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

Gemma Salvadó; Daniel Ferreira; 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 Stomrud; Danielle van Westen; Oskar Hansson; José Luis Molinuevo; Lars-Olof Wahlund; Eric Westman; Juan Domingo Gispert; ALFA study†, BioFINDER, ADNI; Annabella Beteta; Alba Cañas; Marta Crous-Bou; Carme Deulofeu; Ruth Dominguez; Maria Emilio; Karine Fauria; José M. González de Echevarri; Oriol Grau-Rivera; Laura Hernandez; Gema Huesa; Jordi Huguet; Paula Marne; Tania Menchón; Marta Milà-Alomà; Albina Polo; Sandra Pradas; Aleix Sala-Vila; Gonzalo Sánchez-Benavides; Anna Soteras; Marc Suárez-Calvet; Marc Vilanova

doi:10.1002/alz.12487

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

Gemma Salvadó, Daniel Ferreira, 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 Stomrud, Danielle van WestenOskar Hansson, José Luis Molinuevo, Lars-Olof Wahlund, Eric Westman^*, Juan Domingo Gispert^*, ALFA study†, BioFINDER, ADNI, Annabella Beteta, Alba Cañas, Marta Crous-Bou, Carme Deulofeu, Ruth Dominguez, Maria Emilio, Karine Fauria, José M. González de Echevarri, Oriol Grau-Rivera, Laura Hernandez, Gema Huesa, Jordi Huguet, Paula Marne, Tania Menchón, Marta Milà-Alomà, Albina Polo, Sandra Pradas, Aleix Sala-Vila, Gonzalo Sánchez-Benavides, Anna Soteras, Marc Suárez-Calvet, Marc Vilanova

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 language	English
Journal	Alzheimer's and Dementia
Early online date	2021
DOIs	https://doi.org/10.1002/alz.12487
Publication status	E-pub ahead of print - 2021

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Salvadó, G., Ferreira, D., Operto, G., Cumplido-Mayoral, I., Arenaza-Urquijo, E. M., Cacciaglia, R., Falcon, C., Vilor-Tejedor, N., Minguillon, C., Groot, C., van der Flier, W. M., Barkhof, F., Scheltens, P., Ossenkoppele, R., Kern, S., Zettergren, A., Skoog, I., Hort, J., Stomrud, E., ... Vilanova, M. (2021). The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals. Alzheimer's and Dementia. https://doi.org/10.1002/alz.12487

@article{bae973928b9b46688cf1214df47ffb8d,

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

abstract = "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.",

keywords = "Alzheimer's disease, Alzheimer's disease signature, apolipoprotein E ε2 carrier, brain maintenance, brain morphology, brain reserve, cognitive reserve, magnetic resonance, multi-site, resilience signature",

author = "Gemma Salvad{\'o} and Daniel Ferreira and Gr{\'e}gory Operto and Irene Cumplido-Mayoral and Arenaza-Urquijo, {Eider M.} and Raffaele Cacciaglia and Carles Falcon and Nat{\`a}lia Vilor-Tejedor and Carolina Minguillon and Colin Groot and {van der Flier}, {Wiesje M.} and Frederik Barkhof and Philip Scheltens and Rik Ossenkoppele and Silke Kern and Anna Zettergren and Ingmar Skoog and Jakub Hort and Erik Stomrud and {van Westen}, Danielle and Oskar Hansson and Molinuevo, {Jos{\'e} Luis} and Lars-Olof Wahlund and Eric Westman and Gispert, {Juan Domingo} and {ALFA study†, BioFINDER, ADNI} and Annabella Beteta and Alba Ca{\~n}as and Marta Crous-Bou and Carme Deulofeu and Ruth Dominguez and Maria Emilio and Karine Fauria and {de Echevarri}, {Jos{\'e} M. Gonz{\'a}lez} and Oriol Grau-Rivera and Laura Hernandez and Gema Huesa and Jordi Huguet and Paula Marne and Tania Mench{\'o}n and Marta Mil{\`a}-Alom{\`a} and Albina Polo and Sandra Pradas and Aleix Sala-Vila and Gonzalo S{\'a}nchez-Benavides and Anna Soteras and Marc Su{\'a}rez-Calvet and Marc Vilanova",

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 ( www.fnih.org ). 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 (adni.loni.usc.edu). 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 ( http://adni.loni.usc.edu/wp‐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 Hj{\"a}rnfonden. 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 {\AA}ke Wiberg Foundation; Demensfonden; Stiftelsen Olle Engkvist Byggm{\"a}stare; 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 Sk{\aa}ne University Hospital Foundation (2020‐O000028), Regionalt Forskningsst{\"o}d (2020‐0314), and the Swedish federal government under the ALF agreement (2018‐Projekt0279). Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2021",

doi = "10.1002/alz.12487",

language = "English",

journal = "Alzheimers & Dementia",

issn = "1552-5260",

publisher = "Elsevier",

}

Salvadó, G, Ferreira, D, Operto, G, Cumplido-Mayoral, I, Arenaza-Urquijo, EM, Cacciaglia, R, Falcon, C, Vilor-Tejedor, N, Minguillon, C, Groot, C , van der Flier, WM , Barkhof, F , Scheltens, P , Ossenkoppele, R, Kern, S, Zettergren, A, Skoog, I, Hort, J, Stomrud, E, van Westen, D, Hansson, O, Molinuevo, JL, Wahlund, L-O, Westman, E, Gispert, JD, ALFA study†, BioFINDER, ADNI, Beteta, A, Cañas, A, Crous-Bou, M, Deulofeu, C, Dominguez, R, Emilio, M, Fauria, K, de Echevarri, JMG, Grau-Rivera, O, Hernandez, L, Huesa, G, Huguet, J, Marne, P, Menchón, T, Milà-Alomà, M, Polo, A, Pradas, S, Sala-Vila, A, Sánchez-Benavides, G, Soteras, A, Suárez-Calvet, M & Vilanova, M 2021, 'The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals', Alzheimer's and Dementia. https://doi.org/10.1002/alz.12487

TY - JOUR

T1 - The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals

AU - Salvadó, Gemma

AU - Ferreira, Daniel

AU - Operto, Grégory

AU - Cumplido-Mayoral, Irene

AU - Arenaza-Urquijo, Eider M.

AU - Cacciaglia, Raffaele

AU - Falcon, Carles

AU - Vilor-Tejedor, Natàlia

AU - Minguillon, Carolina

AU - Groot, Colin

AU - van der Flier, Wiesje M.

AU - Barkhof, Frederik

AU - Scheltens, Philip

AU - Ossenkoppele, Rik

AU - Kern, Silke

AU - Zettergren, Anna

AU - Skoog, Ingmar

AU - Hort, Jakub

AU - Stomrud, Erik

AU - van Westen, Danielle

AU - Hansson, Oskar

AU - Molinuevo, José Luis

AU - Wahlund, Lars-Olof

AU - Westman, Eric

AU - Gispert, Juan Domingo

AU - ALFA study†, BioFINDER, ADNI

AU - Beteta, Annabella

AU - Cañas, Alba

AU - Crous-Bou, Marta

AU - Deulofeu, Carme

AU - Dominguez, Ruth

AU - Emilio, Maria

AU - Fauria, Karine

AU - de Echevarri, José M. González

AU - Grau-Rivera, Oriol

AU - Hernandez, Laura

AU - Huesa, Gema

AU - Huguet, Jordi

AU - Marne, Paula

AU - Menchón, Tania

AU - Milà-Alomà, Marta

AU - Polo, Albina

AU - Pradas, Sandra

AU - Sala-Vila, Aleix

AU - Sánchez-Benavides, Gonzalo

AU - Soteras, Anna

AU - Suárez-Calvet, Marc

AU - Vilanova, Marc

N1 - 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 ( www.fnih.org ). 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 (adni.loni.usc.edu). 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 ( http://adni.loni.usc.edu/wp‐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.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Alzheimer's disease signature

KW - apolipoprotein E ε2 carrier

KW - brain maintenance

KW - brain morphology

KW - brain reserve

KW - cognitive reserve

KW - magnetic resonance

KW - multi-site

KW - resilience signature

UR - http://www.scopus.com/inward/record.url?scp=85121001961&partnerID=8YFLogxK

U2 - 10.1002/alz.12487

DO - 10.1002/alz.12487

M3 - Article

C2 - 34877786

SN - 1552-5260

JO - Alzheimers & Dementia

JF - Alzheimers & Dementia

ER -

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

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