Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment

The hippocampus, crucial in cognitive aging and Alzheimer's disease (AD), shows early atrophy during disease progression. This study investigated 5-year trajectories of hippocampal volumes across AD stages, focusing on genetic predisposition to AD, captured through the polygenic risk score for...

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Autores: Vilor-Tejedor, Natalia, Rodrigo, Albert, Genius, Patricia, Rodríguez-Fernández, Blanca, Anastasi, Federica, Pelkmans, Wiesje, Navarro, Arcadi, Adams, Hieab H, Wisse, Laura, Gispert, Juan D, Evans, Tavia E
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::5ae14787cfc1b55b4b40143fca6f0887
Acceso en línea:http://hdl.handle.net/10261/426668
https://api.elsevier.com/content/abstract/scopus_id/105019321208
Access Level:acceso abierto
Palabra clave:APOE
Genetic risk
Hippocampal atrophy
Mild cognitive impairment
Protein quantitative trait loci
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spelling Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive ImpairmentVilor-Tejedor, NataliaRodrigo, AlbertGenius, PatriciaRodríguez-Fernández, BlancaAnastasi, FedericaPelkmans, WiesjeNavarro, ArcadiAdams, Hieab HWisse, LauraGispert, Juan DEvans, Tavia EAPOEGenetic riskHippocampal atrophyMild cognitive impairmentProtein quantitative trait lociThe hippocampus, crucial in cognitive aging and Alzheimer's disease (AD), shows early atrophy during disease progression. This study investigated 5-year trajectories of hippocampal volumes across AD stages, focusing on genetic predisposition to AD, captured through the polygenic risk score for AD (PRS-AD) and APOE, and their impact on hippocampal atrophy. Analyzing data from 1,051 participants in the ADNI, we found that AD genetic risk accelerates a reduction in hippocampal volume, particularly in individuals with mild cognitive impairment (MCI). Effects were primarily driven by cerebrospinal fluid protein quantitative trait loci of APOE. Excluding the APOE region from analyses negated these effects, underscoring its critical role. This stage-specific effect suggested that AD genetic factors, particularly the APOE region, exert their influence primarily before or during the transition to MCI, highlighting the hippocampus's increased vulnerability during this period. These findings underscored the importance of targeting the MCI stage for early detection and intervention in AD. Further research is warranted to elucidate these dynamics and their potential clinical applications.NV-T is supported by the Spanish Ministry of Science and Innovation – State Research Agency grant RYC2022-038136-I, co-funded by the European Union FSE+, grant PID2022-143106OA-I00 co-funded by the European Union FEDER. Additionally, NV-T is supported by the William H. Gates Sr. Fellowship Cohort I from the Alzheimer’s Disease Data Initiative, and grant WE.08-2024-07 funded by Alzheimer Nederland. FA receives funding from the JDC2022-049347-I grant, funded by the MCIU/AEI/https://doi.org/10.13039/501100011033 and the European Union NextGenerationEU/PRTR. TEE is supported by the Alzheimer Association Research postdoctoral fellowship 25AARF-1377279, Alzheimer Nederland project WE.03-2024-07, and William H. Gates Sr. Fellowship Cohort II from the Alzheimer’s Disease Data Initiative. This project is partly supported by the National Computing Facilities Processing research programme which is financed by the Dutch Research Council (NWO) under the grant [2022.018].Peer reviewedElsevierMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)European CommissionAlzheimer NederlandFoundation for Alzheimer ResearchDutch Research CouncilConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/426668https://api.elsevier.com/content/abstract/scopus_id/105019321208reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-143106OA-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI http://dx.doi.org/10.1016/j.nicl.2025.103889http://dx.doi.org/10.1016/j.nicl.2025.103889Síinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::5ae14787cfc1b55b4b40143fca6f08872026-05-22T06:33:51Z
dc.title.none.fl_str_mv Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
title Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
spellingShingle Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
Vilor-Tejedor, Natalia
APOE
Genetic risk
Hippocampal atrophy
Mild cognitive impairment
Protein quantitative trait loci
title_short Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
title_full Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
title_fullStr Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
title_full_unstemmed Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
title_sort Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
dc.creator.none.fl_str_mv Vilor-Tejedor, Natalia
Rodrigo, Albert
Genius, Patricia
Rodríguez-Fernández, Blanca
Anastasi, Federica
Pelkmans, Wiesje
Navarro, Arcadi
Adams, Hieab H
Wisse, Laura
Gispert, Juan D
Evans, Tavia E
author Vilor-Tejedor, Natalia
author_facet Vilor-Tejedor, Natalia
Rodrigo, Albert
Genius, Patricia
Rodríguez-Fernández, Blanca
Anastasi, Federica
Pelkmans, Wiesje
Navarro, Arcadi
Adams, Hieab H
Wisse, Laura
Gispert, Juan D
Evans, Tavia E
author_role author
author2 Rodrigo, Albert
Genius, Patricia
Rodríguez-Fernández, Blanca
Anastasi, Federica
Pelkmans, Wiesje
Navarro, Arcadi
Adams, Hieab H
Wisse, Laura
Gispert, Juan D
Evans, Tavia E
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
European Commission
Alzheimer Nederland
Foundation for Alzheimer Research
Dutch Research Council
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv APOE
Genetic risk
Hippocampal atrophy
Mild cognitive impairment
Protein quantitative trait loci
topic APOE
Genetic risk
Hippocampal atrophy
Mild cognitive impairment
Protein quantitative trait loci
description The hippocampus, crucial in cognitive aging and Alzheimer's disease (AD), shows early atrophy during disease progression. This study investigated 5-year trajectories of hippocampal volumes across AD stages, focusing on genetic predisposition to AD, captured through the polygenic risk score for AD (PRS-AD) and APOE, and their impact on hippocampal atrophy. Analyzing data from 1,051 participants in the ADNI, we found that AD genetic risk accelerates a reduction in hippocampal volume, particularly in individuals with mild cognitive impairment (MCI). Effects were primarily driven by cerebrospinal fluid protein quantitative trait loci of APOE. Excluding the APOE region from analyses negated these effects, underscoring its critical role. This stage-specific effect suggested that AD genetic factors, particularly the APOE region, exert their influence primarily before or during the transition to MCI, highlighting the hippocampus's increased vulnerability during this period. These findings underscored the importance of targeting the MCI stage for early detection and intervention in AD. Further research is warranted to elucidate these dynamics and their potential clinical applications.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/426668
https://api.elsevier.com/content/abstract/scopus_id/105019321208
url http://hdl.handle.net/10261/426668
https://api.elsevier.com/content/abstract/scopus_id/105019321208
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-143106OA-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI http://dx.doi.org/10.1016/j.nicl.2025.103889
http://dx.doi.org/10.1016/j.nicl.2025.103889
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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