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Alzheimer’s disease (AD) has been associated with many infectious agents such as viruses, bacteria, and fungi. However, this area has been excluded from mainstream research. There are many reasons for this.


As early as sixty years ago, Sjogrend et al. speculated that microbes are related to the pathological process of AD. After this, hundreds of studies have found that AD is associated with various bacterial, viral, and fungal infections. As for the relevance of the virus, there are many studies.


In 1997, Itzhaki from the University of Manchester and colleagues found that HSV-1 in the brain is a highly relevant risk factor for AD, and that researchers have also found HSV-1 in amyloid plaques. And in 2014, Lövheim and colleagues found that AD patients had higher levels of anti-HSV-1 antibodies in their brains. Afterwards, researchers found that AD patients had more HHV-6 in their brains.

In addition to these viruses, researchers have also found correlations between Epstein-Barr, cytomegalovirus, and other viruses and AD.


However, there is also a big problem in the research of this field, because the correlation does not mean the causality. That is to say, even if these viruses are found to be associated with AD, it is difficult to explain whether these viruses/bacteria/fungals cause AD or whether AD makes these patients more susceptible to these viruses.


Another problem is that many viral infections are actually very widespread. For example, by the age of 70, about 90% of people will be infected with HSV-1, and by the age of three, almost everyone will be infected with HSV-1. The incidence of AD and the time of onset vary considerably.

In addition, there is also a lack of in-depth research in this area, such as less research on specific mechanisms. Therefore, although there are a lot of researches in this field, the entire AD academic community has paid little attention to this field.


So when I saw someone forwarding the report about this paper that was just published on Neuron the other day, my first reaction was that the domestic and foreign media began to overinterpret the paper again. But in fact this article is more important than I think.

Interpretation of the article

Although this article does not directly prove the direct causal relationship between AD and contagious factors, it is more advanced than previous studies.


What’s special about this article is that the original author did not deliberately search for viruses in the brain (at least from the logical side of the paper, this is the case). The authors analyzed 622 patients with AD who died and the brains of 322 healthy individuals.

They first analyzed the intracerebral gene activities of healthy individuals and preclinical AD patients who did not develop cognitive dysfunction before their death. They analyzed gene expression differences in areas that are vulnerable to neuronal damage, such as the entorhinal cortex and the hippocampus. It is hoped that the comparison of these two groups of samples will search for genes that may be involved in the disease process.

They then identified the key drivers of these genes, which are genes that are highly related to AD, such as APP, PICALM, and ABCA1. But more importantly, they found that there are a series of common promoters for these key genes. These promoters all have binding sequences for the C2H2 zinc finger protein transcription factor.

These C2H2-TFs are highly correlated with viral biology. For example, C2H2-TF SP1 can bind Epstein-Barr virus proteins, regulate the transcription of HIV genes, and promote the replication of human cytomegalovirus.

But the next question is whether the virus can drive AD-related regulatory networks? And is it a specific virus, several viruses, or all viruses that can cause this effect? In other words, is it as long as a virus infection can trigger this reaction?

In order to clarify this issue, researchers began to look for the relevance of AD with viral RNA and DNA. They found that HHV-6A and HHV-7 are more prone to appear in the prefrontal cortex and superior temporal gyrus. However, it should be noted that this correlation does not exist in all sample analyses. For example, there was no difference in viral load between AD samples from the Memory and Aging Project at Rush and controls.

But what can these viruses do in the brain? Next, the researchers used the virus quantitative trait locus analysis to study the correlation between host genes and virus abundance. They discovered the association of HHV-6A with a variety of genes, many of which are related to immune system function. Next they compared the virus abundance of the prefrontal cortex, supraorbital gyrus, parahippocampal gyrus, and the inferior frontal gyrus to the host genes. They found HSV-1, HSV-2, and HHV-6A. All three viruses can regulate the host genes in these regions.

Among these regulated genes, the most common genes include the genes encoding BACE1, Fyn kinase and PPAR-γ, which have been found to be highly correlated with the pathological processes of AD. For HHV-6A, its regulatory genes include other genes associated with amyloid proteins, such as presenilin 1, clusterin, Bin1, and PICALM.

HHV-6A regulates AD-related genes

In the end, the researchers found that the virus was associated with neuronal loss through transcriptome sequencing, and that this correlation was associated with the gene repression of miR-155, which encodes a neuroprotective effect. Furthermore, APP/PS1 mice knocked out of the miR-155 gene had larger patches of amyloid, suggesting that the virus may directly affect the formation of amyloid plaques.


In fact, it can be clearly seen that this study still does not answer whether the virus is the culprit leading to AD, so some media reports on the study found that the culprit of AD is not accurate.

However, regardless of whether the virus/bacteria/fungus is the culprit leading to AD, it is clear from this study that infectious factors are highly correlated with the pathological process of AD. Whether these factors directly lead to AD or whether it is a factor in accelerating the pathological process of AD still needs to wait for follow-up studies.

And it is clear that these infectious factors will not participate in the pathological process of all AD patients. I can take the cancer I am more familiar with as an example. There are many risk factors for cancer. For example, smoking, drinking, viral infections such as HPV, radiation, exposure to certain chemical substances, and carrying genetic mutations such as BRAC may increase the risk of normal cell cancer and lead to the formation of tumors.

However, AD may also have multiple risk factors. For example, familial inheritance (FAD), such as infectious factors in the above studies, may affect the pathological process of AD and even directly lead to the formation of AD.

And I do not think that this study can negate the amyloid protein hypothesis. It can even be said that the research on miR-155 in this study also affirmed the amyloid protein hypothesis to some extent. In fact, researchers have long suspected that beta amyloid has anti-microbial effects. Whether this series of regulatory processes is to increase the level of amyloid protein to fight viral infections is not yet clear.

But there is no doubt that after numerous failures in clinical trials of AD drugs, this study can indeed provide new ideas for early intervention in AD.

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