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

Alzheimers Dement. 2022 Jul;18(7):1383-1395. doi: 10.1002/alz.12487. Epub 2021 Dec 8.


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.

Publication types

  • Multicenter Study

MeSH terms

  • Alleles
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Apolipoprotein E2* / genetics
  • Cognitive Dysfunction* / genetics
  • Gene Dosage*
  • Genotype
  • Gray Matter / pathology
  • Humans


  • Apolipoprotein E2