APOE ε2 Copies Linked to Larger Gray Matter Volumes, Greater Protection Against Alzheimer


Regions typically affected by Alzheimer disease-related neurodegeneration were similarly protected by the carriership of at least 1 ε2 allele, regardless of their load.

Gemma Salvado, MD

Gemma Salvado, MD

An investigation of cognitively unimpaired carriers of the apolipoprotein E (APOE) ε2 allele showed larger gray matter (GM) volumes than ε3 homozygotes, as well as associations with areas of cognitive resilience. All told, APOE ε2 homozygotes may offer additional protection against Alzheimer disease (AD)-related cognitive decline.1

While it had been previously recorded that having 2 copies of the APOE ε2 allele protects against AD, little had been known about how the effect of this genotype on GM volume in cognitively unimpaired individuals. Lead author Gemma Salvado, MD, post-doctoral researcher, Barcelona Brain Research Center, and colleagues, gathered data on 223 individuals, including 38 individuals with APOE ε2/ε2 allele and 38 matched individuals for each of the other APOE genotypes (ε2/ε3, ε3/ε3, ε3/ε4, ε4/ε4). Only the APOE ε2/ε4 group had 33 individuals due to the unavailability of suitable matches for 5 cases.

The first comparison looked at 2 AD-related GM volume region of interest (ROI) composites: the AD signature and the resilience signature. At the conclusion of the analysis, participants with APOE ε2/ε3 alleles had larger GM volume in the AD signature areas compared to ε3/ε3 homozygotes (ßstd, 2.71 [95% CI, 0.74-4.69]). Within the resilience signature, ε2 homozygotes had larger GM volumes than the ε3/ε3 and ε4/ε4 groups.

The largest differences between ε2 genomic groups came from the ε2/ε2 and ε2/ε4 groups, and more specifically, in bilateral postcentral gyri, and right parahippocampal and posterior cingulate gyri. APOE ε2 homozygotes only showed larger volumes than ε2/ε3 participants in the right precentral gyrus, but this difference did not survive after false discovery rate (FDR) adjustment.

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"Altogether, our large multi-cohort data advocates for increased brain reserve in APOE ε2 carriers, especially in ε2 homozygotes, which may in turn confer them additional protection against AD-related cognitive decline, independent of the well-known effects of APOE on Aβ,” Salvado and coauthors wrote.

Global APOE genotype-related AD risk showed a negative association with GM volume in the AD signature (F = 4.61; P = .033) on composite-based analysis, as well as a trend in the resilience signature toward the same direction (F = 2.81; P = .096).

Investigators also found specific regions of negative correlation for the APOE genotype-related AD risk with GM volume. Less GM volume in brain areas overlapping with parts of the AD signature, such as the entorhinal and the fusiform, correlated with the increased risk of AD dementia related to APOE genotype. This was also seen in parts of the resilience signature, including the anterior cingulate.

In the ROI analyses, investigators found a significant dose-dependent effect of higher GM volume associated with dominant ε2 allele on both AD-related composites (AD signature: ßstd, 2.64 [95% CI, 0.66-4.62]; P <.010; Resilience signature ßstd, 2.07 [95% CI, 0.09-4.05]; P <.041). Additive ε2 allele trended toward the same direction of significance for the resilience signature (ßstd, 1.92 [95% CI, ­–0.07 to 3.87]), but no other significant effects were observed.

These findings extend previous studies that have shown that having at least 1 ε2 allele confers larger GM volumes in areas known to be affected in AD. A 2010 study by Ming Fan, et al. and the Alzheimer’s Disease Neuroimaging Initiative showed that APOE ε2 carriers have a significantly thicker (corrected, P <.05) cortical thickness in the superior temporal cortex compared with the ε3 homozygotes. In addition to this area, the APOE ε2 carriers had a significantly thicker region in the dorsolateral prefrontal cortex (corrected, P <.05) than did the ε4 carriers. All told, these findings suggested that different alleles of APOE gene have distinct neuroanatomic effects in healthy subjects, which may play specific roles in the development of AD.2

1. Salvado G, Ferreira D, Operto G, et al. The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals. Alzheimers Dement. Published online December 8, 2021. doi:10.1002/alz.12487
2. Fan M, Liu B, Zhou Y, Zhen X, Xu C, Jiang T. Cortical thickness is associated with different apolipoprotein E genotypes in healthy elderly adults. Neurosci Lett. 2010;479(3):332-336. doi:10.1016/j.neulet.2010.05.092.
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