Human drug trials explore strange link between gum disease bacteria and Alzheimers
A provocative new study, published in the prestigious journal Science Advances, is suggesting the same bacteria responsible for gum disease is also the primary pathogenic cause of Alzheimer's disease. Not only that, but a new drug developed to inhibit these bacterial toxins and treat Alzheimer's is moving into major human clinical trials later this year.
Over the last decade many scientists have grown increasingly skeptical of the primary hypothesis behind the cause of Alzheimer's. For some time researchers have suggested the neurodegenerative symptoms associated with the disease are caused by the build up of toxic amyloid and tau proteins in the brain. However, almost every drug developed to battle these protein aggregations has failed in human clinical trials.
Some researchers have rekindled an older hypothesis, suggesting Alzheimer's may be caused by bacterial or viral infections. The most common of these ideas centers on the assumption that the herpes virus plays a major role in bringing on the disease.
Although these unconventional hypotheses sit on the outskirts of common scientific consensus, they are being increasingly reconsidered by many, as the amyloid hypothesis consistently fails. The latest weird idea being explored by scientists is that Porphyromonas gingivalis (Pg), the bacterium responsible for a common type of gum disease, is also the fundamental pathogenic cause of Alzheimer's disease.
This is an undoubtedly bold hypothesis, but it is not entirely without merit.
Last year a team from the University of Illinois at Chicago published a study that revealed a strong association between periodontitis and cognitive impairment. Not only was this an observable correlation, but the researchers demonstrated a causal connection, suggesting the bacteria can move from the mouth into the brain, instigating neuroinflammation and neurodegeneration closely resembling the pathology of Alzheimer's disease.
"Infectious agents have been implicated in the development and progression of Alzheimer's disease before, but the evidence of causation hasn't been convincing," says Stephen Dominy, lead author on the paper and co-founder of Cortexyme, a clinical-stage pharmaceutical company behind the new research. "Now, for the first time, we have solid evidence connecting the intracellular, Gram-negative pathogen, Pg, and Alzheimer's pathogenesis while also demonstrating the potential for a class of small molecule therapies to change the trajectory of disease."
The newly published paper outlines, across several stages, how Pg infection in mouse models can lead to brain colonization and neuronal damage associated with an increase in both amyloid and tau proteins. The research also demonstrates the development of a compound called COR388 that inhibits the activity of gingipains, a compound secreted by the Pg bacteria, and suspected to be responsible for the negative neurodegenerative effects.
COR388 was shown to be effective at reducing the Pg bacterial infection load in mice brains, as well as improving all the corresponding pathological signs associated with Alzheimer's, including reducing neuroinflammation and blocking amyloid protein production. So far, the researchers have completed Phase 1 trials for COR388 in human subjects, announcing the new compound to be both safe and well-tolerated.
Unsurprisingly, the unconventional idea that Alzheimer's disease is actively caused by the same bacteria that causes periodontal disease is receiving mixed responses from the wider scientific community. Other microbial pathogens have been commonly discovered in the brains of Alzheimer's sufferers so it is unclear whether one singular pathogen can be so clearly causally targeted.
Howard Fillit, from the Alzheimer's Drug Discovery Foundation, suggests the new research is strong and deserves further human trial testing. "They did a lot of different experiments to build the case that gingipains are a drug target in Alzheimer's disease," says Fillit in an interview with Science. "I think it's worth pursuing, and I'm glad they're in a clinical trial."
The Pg hypothesis is still in its nascent stages and there are plenty of unanswered questions, not the least of which is, could good oral health be an effective long-term defense against the onset of Alzheimer's disease?
While this new study is appearing in a reputable, peer-reviewed journal, it's important to note that it is fundamentally generated by a private company with an obvious commercial stake in a pharmaceutical outcome. Cortexyme is moving into Phase 2 and 3 human trials later this year to rigorously test the efficacy of the new drug in patients suffering from mild to moderate Alzheimer's. It is unclear from the early Phase 1 results exactly how efficacious the drug is. The company claims positive trends across cognitive tests are promising but we will not clearly know for several years whether this strange new hypothesis is backed up by good evidence.
The new research is published in the journal Science Advances.