Periodontal disease bacterium appears to drive Alzheimer’s disease

The paper details how researchers identified P. gingivalis in the brains of patients with Alzheimer's disease. Dr Jan Potempa, professor and scholar at the University of Louisville’s Department of Oral Immunology and Infectious Diseases, was part of the team of international scientists led by Cortexyme, a clinical-stage pharmaceutical company that develops therapeutics to reverse the course of Alzheimer's disease and other degenerative disorders.

According to Potempa, although there have already been implications of infectious agents in the development and progression of Alzheimer’s, the evidence regarding its causation was not convincing. However, “we now have strong evidence connecting P. gingivalis and Alzheimer's pathogenesis, but more research needs to be done before P. gingivalis is explicitly implicated in the causation or morbidity of Alzheimer’s,” explained Potempa. “An even more notable aspect of this study is demonstration of the potential for a class of molecule therapies targeting major virulence factors to change the trajectory of Alzheimer’s, which seems to be epidemiologically and clinically associated with periodontitis,” he continued.

In animal models, oral P. gingivalis infection resulted in brain colonization and increased production of amyloid beta (Aβ)—a component of the amyloid plaques typically associated with Alzheimer’s. The research team also discovered the organism’s toxic enzymes, or gingipains, in the neurons of patients with Alzheimer’s. Gingipains are secreted and transported to outer bacterial membrane surfaces and have been shown to mediate the toxicity of P. gingivalis in various cells.

Seeking to block P. gingivalis-driven neurotoxicity, Cortexyme designed a series of small molecule therapies specifically targeting P. gingivalis gingipains. During the preclinical experiments, researchers demonstrated that the inhibition of the compound COR388 resulted in a reduced bacterial load of an established P. gingivalis brain infection, blocked Aβ42 production, reduced neuroinflammation and protected neurons in the hippocampus.

In October 2018, Cortexyme announced results from its Phase 1b clinical trial of COR388 at the 11^th Clinical Trials on Alzheimer’s Disease conference. COR388 showed positive trends across several cognitive tests in patients with Alzheimer’s disease and Cortexyme is planning to initiate a second and third phase of clinical trials with COR388 in patients with mild to moderate Alzheimer’s in 2019.

The study, titled “Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors,” was published in the January issue of the Science Advances journal.

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