The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals

Gemma Salvadó, Daniel Ferreira, ALFA study†, BioFINDER, ADNI, Grégory Operto, Irene Cumplido-Mayoral, Eider M. Arenaza-Urquijo, Raffaele Cacciaglia, Carles Falcon, Natàlia Vilor-Tejedor, Carolina Minguillon, Colin Groot, Wiesje M. van der Flier, Frederik Barkhof, Philip Scheltens, Rik Ossenkoppele, Silke Kern, Anna Zettergren, Ingmar Skoog, Jakub Hort, Erik StomrudDanielle van Westen, Oskar Hansson, José Luis Molinuevo, Lars Olof Wahlund, Eric Westman*, Juan Domingo Gispert*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Introduction: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). Results: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. Discussion: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline.

Original languageEnglish
Pages (from-to)1383-1395
Number of pages13
JournalAlzheimer's and Dementia
Issue number7
Early online date8 Dec 2021
Publication statusPublished - Jul 2022

Bibliographical note

Funding Information:
Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Funding Information:
Data used in pre‐creation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database ( As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at (‐content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf ). The project leading to this study has received funding from “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN17/50300004. Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant number 2017‐SGR‐892. EMAU is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018‐026053‐I). FB is supported by NIHR biomedical research centre at UCLH. IS is supported by the Swedish Research Council (2019‐02075), Swedish Research Council for Health, Working Life and Wellfare, Swedish state under the agreement between the Swedish government and the county councils, the ALF‐agreement (ALF 716681, ALFGBG‐81392, ALFGBG‐771071), Alzheimerfonden, and Hjärnfonden. DF, LOW, and EW are supported by the Swedish Foundation for Strategic Research (SSF); the Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro); the Swedish Research Council (VR, 2016‐02282); the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet; Center for Innovative Medicine (CIMED); the Swedish Alzheimer Foundation; the Swedish Brain Foundation; the Åke Wiberg Foundation; Demensfonden; Stiftelsen Olle Engkvist Byggmästare; and Birgitta och Sten Westerberg; Funding for Research from Karolinska Institutet; Funding for Geriatric Research from Karolinska Institutet; Stiftelsen Loo och Hans Ostermans; Stiftelsen Gun och Bertil Stohnes; and Stiftelsen Sigurd och Elsa Goljes Minne. JDG is supported by the Spanish Ministry of Economy, and Competitiveness (RYC‐2013‐13054). OH and the BioFINDER study was supported by the Swedish Research Council (2016‐00906), the Knut and Alice Wallenberg foundation (2017‐0383), the Marianne and Marcus Wallenberg foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Foundation (AF‐939932), the Swedish Brain Foundation (FO2019‐0326), The Parkinson foundation of Sweden (1280/20), the Skåne University Hospital Foundation (2020‐O000028), Regionalt Forskningsstöd (2020‐0314), and the Swedish federal government under the ALF agreement (2018‐Projekt0279).

Publisher Copyright:
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.


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