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Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study

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dc.contributor.author Rodríguez-Fernández, Blanca
dc.contributor.author Vilor Tejedor, Natàlia, 1988-
dc.contributor.author Arenaza Urquijo, Eider M.
dc.contributor.author Sánchez Benavides, Gonzalo
dc.contributor.author Suárez-Calvet, Marc
dc.contributor.author Operto, Grégory
dc.contributor.author Minguillón, Carolina
dc.contributor.author Navarro i Cuartiellas, Arcadi, 1969-
dc.contributor.author Gispert López, Juan Domingo
dc.contributor.author Sala Vila, Aleix
dc.contributor.author ALFA Study
dc.date.accessioned 2022-12-15T07:16:28Z
dc.date.available 2022-12-15T07:16:28Z
dc.date.issued 2022
dc.identifier.citation Rodríguez-Fernández B, Vilor-Tejedor N, Arenaza-Urquijo EM, Sánchez-Benavides G, Suárez-Calvet M, Operto G et al. Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study. Alzheimers Res Ther. 2022 Nov 7;14(1):167. DOI: 10.1186/s13195-022-01101-9
dc.identifier.issn 1758-9193
dc.identifier.uri http://hdl.handle.net/10230/55143
dc.description.abstract Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations.
dc.description.sponsorship The project leading to these results has received funding from the Alzheimer’s Association (Grant AARG-19-618265). This project has received funding from Instituto de Salud Carlos III (PI19/00119). Additional support has been received 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), the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201), and the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. All CRG authors acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. NV-T is funded by a post-doctoral grant, Juan de la Cierva Incorporación Programme (IJC2020-043216-I), Ministry of Science and Innovation–Spanish State Research Agency. EMAU is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). MS-C receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement no. 948677). MS-C 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). 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 AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C); the Olav Thon Foundation; the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228); 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. 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); and the National Institute of Health (NIH), USA, (grant #1R01AG068398-01). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). AS-V. is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Alzheimers Res Ther. 2022 Nov 7;14(1):167
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 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.uri http://creativecommons.org/licenses/by/4.0/
dc.title Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/s13195-022-01101-9
dc.subject.keyword Alzheimer’s disease
dc.subject.keyword Cerebrospinal fluid biomarkers
dc.subject.keyword Mendelian randomization
dc.subject.keyword Neuroimaging
dc.subject.keyword Polygenic risk score
dc.subject.keyword Telomere length
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RYC2018-026053-I
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681712
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/860197
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/RYC-2013-13054
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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