The Tangled Neuron

Chlamydia Pneumoniae and Alzheimer's

Summary: Infection with a common bacterium called Chlamydia pneumoniae may increase the risk of developing Alzheimer’s. The bacterium has already been linked to heart disease and hardening of the arteries. Work to investigate the role of viruses and bacteria such as Chlamydia pneumoniae in chronic diseases is in the early stages, but researchers hope it will help identify and treat the underlying causes of Alzheimer’s.

More study is needed to confirm the bacterium’s relationship with dementia, and rigorous clinical trials would be necessary before any treatments based on this research could be recommended.

I’ve written before about how viruses and bacteria can contribute to chronic diseases not previously linked to infections. It is now accepted that a type of bacteria contributes to ulcers, and that human papillomaviruses are the major cause of cervical cancer. A common bacterium called Chlamydia pneumoniae (also called Chlamydophila pneumoniae and C. pneumoniae) has been linked to atherosclerosis (hardening of the arteries) and other chronic diseases.

Dr. Brian Balin, a professor at the Philadelphia College of Osteopathic Medicine and Basic Science Director of the school’s Center for Chronic Disorders of Aging thinks that same bacterium may also contribute to many cases of Alzheimer’s. As the name indicates, the bacterium causes a type of pneumonia - it’s not the same as the sexually transmitted type of Chlamydia.

Although the link between C. pneumoniae and Alzheimer’s is not well-accepted, Dr. Balin has been researching the relationship for years. At a 1995 meeting he attended, talk turned to the possible link between the bacterium, hardening of the arteries and heart disease.

“I asked whether anyone had ever looked for the organism in brain tissue,” he remembers. “My background in neuropathology dealt with the blood brain barrier, and I had for some time believed that damage to the blood vessels in the brain could be involved in Alzheimer’s disease. My beliefs were not widely held….”

“Anyway, after asking the question, I performed a search of the literature and found that no one had ever looked in brain tissues for the presence of this infection.... So, I went to our -80 C freezers and pulled out frozen brain tissues from both AD [Alzheimer’s disease] and non-AD brains. I sent these samples in a coded or blinded fashion to Dr. Alan Hudson for analysis by polymerase chain reaction (PCR), which is a way of testing whether the DNA of the organism was in the tissue samples.” [Dr. Hudson is a Wayne State University School of Medicine professor whose lab focuses on Chlamydia research.]

It turned out that the AD tissue samples contained the DNA from the bacterium, while the non-AD tissues did not. The two researchers repeated the experiment with different samples, and got the same results.

“This then led to our expanded experiments to determine whether C. pneumoniae could be detected using a variety of methods,” says Dr. Balin. “All in all, we used six different techniques which gave consistent results. The first publication of our work was in 1998 in Medical Microbiology and Immunology.”

Chlamydia Pneumoniae - An Elusive Bacterium

All these different testing methods were necessary because Chlamydia pneumoniae is the Loch Ness Monster of the bacteria world – hard to categorize, and even harder to find.

“Because of the nature of this organism, one cannot take a ‘quick and dirty’ approach to this problem,” says Dr. Balin. The bacterium is hard to categorize because it acts more like a virus than a bacterium, growing inside cells and using the resources of the cell to reproduce. Even worse, he says, it keeps changing form. “C. pneumoniae has multiple developmental phases in its life cycle and expresses genes and proteins variably depending on things such as life cycle, environment, and tissue in which it is located.”

This may be why some labs report they have not found C pneumoniae in Alzheimer’s brains. But Dr. Balin thinks the extensive testing he and his colleagues have done is accurate. “There are a number of techniques used to detect C. pneumoniae in clinical samples… What we do, and which is not consistently done in other labs, is use multiple techniques with many different types of probes to detect the presence or not of C. pneumoniae in a clinical sample. We have used at least 15 different antibodies specific either to Chlamydia genus or Chlamydophila pneumoniae on our brain samples to determine if antigens from the bacterium can be detected in the tissues. In addition, multiple PCR primer sets have been used to detect different genetic sequences of C. pneumoniae. We also have used biochemical techniques, electron microscopy, and tissue culturing to demonstrate C. pneumoniae in brain samples. We believe the most thorough sampling is required to truly rule in or rule out presence of the organism in brain tissues.”

He received some confirmation of his findings this year, when scientists at the Wroclaw Medical University in Poland reported finding Chlamydia pneumoniae in the spinal fluid of 44 percent of the Alzheimer’s patients they tested, but only 11 percent of a control group. The Polish researchers suggested that testing for the bacterium in spinal fluid could be useful in the diagnosis of Alzheimer’s.

How Chlamydia Pneumoniae May Trigger Alzheimer’s

How could a type of pneumonia affect the brain? “My group has found that C. pneumoniae, once inhaled, infects white blood cells, in particular the monocytes that circulate throughout the blood stream,” Dr. Balin explains. “These cells can enter through the walls of the blood vessels and can carry the organism into different tissues, including the brain.”

“We also have evidence that the cells in our upper noses known as the olfactory neuroepithelial cells (those cells controlling our sense of smell) are infected by C. pneumoniae.” The olfactory neuroepithelial cells are close to the olfactory bulb region of the brain and to the hippocampus, where short term memory is formed. These areas of the brain are among the first to be affected by Alzheimer’s. This suggests there may be a link between infection with C. pneumoniae and the reported association between the loss of sense of smell and the onset of Alzheimer’s.

Finally, there is some tantalizing evidence that the bacterium may actually trigger the formation of the amyloid plaques characteristic of Alzheimer’s brains. When mice in Dr. Balin’s lab were infected with C. pneumoniae, they developed amyloid plaques in their brains. Adding to the evidence of the link between the bacterium and Alzheimer’s pathology, the bacterium was found near plaques and tangles in human Alzheimer’s brains studied in his lab.

C. Pneumoniae – Another Piece of the Dementia Puzzle?

Dr. Balin points out that the connection between C. pneumoniae and Alzheimer’s is consistent with other research on the disease. Some scientists think inflammation causes the brain damage seen in Alzheimer’s. “Quite possibly the inflammatory response due to a chronic persistent infection with C. pneumoniae and/or other infectants causes much of the cellular damage in the brain,” he says. “Also, genetic risk factors such as having the ApoE 4 variant which has been correlated with Alzheimer’s disease may actually increase one’s risk for being infected with C. pneumoniae and other infectants such as Herpes Simplex Virus 1. The interrelationship of ApoE with infectants may be how this variation confers greater risk for getting both infections and Alzheimer’s disease. Our data have shown that Alzheimer’s brains that express the ApoE4 variation actually have greater concentrations of C. pneumoniae than Alzheimer’s brains not expressing the variant.”

He thinks the connection between C. pneumoniae and hardening of the arteries may also be relevant to dementia. Of course, arteries are a type of blood vessel. Once white blood cells infected with C. pneumoniae reach the brain, Dr. Balin theorizes, they may damage the blood vessel walls there. This would contribute to vascular dementia and brain tissue damage.

But if exposure to Chlamydia pneumoniae is common, as indicated by the antibodies in many people’s blood, why don’t we all develop Alzheimer’s? “Exposure to an infectious agent does not necessarily translate into a specific disease,” says Dr. Balin. “There are many other factors, both genetic and environmental, that would dictate why some get a disease and others do not, even when you have a large percentage of the population exposed to the infectious agent. One example is exposure to the common cold viruses, which are very ubiquitous. Not everyone exposed gets a cold. …so, not everyone exposed to C. pneumoniae would develop Alzheimer’s, but the potential for the disease would be ever-present.”

Potential Treatments for Alzheimer’s and Dementia

Dr. Balin cautions against rushing to treat Alzheimer’s based on the possibility that C. pneumoniae could trigger the disease. “The dilemma that we face is that without current long-term effective treatments for AD, many people may want to try, even experimentally, other types of drug regimens based on the work that we and others are doing with infection,” he says. “Obviously, without clinical trials first, we cannot know for sure who would be most likely to benefit. We have to determine who is infected with which organism(s) and try to treat appropriately. This is why we really need a concerted effort to develop controlled clinical trials.”

He’s done some thinking about what types of therapies a clinical trial could test. “We know that Herpes Simplex Virus 1 may be involved in a significant number of AD cases and this may also have to be considered in a therapeutic regimen. All in all, I think that infection data (even at this point in time), suggests that using combination therapy of an anti-inflammatory, anti-chlamydial and an anti-viral for Herpes could be beneficial."

The “cocktail” he is proposing for trials includes anti-inflammatory medicines or NSAIDs (non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen). Although some population studies have shown a link between NSAID use and decreased risk of Alzheimer’s, evidence from clinical trials using NSAIDs to slow progression of the disease is not very encouraging. If inflammation is caused by infection with C. pneumoniae, Dr. Balin says, it’s unlikely that it could be controlled in the long run by NSAIDs alone.

Antibiotics targeted to Chlamydia bacteria are also part of the proposed cocktail. At least one study has shown antibiotics may slow progression of mild to moderate Alzheimer’s, but more research is needed. “Our research suggests that treating individuals who have Mild Cognitive Impairment, and those who have newly diagnosed and/or existing Mild AD, with anti-chlamydial antibiotics may have a positive effect by either stopping a trigger for the disease or preventing disease onset in the case of MCI,” Dr. Balin says.

But antibiotics don’t always wipe out C. pneumoniae, and as with other infectious disease, there are worries that the bacterium will become resistant to treatment. These worries have scientists searching for alternative therapies, Dr. Balin says. “The use of more novel anti-infection compounds, and potentially the development of a vaccine for these infectants could result in combating dementia-causing organisms.”

Hopes For Finding And Treating The Causes Of Alzheimer’s

“I believe that we have uncovered a non-conventional infectious agent that likely is
increasing the risk for the development of Alzheimer’s,” Dr. Balin says. “We don’t yet have all the answers. However, there is hope because we are still discovering and studying how this actually works. Similar to how the discovery of a bacterium is the cause of gastric ulcers and some types of gastric cancers, we are hopeful that our findings result in expanded efforts by others to consider how infection may be causing many diseases in the nervous system not currently considered to be infectious. This understanding is vital to proceeding in a rational fashion to treat the problem based on the evidence. This will take us from simply trying to treat the symptoms of disease to actually treating the causes. This is why I have great hope that we will defeat this and other neurodegenerative diseases in our lifetimes.”

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.