January 23, 2019
By Jocelyn Kaiser
Poor oral health is a risk factor for Alzheimer’s disease. What’s not clear is whether gum disease causes the disorder or is merely a result—many patients with dementia can’t take care of their teeth, for example. Now, a privately sponsored study has confirmed that the bacteria that cause gum disease are present in the brains of people with Alzheimer’s, not just in their mouths. The study also finds that in mice, the bacteria trigger brain changes typical of the disease.
The provocative findings are the latest in a wave of research suggesting microbial infections may play a role in Alzheimer’s disease. But even some scientists who champion that once-fringy notion aren’t convinced that Porphyromonas gingivalis, the species fingered in the new study, is behind the disorder. “I'm fully on board with the idea that this microbe could be a contributing factor. I'm much less convinced that [it] causes Alzheimer’s disease,” says neurobiologist Robert Moir of the Harvard University–affiliated Massachusetts General Hospital (MGH) in Boston, whose work suggests the β-amyloid protein that forms plaques in the brains of Alzheimer’s patients is a protective response to microbial invaders.
The new study, published today in Science Advances, was sponsored by the biotech startup Cortexyme Inc. of South San Francisco, California. Co-founder Stephen Dominy is a psychiatrist who in the 1990s became intrigued by the idea that Alzheimer’s could have an infectious cause. At the time, he was treating people with HIV at the University of California, San Francisco. Some had HIV-related dementia that resolved after they got antiviral drugs. Dominy began a side project looking for P. gingivalis in brain tissue from deceased patients with Alzheimer’s, and—after his work found hints—started the company with entrepreneur Casey Lynch, who had studied Alzheimer’s as a graduate student.
Working with labs in Europe, the United States, New Zealand, and Australia, the Cortexyme team confirmed earlier reports that P. gingivalis can be found in the brains of deceased people with Alzheimer’s, and they detected the microbe’s DNA in living patients’ spinal fluid. In more than 90% of the more than 50 Alzheimer’s brain samples, they also spotted toxic enzymes produced by the bacteria called gingipains. Brains with more gingipains had higher quantities of the Alzheimer’s-linked proteins tau and ubiquitin. Even the brains of roughly 50 deceased, apparently dementia-free elderly people selected as controls often had lower levels of both gingipains and the proteins indicating Alzheimer’s pathology. That early appearance is important, Lynch says, because “you would expect it to be there before the onset” of symptoms.
To explore whether the bacteria were causing disease, the team swabbed the gums of healthy mice with P. gingivalis every other day for 6 weeks to establish an infection. They later detected the bacteria in the animals’ brains, along with dying neurons and higher than normal levels of β-amyloid protein. In a lab dish, the gingipains—whose job is to chop up proteins—damaged tau, a regularly occurring brain protein that forms tangles in people with Alzheimer’s. In the brain, this protein damage may spur the formation of tangles, they say.
Giving the mice a drug that binds gingipains cleared P. gingivalis from the brain better than a common antibiotic, and it reduced the β-amyloid production and resulting neurodegeneration. Targeting gingipains likely works by cutting off nutrients and other molecules that the enzyme supplies to the bacteria, Dominy says. In initial tests with human volunteers, a similar drug seemed safe and showed signs of improving cognition in nine participants with Alzheimer’s, the company says. A larger study is slated to start this year.
Although the paper refers to “evidence for causation,” Dominy goes a step further and says the experiments suggest “P. gingivalis is causing Alzheimer’s.” He and Lynch note that a study published in PLOS ONE in October 2018 by a team at the University of Illinois in Chicago also found that an oral infection with P. gingivalis can cause amyloid buildup and neurodegeneration in the brains of mice.
The Cortexyme study is “the largest to date” to find P. gingivalis in Alzheimer’s brains, and it “is clearly very comprehensively approached,” says neurologist James Noble of Columbia University, who has studied the link between periodontal disease and Alzheimer’s. “These are strange ideas, but they seem to be getting some traction.”
Other pathogens have been found in the brains of people with Alzheimer’s, including spirochete bacteria, which can cause Lyme disease, and some herpesviruses. Moir and Rudolph Tanzi at MGH have shown that β-amyloid in the brain appears to protect mice from bacterial and viral infections by trapping the invaders. Too much of this protective response to pathogens could trigger the buildup of the disease’s signature amyloid plaques, they suggest.
Moir thinks P. gingivalis is likely one of a variety of pathogens that contribute to the β-amyloid buildup and neuroinflammation. But he’s skeptical that the bacteria or its toxin directly cause Alzheimer’s. That’s partly because other recent studies that have explored the link with periodontal disease have not always found it in people with Alzheimer’s.
Howard Fillit, a neuroscientist and chief science officer at the nonprofit Alzheimer’s Drug Discovery Foundation in New York City, is more impressed. “They did a lot of different experiments to build the case that gingipains are a drug target in Alzheimer’s disease,” he says. “I think it’s worth pursuing, and I'm glad they're in a clinical trial.”
If the findings hold up, do they mean that everyone with gum disease—nearly 50% of the U.S. adult population—will develop Alzheimer’s? Not necessarily. But if healthy people want to stay on the safe side and potentially reduce their risk, Noble says, “the main conclusion we still have is: brush and floss.” [read more]