Steve Dominy led a landmark study that linked gum disease bacteria to Alzheimer’s disease. He tells New Scientist why we should stop treating medicine and dentistry separately
IN JANUARY, we broke the news that we may finally know what causes Alzheimer’s disease. For decades, it had been thought that the condition is caused by a protein called beta-amyloid going awry in the brain. But in 2019, evidence pointed the finger elsewhere: at Porphyromonas gingivalis, a type of bacteria involved in gum disease.
Research conducted by labs around the world, and led by the firm Cortexyme in San Francisco, suggests that beta-amyloid is a symptom, not a cause of the condition. Instead, it may be the toxins released by P. gingivalis, called gingipains, that result in the brain damage that brings on the disease.
The hope is that blocking gingipains may at last lead to effective treatments. I caught up with Steve Dominy, head of science at Cortexyme, to find out what has happened since the findings were published.
What was the reaction to your study linking Alzheimer’s to Porphyromonas gingivalis?
The response has been tremendous. A few days after it came out, we’d been invited to present the work at three big international Alzheimer’s conferences. By the following week, we’d been contacted by labs around the world wanting to collaborate.
Some researchers have expressed doubts about the work, including those who have long thought beta-amyloid is to blame.
It’s never easy to challenge conventions in science. But when we were able to show our data, and the depth of the evidence, to people at conferences, they became very enthusiastic. Some of the leading figures working in Alzheimer’s clinical trials have now joined our clinical advisory board.
Are you conducting clinical trials now?
We are testing our experimental drug, COR388, which blocks gingipains, to see if it improves symptoms. We are enrolling up to 570 people with mild to moderate Alzheimer’s at 95 centres across the US and Europe, and randomly assigning them to get the drug or a placebo. The results won’t be back until late 2021.
What else have you been working on?
We have been researching the link between gingipains and a protein called ApoE, which helps maintain neural synapses and controls immune responses in the brain. People with one variant of it, ApoE4, are much more likely to get Alzheimer’s than people with ApoE3, while a recent analysis suggests people with ApoE2 have an exceptionally low risk of getting Alzheimer’s.
P. gingivalis makes two gingipains, and one cuts proteins up only at a particular amino acid, arginine. ApoE4 has two arginines, ApoE3 has only one and ApoE2 has no arginine at all. So it seems people who make ApoE with more arginines are much more likely to develop Alzheimer’s. We have confirmed experimentally that the more arginines ApoE has, the more susceptible it is to gingipains.
COR388 blocks that, and people who received it in early trials of the drug in 2018 had significant reductions in ApoE fragments in their cerebrospinal fluid, as well as some improvements in symptoms.
Would an anti-gingipain drug help treat gum disease too?
We hope so. In some people in the clinical trial, we will be looking at gum disease as well as dementia. Because medicine and dentistry have been separate professions, the mouth is often treated as separate from the body, but, of course, it is not. In 2020, we hope to publish work showing that anti-gingipain drugs also treat gum disease in animals – and whether targeting P. gingivalis in the mouth lowers it in the brain.
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