Scientists are pursuing the theory that the brain’s protective response to common viruses could sow the seeds for dementia.
The search for a cause and cure for dementia has been frustratingly slow in comparison to the advances made in many other medical fields. There is a very good reason for this. Dementia often develops slowly over decades and is difficult to study in its early stages. You can’t easily take samples from the brain of a living person, for instance. And, since the brain is a dense and crowded place, even with advanced imaging techniques it is tricky to see exactly what is going on at a cellular level. So far, much of the research for Alzheimer’s has relied on using genetically modified mice or examining the brains of patients after their death.
“When you look at an Alzheimer’s brain, you see it at the very end of the road,” says neuro-engineer Or Shemesh. “You don’t know what might have happened 40 years ago which brought it to that state.”
Having a grandfather who developed Alzheimer’s and died in 2004 means the fight is a personal one for Shemesh. Based between the Hebrew University of Jerusalem and the University of Pittsburgh, he is working on creating new technologies to understand and treat brain disease.
Only about 1-2% of Alzheimer’s cases are caused by specific gene mutations. For the rest, something else must be going on. Shemesh is among a growing number of scientists who believe they may have identified what that something else could be. They have found a link between diseases of the brain and a number of common viruses, bacteria and fungi that are able to get inside it.
The blood-brain barrier is a layer of cells that is there to protect the brain, although it isn’t completely impenetrable. It allows small molecules to pass through, such as nutrients, and also some harmful pathogens. The thinking now is that these cause a protective inflammatory response that, in some people, can lead to cognitive decline later in life.
In the post-mortem Alzheimer’s brains that Shemesh and other scientists have been studying, a striking feature is the deposits of proteins known as tau tangles and amyloid plaques. “But these are downstream factors,” says Shemesh. “Something created them, and we believe it is pathogens.
“Until recently, this was considered a left-field hypothesis and was shunned. Now, the science is advancing and the community is accepting it more and more.”
Shemesh’s latest research used expansion microscopy to look for the virus that causes cold sores and genital herpes – known as herpes simplex virus-1 (HSV-1) – in post-mortem brains. There was plenty of it to be found. “We didn’t find a single person without herpes in their brain,” he says. “The difference between Alzheimer’s and non-Alzheimer’s brains, however, is how spread out it was. In a person who didn’t have Alzheimer’s disease it was here and there – less than a percentage of the entire image was taken up by the green particles that are the virus. In Alzheimer’s patients, it was way more spread out and the brain was full of HSV-1 proteins.”
The theory that emerges from the study is that the brain produces tau protein as a protective response to these pathogens in the short term but, just like inflammation in the rest of the body, if it gets out of control and becomes chronic, then it starts to cause damage.
Environmental factors
There are various reasons why such a common virus as herpes might lead to dementia in some people but not others. “The difference could be related to their immune system, how they age, what environmental factors they are exposed to, what other viruses,” says Shemesh. “A knock on the head may reactivate a latent virus. My grandfather was the victim of a hit-and-run accident and had a traumatic brain injury. Three months later, he started having symptoms of early Alzheimer’s.”
With further studies, on miniature models of human brains in a petri dish, Shemesh showed that when cells were infected with HSV-1, there was lots of tau expression that seemed to have a protective effect, preventing the cell from dying.
Herpes isn’t the only pathogen that’s been discovered inside the brain. Candida albicans is the most common cause of fungal infections in humans. Research by David Corry, of Baylor College of Medicine in Houston, Texas, has shown it can enter the brains of mice, causing an inflammatory response and memory problems. When the infection was treated and cleared up, the mice’s memory went back to normal.
The bacteria that causes gum disease, Porphyromonas gingivalis, has been found in the brains of Alzheimer’s patients and is associated with cognitive decline. The same goes for a common respiratory bacteria, Chlamydia pneumoniae.
The idea that pathogens are linked to Alzheimer’s isn’t particularly new. UK scientist Ruth Itzhaki has been researching it for 30 years. In 1991, her research group was the first to detect signs of HSV-1 in human brains. Recently, she co-led a study at the Oxford Institute of Population Ageing that found repeated head injuries could reawaken a dormant virus in the brain, setting off inflammation and triggering the onset of dementia (potentially what happened to Shemesh’s grandfather).
Citizen scientist
For a long time, Itzhaki had her findings dismissed or greeted with hostility but that is changing. At least some of the credit for this increased acceptance should go to Nikki Schultek, a “citizen scientist” who has brought together a group of researchers – 24 so far, including Itzhaki – to form the Alzheimer’s Pathobiome Initiative with the aim of breaking down silos, sharing knowledge and making faster progress.
North Carolina-based Schultek is driven by personal experience of her health dramatically deteriorating due to microbes infecting her brain and the difficulties she had getting diagnosed. She was in her 30s and a robust mother of two pre-schoolers when, for no apparent reason, her health spiralled downwards. It began with her asthma, which previously had been well-controlled, becoming unmanageable.
“After that, a whole litany of other auto-immune disorders came down the pike,” she says. “I developed joint pain, arrhythmia, problems digesting my food, a bladder disorder that would rank as one of the most painful things a person can suffer from. And then, finally, neurodegenerative symptoms that were most clinically consistent with multiple sclerosis.”
None of this made any sense to Schultek. Having worked in the pharmaceutical and biotechnology industries, she turned to science for answers. First, she came across a small study that linked her bladder pain disorder with Chlamydia pneumoniae. Then she turned up some research linking the same chronic bacterial infection with severe asthma. She emailed its author, the late microbiologist Charles Stratton, asking for advice. “I didn’t expect to hear back because he was such a global authority but he literally replied within five minutes and suggested that blood tests could rule out certain infections.”
Eventually, Schultek discovered she had multiple infections including Borrelia burgdorferi, which causes Lyme disease and results from the bite of an infected tick. She was treated with broad spectrum antibiotics and continues to take a maintenance dose because Borrelia burgdorferi is difficult to eradicate from the brain.
“I was misdiagnosed for such a long time, and kept getting sicker and sicker, so I’m someone who is very fortunate to be here today. I don’t know how my illness will affect my life’s trajectory but, with every well day that I have, my aim is to bring together brilliant scientists who are doing amazing work. Virologists, scientists who are studying bacteria, or molecular diagnostics, even veterinary medicine, all these people need to be communicating.
“We’re keen to develop a better diagnostic approach that will pick up on the majority of organisms in a sample, not just bacteria but viruses, fungi, parasites.
“The other aim we have as a group is to do studies that will show how infections affect the brain. Over a lifetime, we’re all exposed to a lot of things. We get sick, we get better, we get sick.
“We pick up things that are chronic, like Epstein-Barre, and pick up herpes viruses that live in our bodies for a lifetime. We’re aiming to see how exactly these kinds of polymicrobial situations induce chronic inflammation and the changes that are characteristic of neurodegenerative diseases.”
Gut-brain axis
During the past couple of decades, scientists have come to understand that the gut microbiome influences the brain, and the idea of the gut-brain axis has been established. The colony of bacteria we play host to in our gastrointestinal tract can influence mood and brain health. Whether the brain has its own microbiome remains debatable but there is some science to suggest it might.
At Drexel University College of Medicine, Philadelphia, microbiologist Garth Ehrlich has been using a sophisticated gene amplification technique to profile the bacterial communities present in the post-mortem brains of people with and without Alzheimer’s. Bacterial flora were found in all 130 samples that his team examined but there was a marked difference in bacterial profiles.
In the non-dementia brains, researchers found the non-pathogenic Comamonas sp. bacteria. Meanwhile the Alzheimer’s patients had a range of other, more pathogenic bacteria that appeared to have overpowered and replaced Comamonas sp.
“Perhaps destruction of the Comamonas bacteria, part of a healthy brain microbiome, is the first sign of impending dementia,” Ehrlich has theorised.
The unique set of bacteria found in the Alzheimer’s-afflicted brains are also commonly found in the brains of people with the neurodegenerative disease amyotrophic lateral sclerosis (ALS) – suggesting this set of bacteria may contribute to more than one neurological illness.
Although the development of Alzheimer’s and other dementias is complex and likely involves the interaction of many systems, Ehrlich believes the more infections a person gets in the brain, the higher the risk to its long-term health.
Another member of Schultek’s global interdisciplinary group is neuroscientist Brian Balin. He has been studying Alzheimer’s since the late 80s and was an early adopter of the theory that infections might be playing a role. Now based in the Department of Bio-Medical Sciences at Philadelphia College of Osteopathic Medicine, his focus has been on Chlamydia pneumoniae. “I’m a firm believer that this organism is involved with Alzheimer’s and possibly many other types of diseases in the body,” he says.
The more infections a person gets in the brain, the higher the risk to its long-term health.
Chlamydia pneumoniae is an intracellular bacterial pathogen, so lives inside our cells, hiding from immune detection. It is even capable of living inside the immune cells themselves. “It is a very ubiquitous organism and I don’t think most people are getting it into their brains,” says Balin. “But it does seem that vulnerability increases with age. This may be linked to the olfactory neuroepithelial cells in the upper nasal respiratory regions and how the natural process of them degenerating and regenerating with ageing may provide a route for infection into the brain.”
The majority of the Alzheimer’s brains studied by Balin and his colleagues were found to be infected by Chlamydia pneumoniae, and it was located inside different types of cells and in various regions that are associated with amyloid plaques and tau tangles. “Meanwhile, we found it in only 5-10% of the brains of people who didn’t have a diagnosis of Alzheimer’s when they died, so it’s quite disparate,” he says.
After infecting wild-type mice (rather than those genetically programmed to develop Alzheimer’s) with Chlamydia pneumoniae, they saw amyloid generated in the brain as a result, so it’s possible an inflammatory response to the pathogen is leading to amyloid plaques forming over time.
It is impossible to say how many cases of dementia may have been seeded by the various pathogens, because a lot of different organisms have been found in brain tissue and scientists don’t know enough about how they might work, either individually or together, to affect brain health.
“But I think it could be as high as 50%,” says Balin, “possibly even higher because we’re finding pretty routinely evidence for the microbial population in human brains.”
Testing, testing
Given that so many of these microbes are extremely common in the environment, and we are likely to be exposed to some or all of them during a lifetime, what can we do to limit the chance of longer-term harm to our brains? Balin suggests mask-wearing as one option. Failing that, monitoring what we are exposed to through regular blood, saliva and nasal swab testing could be one way of developing a risk profile. “You could also do [smell and taste] testing on a periodic basis because the olfactory system is highly vulnerable and has been shown to be affected early with conditions like Alzheimer’s, Parkinson’s and Huntington’s disease.”
Maintaining a strong immune system to keep these organisms in check is also important. Shemesh and Balin agree one very effective way to prevent infection in the first place is through vaccination. There’s mounting evidence that adult vaccines are useful for preventing later stage dementia. For instance, researchers at Saint Louis University found that the tetanus, diptheria and pertussis vaccine (known as Tdap) was associated with a 42% lower dementia risk.
Meanwhile, a University of Oxford study found that Shingrix, the latest vaccine against the herpes zoster virus that causes shingles, was linked to a 17% lower risk of dementia diagnoses in the six years after it was administered compared with the previous vaccine, Zostovax. This benefit was seen in both sexes, but was greater in women.
In New Zealand, people aged 65 are eligible to be vaccinated with Shingrix for free, and some immuno-compromised people are funded at a younger age. It requires two doses and costs $600-$800 for everyone else. Shemesh suggests age 50 as the ideal time to be vaccinated for a chance of lowering dementia risk. At this stage, it’s not known if it’s inhibiting the virus that reduces risk or whether other chemicals contained in vaccines might have beneficial effects on brain health. But routine flu vaccinations have been associated with lower dementia risk, as has pneumococcal vaccination and, given that a Covid-19 infection has adverse neurological effects, there is a possibility that increased immunity to that virus may have long-term brain benefits.
Schultek would like screening for infections to be routine when people present to their doctor with memory issues. Although some organisms will be difficult to evict from the brain, there is the possibility that existing antimicrobial and antiviral drugs could be repurposed while new treatments are developed and at least keep them under control. The GLP-1 agonist weight-loss and diabetes drugs, such as Ozempic, have been associated with an up to 30% decreased risk of developing dementia so could be used as preventively for people deemed high risk.
“There may be clinicians out there right now who are open to screening a patient and checking to see what their antibody levels are for Chlamydia pneumoniae and herpes simplex 1 and 2,” says Schultek.
“I think as we move forward and identify which organisms are present, we will have a growing arsenal of therapeutics at our disposal, along with ways of preventing infections happening in the first place.”
Inflammation key
Balin sees potential in phage therapies, which use viruses that target and kill selective bacteria, and the genome editing technology CRISPR to offer a new generation of treatments. In his view, even if pathogenic organisms living in the brain are proving hard to eradicate, controlling inflammation is likely to be the key to preventing longer-term damage.
Dementia tends to happen later in life, but he believes this same “germ theory” may well apply to other neurological conditions that are diagnosed far earlier.
“Autism is usually diagnosed at a young age, then obsessive compulsive disorder and schizophrenia in teenagers, multiple sclerosis in young adults. We know the flu virus has been linked to schizophrenia, as has the parasite Toxoplasma gondii. So, if we’re infected at a certain point in time, does that lead to brain changes? It’s interesting to consider. And I think just about every chronic disease in the body will have some type of potential microbial involvement. It’s not all going to be causative, but it will be contributing to the nature of the chronic disease.”
A team-science approach seems to offer the best chance of finding out. “We have to throw out our egos, utilise the different strengths we all have and build on our knowledge base,” says Balin.
Shemesh believes fresh approaches are needed in Alzheimer’s research. He notes past studies have faced challenges, as researchers often shift focus to other conditions or produce data-heavy papers without clearly addressing the underlying causes of the disease.
He also highlights concerns about reliance on genetically engineered mouse models with mutations far beyond those typically found in humans.
Another criticism is that science has been too focused on finding a cure rather than the cause. The Alzheimer’s Pathobiome Initiative aims to change that.
Schultek appreciates it may be scary to confront the idea of a virus that leaves you with a cold sore today causing your brain to decline down the track. “But to me, what is actually scarier is people getting these diagnoses of dementia and having nearly no option for treatment.”
