Gum Disease Bacteria Again Linked to Alzheimer's Disease

Gum disease is linked to the development of age-related conditions, particularly cardiovascular disease and neurodegenerative conditions such as Alzheimer's disease. There is a noted association between gum disease and overall mortality rates in late life. One possibility is that this relationship arises due to inflammation, with gum disease (and the bacteria that cause it) acting to boost levels of inflammation. Greater inflammation in turn accelerates the progression of a range of age-related conditions, from atherosclerosis to cognitive decline. There may be more to it than that, however. The research here suggests that other activities of the bacteria involved in gum disease may be as important, and development of a first attempt at a therapy targeting these bacteria is well underway.

Although infectious agents have been implicated in the development and progression of Alzheimer's disease (AD), the evidence of causation hasn't been convincing. In a new study in animal models, oral Porphyromonas gingivalis (Pg) infection led to brain colonization and increased production of amyloid beta (Aβ), a component of the amyloid plaques commonly associated with AD. The study team also found the organism's toxic enzymes, or gingipains, in the neurons of patients with AD. Gingipains are secreted and transported to outer bacterial membrane surfaces and have been shown to mediate the toxicity of Pg in a variety of cells. The team correlated the gingipain levels with pathology related to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a small protein tag that marks damaged proteins.

Seeking to block Pg-driven neurotoxicity, Cortexyme set out to design a series of small molecule therapies targeting Pg gingipains. In preclinical experiments, researchers demonstrated that by inhibiting the compound COR388, there was reduced bacterial load of an established Pg brain infection, blocked Aβ42 production, reduced neuroinflammation, and protected neurons in the hippocampus - the part of the brain that mediates memory and frequently atrophies early in the development of AD. In October 2018, Cortexyme announced results from its Phase 1b clinical trial of COR388. COR388 showed positive trends across several cognitive tests in patients suffering from AD, and Cortexyme plans to initiate a Phase 2 and 3 clinical trial of COR388 in mild to moderate AD in 2019.