JAMA Neurology: Waist chopping risk of Alzheimer's disease, Stanford team found two key mutations!

*For medical professionals only

Alzheimer's disease (AD) has long been one

According to statistics, there are currently about 44 million AD patients worldwide, and according to a cross-sectional study published in Lancet Public Health by Xuanwu Hospital of Capital Medical University in 2020, there are about 9.

In patients with AD, the vast majority of onset is over 65 years of age, also known as late-onset AD

Recently, a research team led by Michael D.

They analyzed data from 544384 subjects, combined with pre-case controls and the results of late cohort studies, and found two rare APOE missense mutations (R251G mutations in ε4 versus V236E mutations in ε3, both occurring less frequently than 0.

This study is by far the largest clinical study

Screenshot of the first page of the paper

Friends who have studied biochemistry should remember APOE, right?

In humans, APOE is able to bind to low-density lipoprotein receptors (LDL-R), promoting the metabolism

Due to the presence of single nucleotide polymorphisms (SNPs), APOE has three alleles of ε2/ε3/ε4, which produce three homozygotes (ε2/ε2, ε3/ε3, ε4/ε4), three heterozygous (ε2/ε3, ε2/ε4, ε3/ε4) for a total of six genotypes
.

Among them, ε3 is the most frequent in healthy people, while the ε2 and ε4 alleles are associated with a variety of diseases, and there are still many unsolved mysteries
.

Previous studies have clearly confirmed that ε4 is a risk factor for sporadic AD[3], and the risk of AD in individuals with the ε4/ε4 genotype is 20 times higher than in the general population[4], and ε2 has some protective effect on AD [5].

However, the above conclusions vary in studies of different ethnic groups and regions
.

In addition, multiple mutations occur in three alleles (such as the V236E and R251G mutations studied in this article), how do combinations of different alleles and mutations affect the risk of AD onset? There was no clear answer
to this question.

The APOE allele and the two mutations studied in this article

In response to the above questions, Professor Greicius et al.
explored
large-scale clinical data.

Let's take a look at how this research unfolds
.

Their large sample of case-control studies included information on 544384 people, 57.
4 percent of whom were women with an average age of 64.
9 years
.

First, based on these data, Greicius's team found that while both V236E and R251G mutations occurred less frequently than 0.
1%, without distinguishing between alleles, they were associated with a 4-5-fold reduction in the risk of developing AD (0.
23 for V236E and 0.
20 for R251G, marked in blue in the figure below).

The analysis results of distinguishing the APOE allele were also significant, with an OR value of 0.
31 in V236E in ε3/ε3 individuals and an OR value of 0.
17
in R251G in ε3/ε4.

The above data preliminarily confirm the protective effect
of V236E and R251G on the risk of AD development.

Two genetic mutations with AD risk results

Subsequently, they included data from multiple cohort studies from Europe and performed meta-analysis to find that V236E and R251G mutations still have a protective effect on AD when genes are not stratified (OR value for V236E is 0.
37, R251G is 0.
44), which is consistent
with previous conclusions.

In order to further understand the relationship between the variants of different APOE subtypes and AD, they classified the different alleles of APOE, taking the most common ε3/ε3 genotype in the population as the control (OR value 1), and found that the OR values of ε3/ε3 (V236E) and ε3/ε4 (R251G) types were significantly reduced, and the protective effect was similar
to that of ε2/ε3 genotype.

These results confirm the protective effect
of these two mutations on AD.

Risk comparison of different genotypes

On the basis of the case-control study, they also observed the protective effects
of both mutations on AD in a cohort study.

In the absence of alleles, V236E mutation carriers were about 10 years older than the average age of onset of unborn, while R251G mutations were not significantly associated
with age of onset.

The analysis results of distinguishing alleles were consistent with the undifferentiated results, the age of onset of ε3/ε3 V236E was more than 10 years higher than that of the control group, while the ε3/ε4 R251G mutation could delay the age of onset by about 6 years, but there was no statistically significant difference
.

The results of the competitive risk analysis further showed the significant protective effect of the above two mutations on AD (HR 0.
4 and 0.
26, respectively
).

Analysis results of V236E and R251G mutations to distinguish between and indistinguishable mutation locations

Overall, Professor Greicius et al.
confirmed that two rare mutations, ε3 V236E and ε4 R251G, significantly reduce the risk of AD onset and delay the age
of onset.

Since the vast majority of ε4 mutations are known to be associated with an increased risk of AD, this study is the first to identify and identify APOE ε4 mutations
that reduce the risk of AD.

In addition, there is no research to explore the effect of R251G mutation on the pathogenesis of AD, R251G mutation only through the replacement of a single amino acid to reverse the effect of ε4 to increase the risk of AD disease, this phenomenon will inevitably cause more researchers to pay attention to the ε4 allele, but also for the treatment of AD by regulating this target to bring new possibilities
.

It is believed that more research will focus on these two gene mutations in the future, and further explore why they can have a protective effect
on AD.

References:

1.
Jia L, Du Y, Chu L, et al.
Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study.
Lancet Public Health.
2020; 5(12):e661-e671.
doi:10.
1016/S2468-2667(20)30185-7

2.
Le Guen Y, Belloy ME, Grenier-Boley B, et al.
Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.
JAMA Neurol.
2022; 79(7):652-663.
doi:10.
1001/jamaneurol.
2022.
1166.

3.
Sadigh-Eteghad S, Talebi M, Farhoudi M.
Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer`s disease.
A meta-analysis.
Neurosciences (Riyadh).
2012; 17(4):321-326.

4.
Hauser PS, Ryan RO.
Impact of apolipoprotein E on Alzheimer's disease.
Curr Alzheimer Res.
2013; 10(8):809-817.
doi:10.
2174/15672050113109990156.

5.
Corder EH, Saunders AM, Risch NJ, et al.
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease.
Nat Genet.
1994; 7(2):180-184.
doi:10.
1038/ng0694-180.

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