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 journalArticleAcademicpeer-review


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
JournalAlzheimer's and Dementia
Early online date2021
Publication statusE-pub ahead of print - 2021

Cite this