Alzheimer’s Disease (AD) is thought to contribute to between 60-70 per cent of dementia cases. It is characterised by memory loss, behavioural changes, and a lack of ability to perform daily tasks. Patients with late-stage dementia will eventually need full-time care and face lower life expectancy.
The pathological hallmarks of AD include Amyloid-Beta protein (Aβ) in the brain, and intracellular Tau protein aggregation (forming neurofibrillary tangles), leading to neuroinflammation and eventually neuronal death. Currently, over 55m people have dementia worldwide, with nearly 10m new cases every year. Globally, cases are expected to reach 78m by 2030, and 139m by 2050.
Both periodontal disease and endodontic disease have a high global prevalence, of more than 50 per cent. Similar oral bacteria have been implicated in periodontal and endodontic diseases, such as the keystone pathogen Porphyromonas gingivalis. As a major cause of tooth loss, these oral diseases compromise mastication, aesthetics, self-confidence and quality of life. Over the past several decades, significant associations between oral health status and systemic diseases have been established, including cardiovascular disease, diabetes and AD (Figure 1).
My PhD supervisor at the University of Central Lancashire (UCLan), Sim Singhrao, was one of the first researchers to link periodontitis and AD after detecting a known virulence factor of P. gingivalis in post-mortem brains of AD patients more than a decade ago. Since then, mounting evidence has consistently pointed to the infectious and inflammatory aetiology of AD.
Figure 1.
The importance of research
Currently, the Alzheimer’s Society and the World Health Organization (WHO) do not consider oral disease to be a modifiable risk factor. Whilst AD causation due to infection is difficult to prove, recent discoveries have reignited interest in the links to oral health.
Epidemiological studies have reported lower odds of developing AD when procedures that remove oral infection were carried out such as endodontic treatment and limited extractions of grossly carious teeth. Patients who had frequent periodontal emergencies and those with more than four teeth extracted increased their odds of AD. Clinical studies have shown a correlation between periodontal disease with serum levels of Aβ. It is important to acknowledge the potential bi-directional relationship in discussions with patients to encourage preventive measures.
Research techniques and key findings
My research involved several laboratory studies using various methods, including scanning electron microscopy (SEM), immunohistochemistry, transmission electron microscopy (TEM), antimicrobial assays, and cell culture studies.
The detection of Aβ protein in endodontic-periodontal infected teeth
This study on extracted teeth found that microbes associated with endodontic and periodontal disease produced insoluble Aβ. Like prions, insoluble Aβ can have the potential for cross-seeding to the brain and aggregating to form plaques, potentially increasing the risk of development of AD later in life.
In the UK, endodontic instruments are single-use to minimise the risk of cross-seeding prions, which theoretically confers protection from the cross-contamination of the Aβ protein as well.
The Tau peptide and gingipains study
The gingipains enzyme from P. gingivalis can release the Tau protein from nerve cells. Once released, Tau changes its form to filaments and re-attaches to nerve cells, causing severe damage, becoming incorporated into the lesion known as neurofibrillary tangles. This kills nerve cells, leaking more Tau peptides into the brain and the process is repeated leading to further cognitive impairment as AD progresses.
The P. gingivalis - human neuroblastoma cell culture study
This cell culture study showed that P. gingivalis and its virulence factors, in the presence of inflammatory mediators, can increase the production of Aβ proteins. This suggests that P. gingivalis virulence factors can act as antigens of the immune system. The Aβ proteins may be harmless when they exist in low quantities, but when they are at consistently high levels, along with inflammation, the risk of developing AD is likely higher.
Impact on the profession
At the recent British Endodontic Society’s (BES) Spring Scientific Meeting, I was honoured to win the Poster Prize. This was a unique opportunity to share my research findings with a diverse range of dental professionals, including specialists, private practitioners, NHS dentists, and consultants in attendance. I would encourage more colleagues who are conducting endodontic research to engage with the BES as a platform to showcase their scientific findings, as it is a great way to raise awareness about your research. The BES also provides many opportunities for young researchers via the Undergraduate Research Prize and Aspiring Endodontic Researcher Prize, as well as the BES Research Grant.
I hope my research will facilitate further conversations around oral diseases and systemic health, particularly Alzheimer’s Disease, and increase awareness of this link in the profession. Longitudinal clinical studies will be able to produce stronger correlations but will likely require tracking larger patient cohorts over a long period of time, thus requiring sufficient funding.
With stronger evidence, organisations like the Alzheimer’s Society and the WHO may consider acknowledging oral diseases as a modifiable risk factor. This is crucial for increased public awareness and contributes to AD prevention.
Looking to the future
Going forward, awareness of the bi-directional relationship between oral health and general health amongst patients is crucial. Clinicians must have conversations with patients about the benefits of good oral hygiene practices as well as the importance of retaining as many natural teeth as possible as they age. Many infected teeth need not be extracted with early endodontic intervention. Attending regular dental appointments is crucial for both dental and overall health – and the whole dental team must remind patients of this. In the context of AD and many other systemic diseases, interdisciplinary research collaboration between the specialties of endodontology, periodontology, together with our medical colleagues could pave the way for improved patient outcomes.
References available on request.