, Marc
dc.contributor.author Gispert López, Juan Domingo
dc.contributor.author ALFA Study
dc.date.accessioned 2022-10-17T06:18:02Z
dc.date.available 2022-10-17T06:18:02Z
dc.date.issued 2022
dc.identifier.citation Cacciaglia R, Operto G, Falcón C, de Echavarri-Gómez JMG, Sánchez-Benavides G, Brugulat-Serrat A, et al. Genotypic effects of APOE-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation. Cereb Cortex. 2022 Jun 27: 1-13. DOI: 10.1093/cercor/bhac239.
dc.identifier.issn 1047-3211
dc.identifier.uri http://hdl.handle.net/10230/54413
dc.description.abstract The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer's disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-ε4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the ε4 allele. Yet, no study has assessed APOE-ε4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-ε4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of ε4 homozygotes (n = 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-ε4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the ε4-homozygotes. Our data indicate that APOE-ε4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.
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 the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 948677) and the Instituto de Salud Carlos III (PI19/00155). KB is supported by the Swedish Research Council (#2017-00915), 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), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495). 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.language.iso eng
dc.publisher Oxford University Press
dc.rights © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Genotypic effects of APOE-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1093/cercor/bhac239
dc.subject.keyword APOE-ε4
dc.subject.keyword Alzheimer’s disease
dc.subject.keyword Compensation
dc.subject.keyword Resting-state connectivity
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/860197
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/RYC-2013-13054
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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