Alzheimer’s disease (AD) is the top neurodegenerative disease, characterized by progressive cognitive deterioration. It affects one person in the United States every 65 seconds. As the aging population keeps increasing owing to improved healthcare, there is a global need to identify risk factors for AD in the hope of lowering its prevalence with proper interventions.
To this end, researchers from China, Brazil, Sweden, Korea, Japan, England, and the USA have observed that people who had tooth loss are more likely to develop AD. The risk is about 2.62-fold 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.
The main oral pathogen that causes periodontal and gingival diseases is Porphyromonas gingivalis which 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, habitual smoking, or frequent alcohol consumption. In laboratory animals, P. gingivalis has been shown to 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 AD patients, which were absent in controls. Their levels were also correlated with the severity (or progression) of the disease. Even in living patients with AD, P. gingivalis DNA was identified more frequently in their cerebrospinal fluid than in controls without the disease.
To determine whether this is a cause or consequence of AD, one team inoculated P. gingivalis into the gums of mice periodically for 6 weeks. The mice later developed amyloid plaques — the hallmark neuropathology of AD— in their brains, along with the presence of P. gingivalis. Treating the mice with gingipain 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 AD. So, inhibiting gingipains will also inhibit gingipain-induced AD processes.
This elegant research was achieved by the collaboration of Stephen Dominy, M.D., with 25 researchers from 4 countries, and published in Science Advances. Their analysis also corroborated a previous study 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 Dr. 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, M.D., 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.”
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., a neuroscientist at the University of Bari Aldo Moro, Italy, and his colleagues wrote in the journal Brain.
To stay on the safe side, “brush and floss,” says James Noble, M.D., a neurologist at 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 over 5000 older adults — showing that people who don't brush their teeth regularly had a 22–65% increased risk of developing AD.
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