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The lipoprotein E (APOE) gene is the main genetic risk regulator of sporadic Alzheimer's disease (AD)
.
Carrying one or two copies of ɛ4 allele will bring a higher risk of AD (allele odds ratio [OR]: 6), while carrying ɛ2 allele will bring a lower AD risk (allele OR of genes: 0.
The increased risk of AD caused by carrying at least one ɛ4 allele is mainly related to the higher burden of amyloid β (Aβ) in the brain, in a dose-dependent manner (that is, the number of ɛ4 alleles)
.
However, neuroimaging studies have shown that there is a relationship between the dose of ɛ4 gene and lower brain glucose metabolism and smaller AD-related brain gray matter (GM) volume, even in individuals with no cognitive impairment
On the other hand, the ε2 allele has received much less attention, possibly due to the low frequency of this polymorphism in the general population (8.
4%)
.
APOEɛ2 carriers have lower Aβ burden among non-dementia participants
These results indicate that ɛ2 carriers may have higher brain reserves, which may enable them to better cope with aging and disease
.
In response to this, there are reports that even in rare cases that develop into AD pathology (ie, Aβ and tau), ɛ2 carriers can still remain cognitively intact for a long time
On the other hand, the maintenance of metabolism in other areas, such as the anterior cingulate gyrus or the temporal region, is related to the preservation of cognitive function
.
These facts indicate that the metabolism and volume measurement of these areas are particularly meaningful when studying features related to AD
In this way, Gemma Salvado and others of Barcelona Beta Brain Research Center (BBRC) in Spain studied the relationship between the APOEɛ2 genotype and the brain morphology of people with advanced/middle-age cognitive impairment, focusing on the relationship between ɛ2/ɛ2 individuals and ɛ2 alleles.
Dose effect
.
Main hypotheses:
(1) APOEε2 carriers are associated with larger GM volumes in areas known to be affected by AD and areas associated with successful aging,
(2) higher doses of ε2 alleles are related to larger GM volumes,
(3) These effects will contribute to the global APOE genotype-related AD risk effects of GM volume
.
Multicenter brain magnetic resonance images (MRIs) from cognitively accessible ε2 homotypes were matched with all other APOE genotypes related confounding (1:1) (n = 223)
.
The GM volume of the ε2 genotype group was compared with the reference group (APOE ε3/ε3)
They found that carrying at least one ε2 allele is associated with larger GM volume in brain areas that are usually affected by AD and areas related to cognitive ability
.
Homotypes of APOE ε2, but not heterozygotes of APOE ε2, show larger GM volumes in areas associated with successful aging
.
The important significance of this study lies in the discovery: In addition to the known resistance to amyloid β deposition, the larger GM volume in key brain regions may give APOE ε2 homozygotes additional protection against AD-related cognitive decline
.
.
Original source:
Salvadó 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.
Alzheimer's & Dementia.
Published online December 8, 2021:alz.
12487.
doi :10.
1002/alz.
12487
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