Alzheimer Disease Pathology May Be Driven by Infectious Agent

Jan Potempa, PhD, from the Department of Oral Immunology and Infectious Diseases in the School of Dentistry at the University of Louisville

Jan Potempa, PhD

(credit: University of Louisville)

New research has suggested that Alzheimer disease pathology may be driven by an infectious agent, Porphyromonas gingivalis (P. gingivalis), a culprit in the development of chronic gum disease, and that inhibiting its protease may be able to treat the neurodegenerative condition.¹

The investigators, including Jan Potempa, PhD, from the Department of Oral Immunology and Infectious Diseases in the School of Dentistry at the University of Louisville, identified this keystone pathogen in chronic periodontitis in the brains of patients with Alzheimer disease, as well as the organism’s gingipains—lysine-gingipain (Kgp), arginine-gingipain A (RgpA), and arginine-gingipain B (RgpB)—in the neurons of these patients.

“We now have strong evidence connecting P. gingivalis and Alzheimer's pathogenesis, but more research needs to be done,” Potempa said in a statement.² “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], which seems to be epidemiologically and clinically associated with periodontitis.”

Potempa and colleagues noted that this work did not address how P. gingivalis may relate to apolipoprotein E4 (APOE4), which is considered the biggest genetic risk factor for Alzheimer. However, based on the available preclinical literature, they proposed that “APOE4 may be more susceptible to gingipain cleavage than APOE3 or APOE2 due to the presence of more arginine residues, resulting in decreased innate immune function and the generation of neurotoxic fragments.” Future studies on APOE4’s role in relation to P. gingivalis need to be conducted.

Previous research has implicated other infectious agents in the progression and development of Alzheimer, but less-than-convincing evidence of causation has been presented. As well, animal models have shown oral P. gingivalis infection leads to brain colonization and increased production of amyloid beta (Aβ), part of the amyloid plaque buildup associated with Alzheimer.

Potempa and the team correlated the gingipain levels with pathology related to 2 markers of Alzheimer: tau and ubiquitin. Ultimately, they wrote that the correlation analyses between the loads of gingipain and the 2 markers “revealed a continuum of gingipain and AD pathology already present in the controls.” Notably, they wrote that these findings are consistent with the concept of preclinical Alzheimer disease.

The investigators acknowledged that their evidence lends support to the evolving notion “that Aβ is an antimicrobial peptide, and mutations contributing to loss of this function could allow more robust infection with P. gingivalis and higher risk for disease.” They also wrote that high levels of antimicrobial Aβ driven by chronic P. gingivalis infection of the brain, if sustained over time, may be toxic to host cells, suggesting that a reduction of Aβ levels after treatment of the P. gingivalis infection would be beneficial to patients.

The investigative team in the trial was led by Cortexyme, a privately held, clinical-stage pharmaceutical company that designed a series of small molecule treatments in an attempt to block P. gingivalis-driven neurotoxicity. Preclinical findings have shown that using COR338, a first-in-class, orally administered bacterial protease inhibitor that targets P. gingivalis, reduced the bacterial load of an established P. gingivalis brain infection, blocked Aß₄₂ production, reduced neuroinflammation, and was neuroprotective of cells in the hippocampus.

In October 2018, Cortexyme announced results from its phase 1b clinical trial of the COR388 compound at the 11th Clinical Trials in Alzheimer's Disease (CTAD) Conference in Barcelona, Spain.³ The results showed positive trends across several cognitive tests in patients suffering from Alzheimer. The company stated that it plans to initiate a phase 2 and 3 clinical trial of COR388 in mild to moderate Alzheimer in 2019.

“We are committed to moving quickly to advance COR388 for the benefit of the global Alzheimer’s community in need of new therapeutic options,” Casey Lynch, Cortexyme’s co-founder and chief executive officer, said at the time of the announcement of the phase 1 results. “Following the completion of our Series B financing this past summer, we are well resourced to advance COR388 into phase 2 clinical development.”

Potempa and colleagues concluded that this orally bioavailable, brain-penetrant Kgp inhibitor currently being tested in human clinical studies for Alzheimer is promising given that “the present data indicate that treatment with a potent and selective Kgp inhibitor will reduce P. gingivalis infection in the brain and slow or prevent further neurodegeneration and accumulation of pathology.”

REFERENCES

1. Dominy SS, Lynch C, Ermini F, et al. Porphyromonas

gingivalis

in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances. 2019;5(1): eaau3333.

doi

: 10.1126/sciadv.aau3333.

2. New science details discovery of bacterial pathogen in brains of Alzheimer's patients [press release]. Louisville, KY: University of Louisville; Published January 23, 2019. eurekalert.org/pub_releases/2019-01/uol-nsd012319.php. Accessed January 24, 2019.

3. Cortexyme announces phase I data demonstrating COR388 is safe and well tolerated in healthy older volunteers and Alzheimer's patients [press release]. South San Francisco, CA: Cortexyme Inc; Published October 24, 2018. cortexyme.com/single-post/2018/10/24/Cortexyme-announces-phase-I-data-demonstrating-COR388-is-safe-and-well-tolerated-in-healthy-older-volunteers-and-Alzheimers-patients. Accessed January 24, 2019.