For years now, there have been suspicions that an oral infection, namely periodontitis, could be one of the causes of Alzheimer's disease. New studies now seem to confirm this hypothesis, and this opens fresh hope. 

Interest in the possible link between Alzheimer's and periodontitis has motivated the Spanish Society of Periodontology and Osseointegration (SEPA) to organise a monographic course entitled "Oral and neurodegenerative diseases: so far or so near!" to be held on the 11th and 12th of July 2019 as part of Madrid’s Complutense University Summer Courses. 

It was conventionally thought that the brain was sterile, as it is isolated from the rest of the body, thanks to the blood-brain barrier. But it is now known that immune cells, inflammatory mediators and microbes, including periodontal pathogens, can pass across the blood-brain barrier. In addition, these peripheral pathogens can reach the brain through the circumventricular organs, cranial nerves and meningeal channels. 

Thus, in patients with Alzheimer's disease, elevated plasma levels of antibodies against periodontal pathogens such as Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Treponema denticola and Porphyromonas gingivalis have been found. 

In recent months, of these pathogens, which are characteristic of periodontal disease, one has come into the limelight. Research by an international team of experts has suggested that Alzheimer's could be associated to a bacterium that causes periodontitis. 

The presence of Porphyromonas gingivalis—one of the most relevant pathogens in periodontitis—has been identified in the brains of patients with Alzheimer's, indicating that this bacterium may contribute to the development of this neurological disease, although it is not yet known whether it is, in fact, the cause. 

It has been possible to isolate P. gingivalis in the brains of deceased patients with Alzheimer's disease, and the DNA of periodontal bacteria has also been found in the cerebrospinal fluid of living patients. In addition, toxic enzymes called gingipains, produced and secreted by P. gingivalis, have been detected in 90% of brains affected by Alzheimer's. 

Brains with more gingipains have more Alzheimer-associated proteins. Gingipain levels thus affect the amount of tau, a protein necessary for normal neuronal function, and ubiquitin, which marks damaged proteins - both associated with Alzheimer's. 

It has been shown that P. gingivalis can form amyloid in mice, the accumulation of which contributes to neurodegeneration in the rodents’ brains. It is believed that this pathogen can travel from the mouth to the brain, where the gingipains would be responsible for destroying nerve cells in the brain. 

AN ARTICLE FOR REFLECTION 

An article recently published in the scientific journal Science Advances explains preclinical and clinical studies showing possible mechanisms by which the most relevant pathogen in periodontitis (P. gingivalis) might be involved in the origin of Alzheimer's disease. In addition, it indicates possible treatment, which may already be under evaluation in clinical studies. 

The article has aroused great interest among the scientific community and throughout the social media. "This publication corroborates a series of recent research findings on the close relationship between Alzheimer's and periodontitis, attributable to the bacteria involved and common inflammatory conditions," says the president of the SEPA Foundation, Dr Adrián Guerrero. 

In analysing the importance of the Science Advances article, Dr David Herrera, a trustee of the SEPA Foundation, affirms that the findings "represent a fundamental advance in proving the association between periodontitis and Alzheimer's disease." As the Professor of Periodontology at the Complutense University of Madrid and member of the Periodontal Disease Aetiology and Therapeutics (ETEP) research group says, "the possible association between periodontitis and Alzheimer's disease was suggested years ago, and may be explained bidirectionally: on the one hand, progressive cognitive deterioration would limit oral hygiene habits, affecting oral health, and on the other, the chronic immunoinflammatory process and systemic inflammation secondary to periodontitis could induce neuroinflammatory phenomena that would favour Alzheimer’s disease." 

The latter hypothesis is what has been shown in the series of studies described in the recently published article. The researchers believe that they have not yet discovered the origin of this degenerative disease, but they are convinced that this line of research is significant. Stephen Dominy, who coordinates the research at the pharmaceutical company Cortexyme, said "Infectious agents have been implicated in the development and progression of Alzheimer's disease before, but the evidence of causation hasn't been convincing. 

Now, for the first time, we have solid evidence connecting the intracellular, Gram-negative pathogen, P. gingivalis, and Alzheimer's pathogenesis. 

The authors of the research sustain that the identification of gingipain antigens in the brains of patients diagnosed with Alzheimer's disease, as well as in those showing pathological signs of the disease but without having been diagnosed with dementia, suggests that cerebral infection by P. gingivalis is not the result of poor dental care after the onset of dementia or a consequence of the disease, but rather an early event that may explain the pathology found in middle-aged people before cognitive impairment. 

The impact of this scientific article goes beyond demonstrating the possible mechanisms mentioned. As Dr Herrera points out, "it suggests, and demonstrates, feasibility in preclinical studies of experimental treatment by blocking gingipains and concludes that they are already being evaluated in human studies." 

ALZHEIMER’S AND PERIODONTITIS 

What now seems clear, given the growing scientific evidence available, is that there may be a two-way link between neurodegenerative diseases and periodontitis, although neither the mechanisms involved, nor the clinical impact are fully understood. Since there are no effective treatments to slow the progression of neurodegenerative diseases, it is critical to establish new therapeutic approaches based on new knowledge of the possible interaction between microbiome and chronic inflammation. The SEPA Summer Course, directed by doctors Mariano Sanz and Juan Carlos Leza, and whose secretary is Dr David Herrera, will be held under this premise. 

Of the main conundrums arising in this field of research, it is considered a priority to determine whether neurodegenerative diseases are inflammatory-based processes, if they have a possibly infectious aetiology and whether an independent association between oral infectious diseases and neurodegenerative diseases is plausible. Similarly, progress is being made in clarifying other doubts of interest as well, such as whether the oral microbiome can reach the central nervous system or if there is experimental evidence of a connection between the mouth and the central nervous system. And most importantly, it remains to be seen what the health implications of the association between these diseases may be. 

In any case, what is irrefutable is the frequent coexistence of Alzheimer's disease and periodontitis. It is currently estimated that in Spain the prevalence of Alzheimer's disease is between 4% and 9%, the most relevant risk factor being age, as its incidence doubles every five years from 65 years on. The resulting dementia has a great impact on morbidity, mortality and disability, and also a huge social impact derived from the degree of dependence, since it is the relatives who take care of 80% of these patients, directly affecting their own health and quality of life. Current treatment is primarily symptomatic, with a limited proven effect on cognition and behaviour. 

Periodontitis is an inflammatory disease, of infectious aetiology —bacteria— which affects the tissues supporting the teeth, causing their destruction, and in the absence of treatment, tooth loss. In Spain, in a recent epidemiological study conducted among the working population, 38.4% had periodontitis, which increased to 65.1% in those over 55 years.