March 7, 2019 -- Close to 6 million Americans now have Alzheimer’s disease. By 2050, that number likely will more than double. The fatal brain disease can’t yet be effectively treated or cured. But recent studies suggest that a theory long on the fringes of Alzheimer’s research may provide new approaches to the disease. Could common infections contribute to its development?
“Scientists are really trying to pin that question down,” says Rebecca Edelmayer, PhD, director of scientific engagement at the Alzheimer's Association.
The latest study appeared in January. Researchers published evidence that may connect Alzheimer’s and a germ that causes gum disease. It’s not the first study to report such a link. In 2017, for example, scientists in Taiwan tracked more than 9,000 people with chronic periodontitis, a common type of gum disease. They found that people who had had gum disease for 10 years were 70% more likely to develop Alzheimers. However, the study did not say that gum disease caused Alzheimer’s.
The authors of the new study, published in Science Advances, pursued the link in the lab, where they examined tissue samples from the autopsied brains of people with and without Alzheimer’s. They found higher levels of the gum disease germ p. gingivalis in the diseased brains. They also discovered its presence in the spinal fluid of living patients diagnosed with Alzheimer’s.
Next, they infected mice with an enzyme produced by the same gum disease germ. Weeks later, the mice’s brains had deteriorated. Also present: Increased amounts of a protein called amyloid beta, accumulates in the brain and forms plaques one of the hallmarks of Alzheimer’s, as well as other signs of the disease.
In the final part of the study, the scientists successfully stopped further brain damage in the mice by blocking the germ thought to be causing it.
A good start, but long way to go
It sounds exciting, but keep in mind that these were mice who responded to treatment, not people. And it’s far from certain that preventing gum disease could impact Alzheimer’s.
“Oral hygiene is a part of healthy living as well as healthy aging,” says Edelmayer, “but we can’t say whether it would be a way to cure or prevent Alzheimer’s disease.”
Harvard neurobiologist Robert Moir, PhD, does not believe that a single germ causes Alzheimer’s. Instead, he says it’s more likely that an infection in the brain could trigger a process that, in some people, results in the disease.
The idea that infection could be connected to Alzheimer’s has been around for more than 100 years, says Moir, an assistant professor of neurology at both Harvard Medical School and Massachusetts General Hospital. However, the idea fell by the wayside in the 1980s when most researchers turned their attention to a protein found in the brains of people with the disease. Called beta-amyloid, it has since been considered a prime suspect in the development of Alzheimer’s.
As Alzheimer’ progresses, amyloid beta proteins build up in parts of the brain. They clump together to form hardened plaques that disrupt the way the brain functions. This leads to memory loss and other devastating Alzheimer’s symptoms. What’s unclear is why this buildup occurs.
Amyloid beta has been seen as “evil, bad, and an accident of metabolism” that serves no purpose, says Moir. He thinks that’s wrong.
Consider evolution, he says. Scientists have traced the same amyloid beta that’s found in human brains back about 450 million years. It’s also present in most other vertebrates, including reptiles, birds, and fish. For something so ancient to remain unchanged for so long, says Moir, it must have a function.
“What we did was look at what that function may be,” he says.
Your body goes on the attack
Here’s what he and his fellow researchers discovered: When a microbe, or infection, enters the brain, amyloid beta goes on the attack. These tiny fibers wrap around the infection, forming into a ball of plaque that neutralizes the intruding germ.
“The microbe is forever trapped,” says Moir. “Amyloid beta is not junk or functionless.”
Instead, it appears to be a key player in the brain’s own immune system, says Moir: “Our research shows it will do the same thing no matter what you throw at it. You can throw fungal infections, bacteria, and viruses at it, and they all get trapped by amyloid.”
The overproduction of plaques that occurs in Alzheimer’s may be caused by a chronic infection, such as gum disease or other germs that have been investigated in recent years. Or, says Moir, it could be a sign that the brain’s immune system has gone off the rails.
“That’s what might be happening in the Alzheimer’s brain,” Moir says.
Plaque buildup, Moir continues, is fine at low levels, but if it continues to increase, it will eventually lead to inflammation in the brain.
“That will cause all sorts of chaos and trouble,” Moir says.
He and his colleagues observed this protective action in response to two common forms of the herpes virus for a study they published in the journal Neuron last summer. They found that they could trigger the development of amyloid plaques by injecting mice with the herpes virus. The same thing occurred in human brain cells in the lab.
Is there a herpes-Alzheimer’s connection?
For another study published in the same issue, a different team of researchers also investigated the link between herpes and Alzheimer’s. They found several types of the herpes virus in brain regions affected by Alzheimer’s. The viruses also appeared to influence the behavior of genes linked to amyloid beta.
The World Health Organization estimates that two-thirds of the world’s population has a type of herpes studied by Moir and his team, known as HSV1. The other herpes virus they looked at is even more widespread. And once infected with herpes, you have it for life. The question then becomes, if herpes is so common, why don’t more people develop Alzheimer’s?
In most people, herpes causes no symptoms, because the virus remains inactive. Moir speculates that a combination of factors like age and genetics could activate the virus and trigger an inflammatory immune response in the brain that potentially leads to Alzheimer’s.
“Perhaps there’s a mutation that prevents a gene from switching off that inflammation,” says Moir.
And there’s some research to suggest that treating herpes could reduce the risk of dementia. Taiwanese researchers found that, over 10 years, HSV1 more than doubled the risk of dementia. However, people with the herpes virus who had been treated with an antiviral medication had the same risk as people who had never been infected. Could treating herpes truly lower the chances of developing Alzheimer’s? The authors of the study say it’s too soon to tell.
A call for more research – now
In 2016, a group of scientists from around the world published a joint statement in the Journal of Alzheimer’s Disease that called for more research into the connection between Alzheimer’s and infection. They noted that previous studies had suggested possible ties to infections such as the sexually transmitted disease chlamydia, fungal infections, and spirochetes, a type of bacteria that causes Lyme disease, syphilis, and other serious illnesses. Herpes, they point out, was first investigated nearly 30 years ago.
Nevertheless, the pursuit of the link between Alzheimer’s and infection has been embraced by only a handful of researchers, says Moir. And not all of them specialize in treating the brain.
Christine Johnston, MD, MPH, is an associate professor of allergy and infectious diseases at the University of Washington in Seattle. Her focus on genital herpes infection has led her to begin a collaboration with colleagues at UW who study Alzheimer’s.
HSV1, she says, can cause inflammation of the brain, called encephalitis. It also can affect some of the same brain regions damaged by Alzheimer’s.
“For a link between Alzheimer’s and this type of herpes, there’s a lot of what we call biological plausibility,” Johnston says.
In other words, the connection makes sense. But she says what’s needed is proof that it’s more than just a link.
“We have to learn the mechanism as well,” she says. “The pieces of the puzzle have to come together.”
Johnston considers research into the possible role of herpes—and infection more broadly—to be in its very early stages. Investigations into other infections, such as gum disease, are further behind.
“This line of research has very exciting potential, but it’s very preliminary,” Johnston says.
Alzheimer’s specialist Rawan Tarawneh, MD, agrees: “There’s been no single study with strong enough evidence to show cause and effect.”
A call for a fresh approach
But Tarawneh, an assistant professor of neurology at the Ohio State University Wexner Medical Center, says that new approaches to Alzheimer’s disease are vital. It’s been 16 years since the FDA last approved a drug to treat even the symptoms of Alzheimer’s. Since then, more than 400 clinical trials have failed to produce any new medications.
The possibility that amyloid beta is part of the brain’s way of fighting infection “revolutionizes our way of thinking about amyloid,” says Tarawneh.
Perhaps, she says, the protective role of amyloid gets overwhelmed due to a variety of factors, including the weakening of the brain’s immune system as we age.
“What is normally a protective role for amyloid beta may become detrimental and pro-inflammatory,” she speculates. “And it could then contribute to the degenerative process.”
Tarawneh, like Johnston, says a lot of work needs to be done in order to confirm the role of infection, much less devise ways to treat, cure, or prevent Alzheimer’s disease.
“There’s no evidence yet that suggests we should change how we manage patients,” she says. “But what this sparks are efforts to further investigate what amyloid beta is doing in the brain.”
One possible treatment now being investigated: anti-viral medications that target certain herpes viruses. Researchers at Columbia University have enrolled 130 people with mild Alzheimer’s who also have herpes. They hope to determine whether treating the virus leads to a smaller accumulation of amyloid plaque compared to similar people who don’t receive any drug treatment. They expect to complete the study in August of 2022.“Even though we are at the very early stages of understanding [the role of infection in Alzheimer’s], there are already NIH-funded studies like this one going on to start pushing this forward faster,” says Johnston.
Is there anything that you can do to protect your brain from Alzheimer’s? The best evidence suggests that maintaining your heart health also will help your brain. That means regular exercise, a nutritious diet, a healthy weight, sufficient sleep, and well-controlled blood pressure. You also may benefit from spending time socializing, doing puzzles and playing strategy games like bridge, and avoiding head injuries (helmet on if you ride a bike!).
It will be some time before we know whether fighting infection should be added to the anti-Alzheimer’s arsenal. Edelmayer, of the Alzheimer’s Association, puts it very simply: “Ideas are great, but data are better. But, as we see the studies continuing and more research in this area, we’re starting to see a body of knowledge grow.”