Herpes Simplex Virus Type 1 and Alzheimer's

Summary: A British scientist, Dr. Ruth Itzhaki, has shown that the combination of latent Herpes Simplex Virus Type 1 (HSV1) in the brain and the type 4 form of the APOE gene could account for 60 percent of all cases of late onset Alzheimer’s disease. Almost all elderly brains are infected with HSV1, which often causes no symptoms. Dr. Itzhaki’s lab found the virus in areas of the brain most damaged by Alzheimer’s, and has data relating HSV1 to plaques and tangles.

The idea that a viral infection could underlie Alzheimer’s is part of an emerging understanding of the role of bacteria and viruses in chronic diseases. This kind of research is neither well-accepted nor well-funded, so don’t expect any Alzheimer’s treatments targeting HSV1 to be on the market anytime soon.

I have only a vague understanding of viruses and bacteria. Most of what I know is based on personal experience and on what little I remember from high school biology class. I know that viruses and bacteria are infectious, and that illnesses caused by them are often short-lived. Until recently, I thought scientists understood and could control most harmful viruses and bacteria.

The leading causes of death in the U.S. seem to be in a different category: the top ten list is dominated by chronic diseases like heart disease and stroke, cancer, and diabetes. Alzheimer’s has moved up to number seven on the list. These illnesses are not infectious, not short-lived, not well-understood and not well-controlled.

But it looks like the two categories might overlap more than I knew - the idea that viral or bacterial infections might contribute to chronic diseases not previously linked to infections is gaining ground. One bacterium called helicobacter pylori has been found to cause ulcers, and another called Chlamydophila pneumoniae (Cp), is linked to coronary artery disease. Human papillomaviruses are now recognized as the major cause of cervical cancer.

These discoveries hint at the possibility of a fundamental shift in the way we view diseases, including Alzheimer’s. In his book Plague Time: The New Germ Theory of Disease, Dr. Paul Ewald, Professor of Biology at University of Louisville in Kentucky, argues that bacteria and viruses are behind many chronic diseases, including Alzheimer’s, cancer and some forms of mental illness.

Herpes Simplex Virus Type 1 Linked to Alzheimer’s

For almost twenty years, Dr. Ruth Itzhaki, Professor of Molecular Neurobiology at the University of Manchester in England, has been exploring possible links between viruses and Alzheimer’s. Viruses are tiny infectious particles that attach themselves to and penetrate cells, then use the capabilities of those cells to reproduce. They can cause diseases like colds, flu and AIDS, or they can just sit there, remaining dormant or latent for long periods of time. A latent virus can become active when triggered by stress, other infections or environmental factors.

Ruth Itzhaki, Ph.D.

For a virus to contribute to the development of Alzheimer’s, Dr. Itzhaki reasoned, it would have to be very common in humans. And because Alzheimer’s appears to develop over a long period of time, it would make sense to look for a virus that has long periods of latency, but could periodically be reactivated and cause damage.

One family of viruses fits her criteria: herpes. There are over 100 types of herpes, of which eight infect humans, causing diseases ranging from chickenpox and shingles to cold sores and mononucleosis. Most people have some type of herpes, even though they may have no symptoms.

When Dr. Itzhaki and her colleagues examined the brains of older people, they found signs of latent Herpes Simplex Virus Type 1 (HSV1) in the areas most affected by Alzheimer’s. Traces of the virus were present in both Alzheimer’s and non-Alzheimer’s brains. Because HSV1 is not prevalent in the brains of younger people, the researchers hypothesize that the virus infects the brain in older age, as the immune system declines.

HSV1 is especially common in humans. The virus, which can be transmitted via skin contact and saliva, infects approximately 58% of people between the ages of 14 to 49, and in older people, almost everyone. Often, there are no symptoms.

Even though the presence of the virus in areas of the brain damaged by Alzheimer’s was intriguing, it was clear that not everyone with HSV1 develops Alzheimer’s. “‘Infect’ doesn’t always mean ‘affect,’ Dr. Itzhaki notes. “With many sorts of infection, some people show no symptoms.” As with other viruses, perhaps an unrelated illness or stress could activate latent HSV1. But Dr. Itzhaki wondered if a combination of HSV1 and some other factor could be involved.

The APOE Connection

The APOE4 genetic variant has already been identified as a risk for developing Alzheimer’s, but is “neither necessary nor sufficient to cause Alzheimer’s,” Dr. Itzhaki points out. She wondered if HSV1 and APOE4 could together trigger a series of events leading to brain damage and degeneration. The idea that APOE status could determine the effect of a virus not new. For example, studies in her own lab had determined the risk for cold sores from HSV1 is higher in people with the APOE4 mutation. Also, her lab found that APOE status determines susceptibility to, or severity of, infections in various other diseases.

When Dr. Itzhaki and her colleagues tested for both HSV1 in brain tissue and APOE4, their data indicated that the combination of these two factors could account for 60 percent of all sporadic Alzheimer’s cases (late onset Alzheimer’s that does not run in families).

It’s interesting that a small study of the brains of three people with familial Alzheimer’s disease by scientists at Aichi Medical University School of Medicine, Aichi, Japan showed signs of active HSV1 in areas with beta amyloid deposits. This would suggest that HSV1 is involved with the type of Alzheimer’s that runs in families, not just the sporadic Alzheimer’s Dr. Itzhaki studied.

How Does HSV1 Damage the Brain?

Just how HSV1 might damage the brain is not known. It could be via inflammation and oxidation. Oxidation is when unstable molecules called oxygen free-radicals combine with other molecules. In the same way that rusting damages metal, oxidation can damage brain cells. Dr. Itzhaki says that oxidation has been found in HSV1 infected cells in the lab and in brain cells harboring latent HSV1.

“We think inflammation must be a major factor,” she says. She lays out the hypothesized chain of events: “When HSV1 is latent (i.e. in a dormant state) in the brain, it can be activated by inflammation of the brain. The latter can occur when somebody has an infection, or is stressed, or immunosuppressed. The virus then augments the inflammation there. So other viral or bacterial infections (not necessary in the brain) can cause indirect trouble.”

What About Other Herpes Viruses?

Dr. Itzhaki and her team have investigated whether other types of herpes might be linked to Alzheimer’s. Their research shows HSV2 (genital herpes) and a type of herpes called cytomegalovirus are not as prevalent as HSV1, and not associated with Alzheimer’s disease. However, cytomegalovirus was found to be present in a high percentage of brains of people who had had vascular dementia. More research is needed to understand this connection.

HSV6 (a virus that is common in infants, but often causes little or no illness), was prevalent in the brains the researchers tested, and was associated with Alzheimer’s. Because it overlapped with the presence of HSV1, it’s not clear whether HSV6 could be a cause or a consequence of Alzheimer’s.

A Unifying Theory?

Dr. Itzhaki’s theory that a combination of HSV1 and the APOE4 genetic variant underlies many cases of Alzheimer’s is appealing because it could explain several factors already linked to an increased risk of the disease:

*Age (the older you are, the more chance you have of having HSV1 in your brain)
*APOE4 (see above)
*Cholesterol (HSV1 is associated with increased cholesterol levels)
*Beta amyloid (Dr. Itzhaki has data [not yet published] linking HSV1 to increased levels of beta amyloid. In addition, increased cholesterol levels seem to increase formation of beta amyloid plaques.)
*Tau (Dr. Itzhaki also has unpublished data linking HSV1 with abnormal tau, the protein in Alzheimer’s tangles).

The hypothesis is also appealing to me because it addresses possible underlying causes of the plaques and tangles that have been the focus of Alzheimer’s research for more than 100 years.

Before this theory is widely accepted, more research in Dr. Itzhaki’s lab and in other labs is needed. Money is tight for any Alzheimer’s research now, with only a small percentage of proposed studies funded. For a theory that’s not “mainstream,” funding is even more difficult.

Future Treatment

What if Dr. Itzhaki’s hypothesis about HSV1’s role in Alzheimer’s proves to be true?

“It would have enormous consequences,” she says, “as antiviral agents, which are currently available and which have relatively small side effects and are cheap, could be used to treat patients and should stop further deterioration.”

A good way to test of the role of HSV1 in Alzheimer’s “would probably be to use antiviral treatment for a year,” Dr. Itzhaki says, “and measure cognitive decline during that year and compare the rate with the patient’s rate a year before and a year after treatment. This would take into account the different rates of decline in different people. Scanning too would be very useful in indicating the course of brain damage during each of the three years.”

This type of clinical trial of antiviral drugs sounds good, but “as antiviral agents are off-patent, pharmaceutical companies have little profit motive in using them thus, especially as trials are hugely costly,” she points out.

In addition to antiviral drugs to stop progression of Alzheimer’s, vaccination against HSV1 could potentially prevent the disease. Dr. Itzhaki and colleagues have shown that vaccination of mice can protect against latent HSV1 infections of their brains.

But right now, she says, there’s no interest in developing Alzheimer’s therapies targeting HSV1. It’s a kind of “Catch-22” – more research is needed to confirm HSV1’s role in dementia, but there’s no funding for that research without confirmation of that role. “The trouble again is not just cost, but also the hostility of many people in the field…as a result, neither we nor others who want to repeat our research can get adequate or even any funding. It’s incredibly frustrating and disheartening. But until funds are available to extend the work, resistance to it will continue,” Dr. Itzhaki says.

Comments

[Gail Rae Hudson]

I wonder if part of the "hostility...in the field" is because this link is simple as well as elegant. I've noticed that Medicine has a tendency to resist simplicity, especially when highly devastating diseases are involved. There's something about mucking around in mud and playing with question marks as though they are Legos that seems to appeal to a lot of researchers. Actually, I guess, a lot of sciences are plagued with this problem.
Thoroughtly enjoyable, provocative post. Thanks, again, Mona.

[Gail Rae Hudson]

Just want to mention, in case anyone reading this is as ill-informed as me regarding antivirals, here's a fairly decent review of basic antiviral information at Wikipedia (take note, it's been tagged as needing clean-up):

http://en.wikipedia.org/wiki/Antiviral_drug

[Patty McNally Doherty]

Mona,

I remember Malcolm mentioning something about Alzheimer's and chicken pox. I can't remember what it was. I'll ask him to comment on this as well.

Thanks for the info,
Patty

[Dennis Levy]

Could the link be via the microglia immune response? Microglia can release chemicals intended to kill the virus, but which can cause brain damage. (If so, a vaccination could be as much of a problem as a solution).

[Captain David Hare]

Outstandingly well thought out.