Exploring the Link Between Alzheimer’s and Chronic Periodontitis

In 2019, 5.8 million Americans were living with Alzheimer’s disease (AD), at a cost to the nation of $290 billion. By 2050, the Alzheimer’s Association projects that these figures will increase to 14 million people and a cost of $1.1 trillion.

Research linking chronic periodontitis and AD may lead to a treatment that can help address this public health and financial crisis. In addition, learning more about the possible connection between AD and gum disease could help patients better understand the long-term importance of maintaining good oral hygiene.

“Multiple studies are showing an association between oral and general health,” says Dr. Richard Panek, surgeon at the Center for Oral Surgery & Dental Implants and medical staff member at Spectrum and Mercy Health Medical System hospitals. “Although association does not mean causation, studies of insurance data show healthy mouths lead to lower overall medical costs. Periodontitis, a significant inflammatory disease, can affect multiple organ systems, so these Alzheimer’s disease studies are significant.”

Chronic Periodontitis and AD

Multiple epidemiological, clinical and molecular studies have shown that chronic periodontitis is linked to an increase in the risk of Alzheimer’s disease (AD) and other dementias. In addition, several studies have connected porphyromonas gingivalis, the major pathogen in the development of chronic periodontitis, to a substantially increased risk for developing AD and more rapid disease progression.

P.gingivalis may be “the missing link that, in time, will reveal if infection driven inflammation represents the early stage in the development of AD pathology followed by appearance of hallmark proteins,” say researchers at the University of Central Lancashire in the United Kingdom and the University of Gainsville, Florida, in an article in Mediators in Inflammation.

Another study, by researchers from the University of Kentucky, Lexington, examined p. gingivalis and six other oral bacteria associated with periodontitis in 158 participants who were cognitively intact at baseline. This study, published in Alzheimer’s & Dementia, showed significant increases in F. nucleatum and P. intermedia antibody levels in patients with AD compared to cognitively intact controls. Antibodies to periodontal disease bacteria were elevated years before subjects developed cognitive impairment. This “suggests that periodontal disease could potentially contribute to the risk of AD,” say the researchers.

A Crucial Link

An international group of researchers examined brain tissue microarrays from nondemented control brains and AD brains and found evidence of P. gingivalis and the gingipains (toxic cysteine proteases) it produces in 96 percent of the 53 brain tissue samples examined.

The levels of gingipains correlated with tau and ubiquitin pathology and were higher in those with AD pathology and symptoms.

In addition, via testing in mice, the researchers showed that P. gingivalis can move from the mouth to the brain and that gingipains can destroy brain neurons. They published the study in Science Advances (January 2019).

Richard Kao, DDS, PhD, president of the American Academy of Periodontology (AAP), commented on the study in an AAP article: “These recent findings present strong evidence on how periodontal disease can impact the pathogenesis of Alzheimer’s disease and should highlight how crucial it is to manage periodontal disease, especially in older adults or individuals who have increased risk for dementia.”

Gingipain Inhibitor May Reduce P. gingivalis Infection

The researchers say that the study also provides “a new conceptual framework for disease treatment.”  They designed and synthesized small-molecule inhibitors targeting gingipains, which consist of lysine-gingipain (Kgp), arginine-gingipain A (RgpA) and arginine-gingipain B (RgpB), and conducted pre-clinical tests. In mice, the molecules reduced P. gingivalis infection, neuroinflammation and production of proteins associated with AD.

COR388, a selective inhibitor of the gingipain Kgp, was the most effective molecule.

A Phase 1B clinical trial was subsequently conducted by Cortexyme, a biopharmaceutical company founded by two of the study’s authors, Stephen S. Dominy and Casey Lynch.

The trial found that COR388 was well tolerated by healthy volunteers and patients with AD. Cortexyme is currently conducting the GAIN Trial, a Phase 2/3 clinical trial of COR388 in subjects with mild to moderate AD. Researchers hope to recruit more than 500 participants in the United States, France, Spain, Poland, the United Kingdom and the Netherlands.

Implications for Clinical Practice

More research is needed for us to fully understand the possible role periodontitis plays in AD, a complex disease that develops over many years and involves multiple factors, including age, gender and genetic predisposition.

In the meantime, as dental care providers we can continue to emphasize to our patients the importance of maintaining good oral hygiene, and educate them about the possible links between oral health and a variety of health conditions, including stroke, diabetes and heart disease as well as Alzheimer’s.

“Preventing disease is the best approach and takes a team including the patient, Dentist and Dental Hygienist,” says Dr. Panek. “However, when the disease is advanced to the point of affecting overall health, tooth extraction may be the best option. That is why our practice motto is ‘don’t live with bad teeth.”