Infection | Brain

Mouth Bacteria Can Invade and Degenerate the Brain

Taking care of oral health helps the brain to stay safe.

Alzheimer’s disease is the leading neurodegenerative disease characterized by progressive cognitive decline. It affects one person in the United States every 65 seconds, and this is only one country. As the ageing population keeps increasing from improving healthcare, there is a global concern on identifying risk factors for Alzheimer’s disease in the hope of lowering its prevalence.

Researchers in China, Brazil, Sweden, Korea, Japan, England, and the USA have observed that people who had tooth loss are more likely to develop Alzheimer’s Disease. The risk is about 2.62-fold (162% increase) to as much as 3.61-fold, as calculated by a 2018 meta-analysis that synthesized data from 21 independent studies. A 2-fold means twice as likely which is not to be taken lightly; so academics have pursued this research field over the years.

The main oral pathogen that causes periodontal and gingival diseases is Porphyromonas gingivalis that affects 50% of adults in the USA. This bacterium is a member of the normal oral microbiota but may overgrow and thrive uncontrollably under conditions of poor oral hygiene or habitual smoking and alcohol consumption. P. gingivalis can leak from the gum into the blood circulation and potentially infiltrate the blood-brain-barrier.

Several independent groups of scientists have detected the presence of P. gingivalis DNA and its toxins (lipopolysaccharides and gingipains) in the brains of deceased Alzheimer’s patients, which were absent in controls. Their levels also correlated with the severity (or progression) of the disease. Even in living patients with Alzheimer’s, P. gingivalis DNA was identified more frequently in their cerebrospinal fluid than controls.

To determine whether this is a cause or consequence of Alzheimer’s disease, one team inoculated P. gingivalis into the gums of mice periodically for 6 weeks. The mice later developed amyloid plaques — the hallmark neuropathology of Alzheimer’s disease — in their brains, along with the presence of P. gingivalis. Treating the mice with gingipains inhibitors lowered the bacterial load in the brain, as well as amyloid formation, neuroinflammation, and neurodegeneration. The function of gingipains is to cleave proteins, including tau protein in the brain, which might explain its capacity to induce Alzheimer’s.

This elegant research was achieved by the collaboration of Stephen Dominy with 25 researchers from 4 countries, and published in Science Advances in 2019. Their research also corroborated a 2018 one that showed oral infection with P. gingivalis caused bacterial accumulation, amyloid plaques, and neurodegeneration in the brains of mice. “P. gingivalis is causing Alzheimer’s,” says Dominy boldly.

His confidence is not entirely unwarranted. In a randomized, placebo-controlled, phase I clinical trial led by the Cortexyme pharmaceutical company — started by Stephen Dominy and Casey Lynch— the similar drug (gingipains inhibitors) appeared harmless and improved the cognition of 9 patients with mild-to-moderate Alzheimer’s disease in 4 weeks. They are going to start phase II/III soon.

“They did a lot of different experiments to build the case that gingipains are a drug target in Alzheimer’s disease,” says Howard Fillit, a neuroscientist and officer at the nonprofit Alzheimer’s Drug Discovery Foundation in NYC. “I think it’s worth pursuing, and I’m glad they’re in a clinical trial.”

P. gingivalis, therefore, is another prominent pathogen that contributes to Alzheimer’s disease. Others include herpes simplex virus type-1 (HSV-1), arguably the leading microbial agent that can cause Alzheimer’s disease.

This is an era of paradigm shift of how we view Alzheimer’s disease and neurodegeneration. The microbial aetiology to Alzheimer’s has already been put forward, and antimicrobials are the new, emerging forms of treatment.

Nonetheless, it could be that “older subjects with dementia are more sensitive to oral bacterial and more prone to develop dental infections and therefore this putative causal association could be inverted,” writes Francesco Panza, M.D., PhD., and a neuroscientist at University of Bari Aldo Moro, Italy, and his colleagues in their 2019 publication in the Brain.

To stay on the safe side, “brush and floss,” says James Noble, neurologist of Columbia University. “Regular surveillance and good oral hygiene throughout life are likely to reduce the unnecessary burden of AD in some individuals,” agrees Singhraoa and Olsen in their 2019 publication in the Journal of Oral Microbiology. In fact, there is data — from an 18-year longitudinal study comprising 5468 older adults — showing that people who don't brush their teeth regularly had a 22–65% increased risk of developing Alzheimer’s.