A century after Alois Alzheimer discovered the disease that bears his name, a central mystery remains. Despite decades of research, no one knows the ultimate causes of Alzheimer’s disease. Suspects have emerged, including genetic mutations, accelerated aging, immune system dysfunction, and environmental factors, but researchers have not converged on an answer. Now a surprising new candidate is emerging: periodontal disease.
A wave of new studies suggests that Alzheimer’s may develop in tandem with periodontal disease, which affects half of adults over 30. The pathogens that cause these chronic bacterial infections burrow below the gumline, and can invade the bloodstream through bleeding gums. Periodontal disease has been strongly tied to heart disease, type 2 diabetes and pre-term births. The links to Alzheimer’s are less well established, but evidence is accumulating.
Periodontal disease may also exacerbate or even drive other common conditions, according to recent discoveries, including rheumatoid arthritis, colon cancer and other gastrointestinal disorders. “These discoveries have sparked a new way of thinking about these diseases and their mechanisms,” says Richard Lamont, a professor of oral immunology and infectious disease at the University of Louisville School of Dentistry.
ZEROING IN ON BACTERIAL CULPRITS
Every 65 seconds, someone in the United States develops Alzheimer’s, and by 2050 the number of Americans living with the disease, currently 6 million, is expected to double or triple. These daunting facts highlight the urgency of finding new approaches to fight this fatal disease, which currently has no cure.
The first clues to a periodontal link emerged from studies of large populations. For example, a study from Taiwan’s Chung San Medical University that followed more than 27,900 people over 10 years found that people with periodontal disease faced up to 70 percent greater risk for developing Alzheimer’s, compared to those with healthy gums. Another 2016 study found that among people who already have the disorder, cognitive decline progressed six times faster in those with oral infections.
More recent studies have strengthened the case by revealing a mechanism by which gum infections could affect the brain. When a person with periodontal disease brushes, flosses or chews food, it often causes gums to bleed. This allows oral bacteria, including the leading culprit in the disease, Porphyromonas gingivalis, to enter the bloodstream through tiny tears in bleeding or inflamed gums.
“That makes it easier for periodontal bacteria to travel from the mouth to the brain,” says Mia Geisinger, a professor of periodontology at the University of Alabama at Birmingham’s School of Dentistry. The oral microbes can then cross the blood-brain barrier. This tissue normally functions as a strict gatekeeper that regulates which substances enter the brain, but it becomes more permeable in Alzheimer’s and other dementias, Geisinger says.
Once inside the brain, P. gingivalis can kill brain neurons and boost production of beta-amyloid plaques, clumps of tangled proteins that are a hallmark of Alzheimer’s, an international team reported in 2019 in Science Advances. The researchers also found that gingipains—toxic enzymes released by P. gingivalis—were present in 96 percent of the brain samples from deceased Alzheimer’s patients and in the spinal fluid of living patients. Chemicals that blocked gingipains beat back P. gingivalis brain infections and restored neurons in the hippocampus, a brain area essential for forming memories.
A PERIODONTAL LINK TO COLON CANCER
Another of the mouth’s microbes, Fusobacterium nucleatum, has long been suspected of instigating colon cancer, the second leading cause of cancer death in the United States. F. nucleatum is well known for its adhesiveness and its role in dental plaque formation. But high levels of the microbe have often been found in colon cancer tissues—and are linked to more aggressive cancer, metastasis to other organs and a poor prognosis. Yiping Han, a professor of microbial sciences at Columbia University’s College of Dental Medicine in New York, strengthened that link in 2013 when she discovered that F. nucleatum produces a protein called FadA adhesin that caused inflammation and spurred the growth of cancerous cells, but not healthy ones. “F. nucleatum appeared to act as an accelerant in cancerous cells, much like throwing gasoline on a fire,” Han says. The team figured out why in 2019, when they found that F. nucleatum spurs colon cells to rev up production of a protein called annexin A1, which in turn fuels cancer growth and acts as a lure for more F. nucleatum.“Basically we discovered a positive feedback loop that explains why this bacterium stimulates colon cancer growth and worsens its progression,” Han says.
RHEUMATOID ARTHRITIS AND THE ‘TWO-HIT’ MODEL
People who have rheumatoid arthritis are far more likely to have infected gums than those who don’t, suggesting that oral infections may drive, and worsen, rheumatoid arthritis. In a recent case-control study, rheumatoid arthritis patients were more than 20 times more likely to have infected gums than patients without the disease. In addition, the more advanced the periodontal disease, the more severe the rheumatoid arthritis.
Researchers have developed a ‘two-hit’ model to explain how periodontitis could potentially cause the joint disease. The first hit is chronic inflammation—in which a prolonged immune response to periodontal bacteria in the mouth and bloodstream leads to systemic inflammation. This is followed by a second hit, such as trauma to the joints.
This double whammy seems to spark the development of autoimmune antibodies that attack the body’s joints and tissues, says Iain Chapple, professor of periodontology at the University of Birmingham in the United Kingdom. This leads debilitating rheumatoid arthritis symptoms, such as painful swelling, joint deformity and damage to a wide range of the body’s tissues, including the heart, skin, eyes and arteries.
P. gingivalis also seems to make joint tissue more susceptible to the new antibodies. It produces an enzyme that partially alters proteins by converting the amino acid arginine into citrulline, a process known as citrullination, Lamont says. “Essentially, this paints a bullseye on the protein’s back that labels it as potentially foreign, causing the antibodies involved in rheumatoid arthritis to mount an attack on the body’s own proteins.”
Dental therapies, such as scaling, root planing and antibiotic treatment, often make rheumatoid arthritis symptoms much less severe, and evidence suggests that periodontal treatment may slow the progression of rheumatoid arthritis. These antibodies appear about ten years before the onset of symptoms, so Veterans Administration researchers are now testing at-risk relatives of people with rheumatoid arthritis to see whether treating periodontal disease might protect them from developing the joint disease in the first place.
While the research linking unhealthy gums with rheumatoid arthritis, Alzheimer’s and colon cancer is still in its infancy, “identifying P. gingivalis and other oral pathogens as supervillains in these diseases is a major breakthrough that could result in novel treatments,” says Thomas Van Dyke, a professor of oral medicine at Harvard University and vice president of clinical and translational research at the Forsyth Institute. Poor oral health is both common and treatable, so the recent results, Van Dyke says, “could lead to a new paradigm for prevention that includes optimal oral care.”
To learn more about the connections between oral and general health, visit the dedicated page from Crest + Oral-B