Sub-Journal of "Nature": Subversion of Cognition!

Alzheimer's disease (AD) is currently the largest degenerative disease of the nervous system.
With the aging of the population, it has gradually become a heavy social burden
.

With the deepening of research, people have found that the risk of AD is closely related to the APOE gene
.

APOE gene has three alleles, ε2, ε3, and ε4.
APOE ε2 is the strongest protective factor for AD, and APOE ε4 is the strongest pathogenic factor for AD.
The existence of this allele directly affects AD The accumulation of the pathological protein-β amyloid (Aβ) increases and the clearance decreases, which ultimately leads to the degeneration and death of neurons [1]
.

We have known since childhood that natural selection of the fittest will survive.
In the process of evolution, genes that are more conducive to survival will be retained, while harmful genes will be gradually eliminated
.

So why does APOE ε4 such a "bad" gene coexist with humans for a long time? This has to mention the theory of antagonistic gene pleiotropic (AP) aging
.

The theory believes that evolutionarily selected genes are generally beneficial to the growth and reproduction of species, and often promote aging in the later stages of life, which is also the most accepted cause of aging [2]
.

The same is true for the APOE ε4 gene
.

It has been found that APOE ε4 is beneficial to human fertility and anti-infection ability, and it can also slightly improve people's cognitive level
.

An important clinical manifestation of AD is the decline in cognitive level, which is mainly caused by neuronal death caused by the deposition of pathological proteins
.

So what kind of effect does APOE ε4 have on cognitive ability, and what will be the result of the superposition of APOE ε4's cognition enhancement effect and Aβ deposition on cognition reduction effect? With this question, researchers from University College London conducted a clinical study on APOE ε4 and visual working memory, which was published in the journal Nature Aging on October 7 this year [3]
.

The study found that carriers of the AD pathogenic gene APOE ε4 have stronger visual working memory and still have this advantage in the presence of early pathological changes in AD
.

Since previous studies were carried out before significant Aβ deposition in the brains of APOE ε4 gene carriers, in order to explore the impact of APOE ε4 on cognition under pathological conditions, the researchers selected the elderly over 70 years old as The study subjects (at this time the deposition of Aβ has already occurred), a total of 502 people were enrolled.
According to whether they carry APOE ε4 and whether they are positive for Aβ, they were divided into groups of "what is where".
Working memory test
.

The "what is and where" test consists of two parts: identification and positioning.
First, it is necessary to recognize which graphic appears, and then to recall where the graphic appears
.

Finally, a total of 398 subjects completed the Aβ deposition test and the visual working memory test at the same time, and did not have clinical cognitive dysfunction, and 30% (120 people) carried APOE ε4
.

"What is where" test diagram In the results of recognition ability, the recognition error rate of the Aβ positive group was 19% higher than that of the Aβ negative group, and the error probability of APOE ε4 carriers was 14% lower than that of non-carriers
.

Further statistics found that these two results are independent of each other, and carrying APOE ε4 can reduce the error rate even in the presence of Aβ deposition
.

In the result of positioning ability, APOE ε4 carriers have better spatial memory ability and are closer to the original target when recalling the location
.

There was no significant difference in spatial memory ability between the Aβ-positive group and the Aβ-negative group
.

Even in the case of Aβ deposition, APOE ε4 gene can still significantly improve the spatial memory ability, even more significantly than without Aβ deposition
.

Researchers believe that this is caused by the opposite effects of Aβ deposition and APOE ε4 on cognition
.

However, this also shows that APOE ε4 gene has a stronger effect on improving cognition than the neurotoxic effect caused by Aβ deposition
.

Figure a: The error rate of the subjects in the recognition pattern.
The Aβ positive group was significantly higher than the Aβ negative group, and APOE ε4 carriers performed better in both groups
.

Figure b: The error rate of subjects in the localization test.
The error rate of Aβ-positive non-carriers is significantly increased, while the error rate of Aβ-positive carriers is significantly reduced
.

The graph shows the results of linear regression of positioning error rate and Aβ deposition
.

It can be seen that APOE ε4 carries a significant drop in the slope
.

In addition, in the two different working modes of long interval recall and short interval recall, subjects performed worse in long interval recall, but the carrying of APOE ε4 significantly improved both processes
.

Seeing such research results, I was also puzzled
.

The cognitive impairment caused by AD is characterized by a decline in spatial positioning ability, but the disease-causing gene APOE ε4 of AD can enhance the ability of visual working memory, and this effect continues into old age
.

But this result seems to be subversive, detailed analysis, and full of logic
.

When conducting other tests on these subjects, the researchers found that APOE ε4 carriers also have obvious advantages in tests that require attention and working memory, but they have no advantages in tests related to learning ability
.

This may not be related to the visual positioning ability itself, but to the activation of the frontal and parietal lobe during the task execution of APOE ε4
.

The frontal lobe and parietal lobe play a role of arrangement and coordination in the process of our tasks.
With the increase of age and the gradual accumulation of pathological proteins, the compensatory activity of the frontal lobe neurons of APOE ε4 carriers increases, and the localization ability Very sensitive to this
.

This also explains why neuronal degeneration in AD patients usually does not involve the frontal lobe
.

What mechanism does APOE ε4 use to affect cognition? What effect does it have on other pathologies of AD, such as the spread of Tau protein? There are still many questions waiting to be answered
.

In addition, this article also gave us inspiration in research ideas
.

In recent years, more and more researchers have focused their attention on the unknown functions of known proteins, and organically combined the independent physiological processes in our past understanding into a whole, which has further broadened our research horizons
.

The process of life is a process of mutual coordination and balance.
There is no absolute good or absolute bad.
Its complexity far exceeds our current understanding
.

But it is these unknowns that attract us to step by step and continue to explore
.

Today’s research reminds me of watching the movie Still Alice before, thinking about why a professor who is clever and capable and who is engaged in mental work every day will get Alzheimer’s disease early.
Is it related to the disease gene that increases our executive ability when we are young?
.

References: [1] Serrano-Pozo A, Das S, Hyman BT.
APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches [published correction appears in Lancet Neurol.
2021 Feb;20(2):e2].
Lancet Neurol.
2021;20(1):68-80.
doi:10.
1016/S1474-4422(20)30412-9【2】 Mitteldorf J.
What Is Antagonistic Pleiotropy?.
Biochemistry (Mosc).
2019;84(12) :1458-1468.
doi:10.
1134/S0006297919120058【3】 Lu, K.
, Nicholas, JM, Pertzov, Y.
et al.
Dissociable effects of APOE ε4 and β-amyloid pathology on visual working memory.
Nat Aging (2021).
https://doi.
org/10.
1038/s43587-021-00117-4 Responsible Editor | Dai Siyu