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

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

Gemma Salvadó  1   2 , Daniel Ferreira  3   4 , Grégory Operto  1   2   5 , Irene Cumplido-Mayoral  1   6 , Eider M Arenaza-Urquijo  1   2   5 , Raffaele Cacciaglia  1   2   5 , Carles Falcon  1   2   7 , Natàlia Vilor-Tejedor  1   6   8   9 , Carolina Minguillon  1   2   5 , Colin Groot  10 , Wiesje M van der Flier  10   11 , Frederik Barkhof  12   13 , Philip Scheltens  10 , Rik Ossenkoppele  10   14 , Silke Kern  15 , Anna Zettergren  15 , Ingmar Skoog  15 , Jakub Hort  16   17 , Erik Stomrud  18   19 , Danielle van Westen  20   21 , Oskar Hansson  18   19 , José Luis Molinuevo  1 , Lars-Olof Wahlund  3 , Eric Westman  3   22 , Juan Domingo Gispert  1   2   6   7 ; ALFA study†, BioFINDER, ADNI
Affiliations
Multicenter Study

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

Gemma Salvadó et al. Alzheimers Dement. 2022 Jul.

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.

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Conflict of interest statement

JLM is currently a full‐time employee of Lundbeck and priorly has served as a consultant or at advisory boards for the following for‐profit companies, or has given lectures in symposia sponsored by the following for‐profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences. HZ has served on scientific advisory boards for Alector, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. GK is a full‐time employee of Roche Diagnostics GmbH. IS is a full‐time employee and shareholder of Roche Diagnostics International Ltd. The remaining authors declare that they have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Association between APOE genotype and GM volume in AD‐related areas. Adjusted GM volume in areas affected in AD (AD signature; left) and in areas known to be associated with successful aging or resilience (resilience signature; right) by APOE genotype. GM volumes were adjusted by age, sex, education, scan, and TIV. *P < 0.05; · P < 0.10. AD, Alzheimer's disease; APOE, apolipoprotein E; GM, gray matter; TIV, total intracranial volume
FIGURE 2
FIGURE 2
Comparisons between APOE ε2 genotypic groups. Comparisons between APOE ε2 genotypic groups and APOE‐ε3 homozygotes as the reference group (A); and between each pair of APOE ε2 genotypic groups (B). Colors indicate the effect size of each effect in regions that were statistically significant (P < 0.05 FDR‐adjusted). AD, Alzheimer's disease; APOE, apolipoprotein E; FDR, false discovery rate; GM, gray matter; LH, left hemisphere; RH, right hemisphere
FIGURE 3
FIGURE 3
Dose‐dependent effects of the APOE ε2 allele. Dose‐dependent effects of the ε2 allele on GM volume (from left to right: dominant, additive, and recessive). APOE ε2/ε4 participants were not included in this analysis. Colors indicate the effect size of each effect in regions that were statistically significant (P < 0.05 FDR‐adjusted). AD, Alzheimer's disease; APOE, apolipoprotein E; FDR, false discovery rate; GM, gray matter; LH, left hemisphere; RH, right hemisphere
FIGURE 4
FIGURE 4
APOE genotype‐related AD risk effect on GM volume and association to APOE ε2 effects. APOE genotype‐related AD risk effects on GM volume (A). Colors indicate the effect size of each effect in regions that were statistically significant (P < 0.05 FDR‐adjusted). Associations between dose‐dependent effects of the ε2 allele (βstd) on GM volume (from left to right: dominant, additive, and recessive) and APOE genotype‐related AD risk effect (βstd) on GM volume. Spearman's ρ and P‐values are shown in the left bottom corner of each plot. AD, Alzheimer's disease; APOE, apolipoprotein E; FDR, false discovery rate; GM, gray matter; LH, left hemisphere; RH, right hemisphere
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