Could Alzheimer’s Disease Be Caused by Viruses?

Română

As you probably know, Alzheimer’s disease is a debilitating neurological disorder affecting primarily older adults. Its most prominent symptom is progressive and irreversible memory loss. Furthermore, despite major concerted efforts of the world’s best scientists, to this day, this disorder remains shrouded in mystery, both in terms of causes, as well as potential treatments.

Genetic Alzheimer’s

There are two forms of Alzheimer’s disease (AD): genetic (familial) and common Alzheimer’s. The first one refers to a rare form of early-onset Alzheimer’s which appears to be more common in some parts of Colombia. In order to understand how a bad gene can cause AD, let’s use a simple analogy. Imagine that at his factory Willy Wonka is making cookies. He has two magical machines which produce dough and cookie cutters according to some blueprints. The cookie cutters cut the dough into many cookies, which are then baked, packed, and shipped out. Now imagine that one day the cookie cutter blueprint is accidentally swapped with a cheese grater blueprint. To make everything worse, none of the machines can be switched off. So the dough machine continues to spit out dough and because instead of cookie cutters we have a bunch of useless cheese graters, the dough starts to accumulate and clump together, until the whole factory is filled with dough and everything inside crumbles down under its weight.

Now that we have a clear picture of what happens in the cookie factory, let’s translate this in scientific terms. We can use the images below to guide us. The blueprint for the cookie cutters is a gene called PSEN1. This is an autosomal (it means that it’s not found on the sex chromosomes) dominant (if you have the gene, you will have the disease) gene. Each cookie cutter is a protein called presenilin. The dough is another protein called amyloid precursor protein and the cookies are a protein named amyloid beta. In scientific terms, we say that presenilin cleaves (i.e., cuts) amyloid precursor protein into amyloid beta.

The cheese grater blueprint is called a defective or mutated PSEN1 gene and the cheese grater itself is a defective presenilin protein. The clumps of dough also have a name: amyloid plaques (you should try to remember this name, as it’s important for AD in general). In a similar way to the dough accumulating in the factory and destroying it, these amyloid plaques accumulate in neurons and kill them.

 

Common Alzheimer’s

The second form of Alzheimer’s, which is the most common one, has significantly less understood causes. Currently, scientists believe it is caused by a complex interaction between genetic, environmental, and lifestyle factors, which affect the brain over time. At the cellular level, however, there are two hypotheses which have dominated the field for decades: the amyloid plaques hypothesis and the neurofibrillary tangles hypothesis. The amyloid plaques hypothesis is the one we have described above, i.e. an excess of amyloid beta accumulates over time and forms amyloid plaques, which kill neurons. The difference is that in the case of common AD it is not known what makes things go haywire and jumpstarts the excess production of amyloid beta. The neurofibrillary tangles hypothesis is related to another protein called tau. Tau is a protein which plays an important role in providing scaffolding and maintaining the structural integrity of axons (think of the axons as very long tunnels and tau as the scaffold which prevents the tunnel from collapsing on the train tracks and cutting all transport in and out of the mine). In Alzheimer’s disease, malfunctioning of this tau protein causes it to form aggregates called neurofibrillary tangles, which over time cause neuronal death.

Viral causes

While these two hypotheses have been intensely studied over the years, there is still a large debate about whether amyloid plaques and neurofibrillary tangles are the cause of Alzheimer’s or just a symptom produced by a completely different, but yet unknown cause. Among these other potential causes, one has started gaining more traction recently, and that is the idea that Alzheimer’s disease could be linked to repeated infection with the Herpes simplex virus, the one which produces cold sores and that the “bad” amyloid plaques are an infection defense of the brain gone wrong. (I know, it sounds weird, doesn’t it? But let’s have a look at the hypothesis and what evidence supports it.)

First of all, why would researchers think to investigate the connection between herpes and Alzheimer’s in the first place? It turns out that the idea of microorganisms as potential causes of Alzheimer’s disease is not new at all, but it actually dates back to the initial discovery of the disease. In the early 1900s, two scientists, Alois Alzheimer (a German scientist based in Munich) and Oskar Fischer (a Jewish Czech scientist based in Prague), independently described a new type of senile dementia. Since it was obviously a disease of the brain, both of them performed autopsies on the brains of deceased patients. Both also used staining techniques (think of them as methods to enhance the contrast) to look at the brain microstructure. But while Oskar had observed changes in the brain consistent with pathogen infections and thus hypothesized these were the cause of the disease, Alois was more interested in cellular changes induced by the disease. Unfortunately, even though both of them made important contributions to the understanding of the disease at the time, given the historical context at the time (the rise of Nazi Germany and anti-semitism), Oskar’s findings were soon forgotten and were not rediscovered until 2008.

Ok, so this is a good starting point: some evidence linked Alzheimer’s disease to microorganisms (in particular, a germ called Streptothrix), but where do the cold sores come in? It turns out that more research into Fischer’s findings revealed that, while indeed present in the brain of some AD patients, this pathogen was not found in all patient brains. That means Streptothrix could not be the direct cause of AD. Think about it like that: we know that HIV causes AIDS, but if we were to find people who had AIDS, but no HIV infection (and we were sure of the diagnosis), we would have to re-evaluate our assumption that HIV is the cause for AIDS. So researchers started to check whether other pathogens might be the cause for Alzheimer’s. Many studies have actually found a bunch of pathogens present in the brains of deceased patients, from spirochetes to chlamydia to herpes. However, herpes has come into the spotlight for a couple of simple reasons:

  • it is very widespread (it is believed that up to 90% of the population has had at least one asymptomatic herpes infection)
  • it has been shown to be more prevalent in the brains of AD patients compared to non-AD patients
  • it has been found in the same areas of the brain as the amyloid plaques are.

To recap, now we know why researchers wanted to investigate the link between herpes and Alzheimer’s disease in the first place. Let’s move on: have they shown that herpes causes Alzheimer’s? The answer is a bit more complicated than a simple yes or no. On the one hand, we have the evidence mentioned before, that herpes is found more often in the brains of Alzheimer’s patients and particularly in the same spots as the amyloid plaques. This is correlational evidence: it means that there could be a link, but we don’t know if one variable causes changes in the other or vice-versa or if both of them are caused by an unobserved, underlying variable. On the other hand, in order to say “herpes causes Alzheimer’s”, one needs to prove a direct causal link between the two. That means that researchers have to manipulate a variable (in this case, they would have to cause herpes infections in neurons) while keeping the others constant and then measure the results. Fortunately, that’s exactly what scientists are working on now.

Recent studies in which researchers injected the herpes virus either in neuronal cell cultures or in mice brains have shown that after infection, both the cell cultures and the mice brains started forming amyloid plaques. The plaques, in turn, were quite effective at trapping the viruses. However, while it might be tempting to say “yes, we’ve found the one true cause for Alzheimer’s”, that would not be correct. The conclusion of the experiment is more nuanced: we found that, when injecting cell cultures and mice brains with herpes, the amyloid protein is capable of protecting against the virus. And since there is an excess of amyloid proteins in the brains of AD patients, as well as higher herpes concentrations due to repeated infections, a logical conclusion is that the two are linked. However, more than providing an answer, this conclusion opens exciting and crucial research avenues. Does the repeated infection actually cause overproduction of amyloid proteins? Or does it break something else (for example, the clean-up of the amyloid)? How does the virus reach the brain? The brain has a strong barrier, the blood-brain barrier, which protects it against pathogens, so if herpes does reach the brain, one needs to prove that this virus can indeed cross the blood-brain barrier and explain how that happens. How many times does the infection need to reach the brain in order to trigger Alzheimer’s? Can other viruses do the same? And many, many others.

Although this doesn’t sound like a flashy, attention-grabbing conclusion, it is still a huge step forward. Sure, it would be amazing to hear that AD has been cured once and for all. But we should consider that for decades, Alzheimer’s disease researchers had been focused on two causes, amyloid plaques and neurofibrillary tangles, and all therapies targeting these two had shown only limited effects. Now we have a new and more promising path to follow, which will hopefully bring us closer to the truth.

What did you think about this article? Do you have any questions about this promising link between Alzheimer’s disease and pathogens? Let us know in the comments.

Don’t forget to follow us on Instagram @neuro.frontiers to see more cool facts about the brain.

References*:

1. Bourgade, K., Garneau, H., Giroux, G., Le Page, A. Y., Bocti, C., Dupuis, G., … & Fülöp, T. (2015). β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology, 16(1), 85-98.

2. Miklossy, J. (2011). Emerging roles of pathogens in Alzheimer disease. Expert reviews in molecular medicine, 13.

3. Broxmeyer, L. (2017). Are the Infectious Roots of Alzheimer’s Buried Deep in the Past. J Mol Path Epidemol, 3, 2.

* In order to keep the list short, I’m only citing a couple of studies here, but please don’t forget that reliable scientific results are always replicated across multiple studies before they gain the trust of the scientific community.

Oh hi there 👋
It’s nice to meet you.

Sign up to receive awesome content in your inbox.

Read our privacy policy for more info.

2 thoughts on “Could Alzheimer’s Disease Be Caused by Viruses?

Leave a Reply