Some brain health researchers are taking a closer look at how viruses and bacteria affect the brain, and rethinking the villainous role of Alzheimer’s Disease’s best-known biomarker, beta-amyloid
Almost 30 years ago, a small faction of Alzheimer’s researchers proposed the infectious theory of Alzheimer’s — the idea that viruses or bacteria may play a role in the neurodegenerative disease. While the theory failed to catch on, the Alzheimer’s research community in recent years is revisiting it with fresh eyes.
“We had incredible trouble getting grants and papers published,” Ruth Itzhaki, visiting professorial fellow at the University of Oxford and Emeritus Professor at University of Manchester, said of her research on infectious theory. “There was really great opposition for no scientific reason.”
One reason for this, Itzhaki said, is that many scientists in the Alzheimer’s field lacked a basic understanding of viruses. Microorganisms, she explained, may hibernate in the body. Over time, they can reactivate and cause damage.
Some scientists were unaware that people can be infected without showing symptoms — a fact that the general public is now becoming well aware of as we learn more about the novel coronavirus — while others may be more susceptible to displaying symptoms of an infection due to their genetics.
“And also, [scientists] thought it would kill their ideas about amyloid — which it doesn’t,” said Itzhaki, whose team discovered in 1991 that herpes simplex virus type-1 (HSV-1) which usually causes oral herpes, was present in postmortem brains of people with Alzheimer’s.
A longstanding theory about Alzheimer’s — the amyloid hypothesis — proposes that the disease is mainly caused by an accumulation of beta-amyloid proteins. But, after decades of research and disappointing track records in drug development and clinical trials, scientists have failed to find a cure using this biomarker as a drug target.
As the scientific community searches for more promising alternatives to the amyloid hypothesis, Itzhaki observed that scientists are beginning to view the infectious theory with more positivity. Research on the role of viruses and bacteria in Alzheimer’s is growing more common, and the number of journals publishing studies on infectious theory has grown from a handful to several hundreds. Some clinical trials for drugs that target bacteria and viruses to treat people with Alzheimer’s are now underway.
Here are some of the viruses and bacteria that have come into focus as Alzheimer’s researchers explore possible links.
Gum Disease and Alzheimer’s
Periodontitis, commonly known as gum disease, affects about 40 percent of American adults 30 years or older. It’s also a risk factor for cognitive decline and Alzheimer’s. The bacteria that is the main culprit of the disease, Porphyromonas gingivalis, is present in the brains of more than 90 percent of people with Alzheimer’s.
Recent findings suggest that the bacteria may trigger an antibacterial response from beta-amyloid as well as impair the function of tau, a protein thought to play a role in regulating the communication between brain cells.
In a study published this month, researchers observed that, after they infected human brain neurons with Porphyromonas gingivalis bacteria, the bacteria reproduced and created toxins called gingipains. According to Stephen Dominy, an author of the study and the co-founder and chief scientific officer of biopharmaceutical company Cortexyme, a quarter of the brain cells died subsequently and the surviving neurons developed pathologies linked to Alzheimer’s, such as the breaking down of tau.
Dominy and other researchers also found in a study last year that Porphyromonas gingivalis may stimulate the production of beta-amyloid 42 peptide, a type of beta-amyloid. The peptides killed the bacteria, he explained, by binding onto and damaging its membrane.
“If you infect mice with Porphyromonas gingivalis in their oral cavity, it will go to their brains and trigger classic Alzheimer’s disease pathology,” Dominy said. “We believe that the [beta-amyloid] response to Porphyromonas gingivalis is actually an antimicrobial response.”
And, the theory is supported by a growing body of research to suggest that beta-amyloid may be a natural defense mechanism of the brain.
According to Dominy, the link his team found between beta-amyloid and Porphyromonas gingivalis drew attention from researchers around the world — another indicator in a growing pile of evidence that finding a cure to Alzheimer’s may lie in gaining a deeper understanding of microbes and their interplay with the brain.
Herpes and Alzheimer’s
HSV-1 is a latent infection that causes cold sores. It infects most people in infancy and remains dormant outside of the brain and spinal cord, but may get reactivated over time — possibly by stress, an impaired immune system and other infections — and cause inflammation. And Itzhaki proposed that HSV-1 may be one of the major causes of Alzheimer’s.
Emerging evidence suggests that herpes, like the gum disease bacteria, can also trigger the accumulation of beta-amyloid. And just as Dominy’s team suspected that beta-amyloid might be a defense against bacteria’s effects on the brain, Itzhaki reckoned it may defend the brain against invading pathogens like HSV-1.
“It looked as if the DNA was kept as a prisoner inside the amyloid deposits,” Itzhaki said.
Despite their potentially noble purpose, Itzhaki noted that the beta-amyloid plaques may also harm brain cells as they accumulate, damaging the chemical signalling abilities of neurons as plaques build up and undergo structural changes.
Recent research on herpes and the brain show that after just three days of herpes infection, large and dense beta-amyloid plaques formed in the brain. The brain then became inflamed, neurons died, and communication between neurons faltered.
Michael Heneka, director of the Department of Neurodegenerative Diseases and Gerontopsychiatry at the University of Bonn, whose research examines how the immune system plays a role in neurodegenerative diseases, agreed with Itzhaki that beta-amyloid may be defending the brain from viruses.
“It’s possible that [beta-amyloid] is an ancient antiviral brain protectant, and it actually deposits through a number of mechanisms because it wants to limit viral brain infection,” he said.
But to develop an effective treatment, Heneka said researchers still need to pinpoint when infections occur during the course of Alzheimer’s.
What We Still Don’t Know About The Infectious Theory of Alzheimer’s
Heneka cautioned against drawing the conclusion that viruses and bacteria can cause Alzheimer’s.
“I’ve talked to an editor recently from one of the top ten journals and she said the [Alzheimer’s] field is exploding,” Heneka said. “And I told her: ‘With every explosion, there’s a lot of dust being generated and we have to wait until that is settled and see what good data remains.’”
Many studies rely on examining postmortem brains, he noted, and from the time of death to when the brain is investigated, various microorganisms may enter the brain and muddy findings.
Brain changes from Alzheimer’s could also make it more difficult to pinpoint how specific microorganisms are linked to a person’s cognitive condition.
“There are a lot of processes that alter the biochemistry of your brain … the cells in the brain, especially the microglia cells, are primed by 40 years of ongoing [Alzheimer’s] disease,” Heneka said. “We believe that Alzheimer’s starts two to three decades prior to the first clinical symptoms.”
Also, many studies rely upon data of a population at a specific point in time, known as cross-sectional data, according to Heneka. To better understand the causes and consequences of bacterial and viral infections for people with Alzheimer’s, more research needs to be done with longer periods and larger numbers of participants.
“I’ve talked to an editor recently from one of the top ten journals and she said the [Alzheimer’s] field is exploding. And I told her: ‘With every explosion, there’s a lot of dust being generated and we have to wait until that is settled and see what good data remains.’”
He also begged the question: Do certain genes render people more likely to be affected by infections? Itzahki and other researchers have found that people with the ApoE4 gene, the largest genetic risk factor of Alzheimer’s, who have HSV-1 in the brain are 12 times more likely to develop Alzheimer’s than those with neither the disease or the virus.
But the biological mechanisms that may explain such phenomena remains unknown, according to Itzahki, though she suggested that as ApoE4 may be less efficient at competing with HSV-1 to enter cells in our body than other types of ApoE proteins.
In the case of periodontitis, Cortexyme’s team found that gingipains produced by Porphyromonas gingivalis had a penchant for damaging ApoE4 proteins, which Dominy said, may explain why carriers of the mutant gene are at a higher risk for developing Alzheimer’s.
Research and Potential Treatments Underway
Scientists are forging ahead with trials of drugs to treat those with Alzheimer’s and herpes. Researchers are conducting the second phase of a clinical trial for a drug that would slow cognitive decline of people with Alzheimer’s who have tested positive for HSV-1 or 2.
Cortexyme is sponsoring a large randomized clinical trial to test whether or not a drug may slow or halt the progression of Alzheimer’s by targeting the toxic gingipains.
“There’s been plenty of drugs and antibodies that do decrease [beta-amyloid] in Alzheimer’s patients, but the Alzheimer’s patients don’t get any better. Lots of trials have shown this,” Dominy said. “And we believe the reason why it’s not beneficial is because [beta-amyloid] is not the causative agent of cognitive decline.”
Meanwhile, the scientific community is now galvanized by the novel coronavirus and there is evidence to suggest that SARS-CoV2, the virus that causes COVID-19, may lead to stroke, seizures and confusion. Cognitive decline may follow and people could potentially become more vulnerable to neurodegenerative diseases.
Aaron Ritter, associate staff of neuropsychiatry and behavioral neurology at Cleveland Clinic Lou Ruvo Center, noted that more research still needs to be conducted to establish the link between COVID-19 and Alzheimer’s as factors such as genetics, underlying diseases and treatment methods may also contribute to the neurological symptoms of hospitalized patients with COVID-19.
Nonetheless, researchers know that influenza and coronaviruses may not only lead to neurological complications but also a “crashing wave” of neuropsychiatric symptoms such as anxiety, depression and delirium.
As the Alzheimer’s research community is figuring out how viruses and bacteria like those involved in gum disease, herpes and coronaviruses interact with neurodegenerative diseases, they are slowly gaining a better understanding of the relationship between infections and neurodegeneration.