The bacteria Porphyromonas gingivalis, known as Pg, lead to the gum infection chronic periodontitis, causing chronic inflammation and potential tooth loss.
This same bacteria were also found in 51 out of 53 brain autopsies of Alzheimer’s disease patients, according to new research by Dr. Stephen Dominy and Casey Lynch, founders of the pharmaceutical firm Cortexyme. The pharmaceutical company, which is focused on developing therapeutics to alter the course of Alzheimer’s disease, funded the research.
Following on from their findings, the team also tested blocking the bacteria in mice by injecting small molecules targeting Pg, to inhibit it, and found that it could reduce neurodegeneration in the brain, showing a potential new way to tackle Alzheimer’s disease.
Lynch said that her team’s “publication sheds light on an unexpected driver of Alzheimer’s pathology – the bacterium commonly associated with chronic gum disease,” adding that it also shows a “promising” approach to address the disease.
Previous studies have established a link between periodontal disease and Alzheimer’s, Lynch said. She said that the new research observes a “highly significant” link between Alzheimer’s and the oral infection and that the mouse study indicates causation.
However, James Pickett, head of research at the UK Alzheimer’s Society, said that “in research we’ve supported to uncover the key risk factors for Alzheimer’s disease, gum disease hasn’t emerged as a major cause for concern.”
Pickett, who was not involved in the new research, added that “the laboratory work does suggest that this infection could cause damage to cells of the brain, but there isn’t yet clear evidence that it can cause this damage in people or result in Alzheimer’s.”
Lynch mentioned that despite “significant funding and the best efforts of academic, industry and advocacy communities, clinical progress against Alzheimer’s has been frustratingly slow.”
Alzheimer’s disease is the most common form of dementia, which is characterized by memory loss that gets worse over time. The condition is believed to be caused by a buildup of beta amyloid plaques and neurofibrillary tangles called tau in the brain. So far, there is no cure for the disease.
In 2014, it was estimated that as many as 5 million Americans live with Alzheimer’s diseases, according to the US Centers for Disease Control and Prevention. In the UK, 850,000 people live with dementia, according to the Alzheimer’s Society.
More research needed
Previous research observed that Alzheimer’s disease patients with the oral infection showed cognitive decline over a six-month period when compared with another group of Alzheimer’s disease patients without the infection.
The new study found that toxic enzymes from the bacteria Pg, called gingipains, were also found in the brains of Alzheimer’s disease patients and that their levels correlated with levels of tau.
When the research team orally infected mice with Pg, an increase of amyloid beta – the plaque associated with Alzheimer’s disease – was seen in the brain.
But the study notes that the bacteria also exist in low levels in 25% of healthy people who did not have any oral disease.
“Infectious agents have been implicated in the development and progression of Alzheimer’s disease before,” Dominy said in a statement. “But the evidence of causation hasn’t been convincing.”
Now, for the first time, we have solid evidence connecting Pg and Alzheimer’s pathogenesis while demonstrating the potential for a class of small molecule therapies to change the trajectory of the disease, he said.
Trying to stop Pg buildup, the team designed small molecule inhibitors targeting the toxic enzyme gingipains. With a series of experiments, the researchers showed that one compound, COR388, was able to reduce the bacterial load of a Pg brain infection in mice. This means neurons in the hippocampus, the brain’s part responsible for memory, were protected in the mice.
The experiment in mice showed “small increases in the levels of one of the Alzheimer’s associated proteins with Pg infection that were prevented with the experimental drug,” commented Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh. “But these mice did not develop any Alzheimer’s pathology and were conducted in small groups (around 10 mice per group).”
“So it’s great news that a recent trial by this company showed this drug is safe in people and this study provides some evidence that it may affect Alzheimer’s related proteins,” added Spires-Jones, who was not involved in the new research. But she warned that larger clinical trial is needed to see if it will be beneficial to people living with Alzheimer’s disease.
Finding new strategies
Tiago Outeiro, professor of neurodegeneration at Newcastle University, mentioned that studies like this, which identify microbes associated with disease, are “extremely attractive, as this might lead to the identification of strategies, such as antibiotics, which may specifically affect those microbes which associate with disease.”
Outeiro, who was not involved in the research, also warned that in this case, the question remains whether the bacteria are specific to Alzheimer’s disease or a signal of general changes taking place during neurodegeneration.
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Spires-Jones added that Alzheimer’s disease patients also have disruption of their blood-brain barriers, “making them more susceptible to getting infections in their brains, so while these data are interesting, it is possible that the infection is a by-product instead of a cause of disease.”
Cortexyme has completed a stage one trial testing the safety of the COR388 compound in humans. Nine adults with Alzheimer’s were given a range of doses of the compound for 28 days. It was well-tolerated, and the nine patients with Alzheimer’s disease showed improved results, compared with another group who did not receive the treatment, when completing several cognitive tests.
In 2019, Cortexyme said, it plans to conduct more trials of COR388 in over 500 people with mild to moderate Alzheimer’s disease.