Author: Dr Shalini Kanagasingam [Senior Clinical Lecturer, University of Central Lancashire and Consultant in Endodontics, King’s College Hospital Trust]
Alzheimer’s Disease (AD) is thought to contribute to between 60-70% 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 55 million people have dementia worldwide, with nearly 10 million new cases every year.[i] Globally, cases are expected to reach 78 million by 2030, and 139 million by 2050.[ii]
Both periodontal disease[iii] and endodontic disease[iv] have a high global prevalence, of more than 50%. Similar oral bacteria have been implicated in both 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 University of Central Lancashire (UCLan), Dr Sim Singhrao, was the 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.[v] Since then, mounting evidence have pointed consistently to the infectious and inflammatory aetiology of AD.
The importance of research
Currently, the Alzheimer’s Society[vi] and the World Health Organization (WHO)[vii] do not include oral disease as a modifiable risk factor. Whilst AD causation due to infection is difficult to prove, recent discoveries have reignited interest into the links to oral health. Epidemiological studies have reported lower odds of developing AD when procedures which removed 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.[viii],[ix] Clinical studies have shown a correlation between periodontal disease with serum levels of Aβ.[x] 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 comprised of a number of laboratory studies using a variety of methods. These included: scanning electron microscopy (SEM), immunohistochemistry, transmission electron microscopy (TEM), antimicrobial assays, and cell culture studies. [xi],[xii],[xiii]
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.x
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.xi
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 to be higher.xii
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 that my research will facilitate further conversations around oral diseases and systemic health, particularly Alzheimer’s Disease, and increase awareness of this link amongst 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.
For more information about the BES, or to join, please visit the website
www.britishendodonticsociety.org.ukor call 07762945847
[i] World Health Organisation. Dementia. Accessed April 24. https://www.who.int/news-room/fact-sheets/detail/dementia
[ii] Shin JH. Dementia Epidemiology Fact Sheet 2022. Ann Rehabil Med. 2022 Apr;46(2):53-59. doi: 10.5535/arm.22027. Epub 2022 Apr 30. PMID: 35508924; PMCID: PMC9081392.
[iii] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211–1259.
[iv]Tibúrcio-Machado CS, Michelon C, Zanatta FB, Gomes MS, Marin JA, Bier CA. The global prevalence of apical periodontitis: a systematic review and meta-analysis. Int Endod J. 2021 May;54(5):712-735. doi: 10.1111/iej.13467. Epub 2021 Jan 22. PMID: 33378579.
[v] Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis. 2013;36(4):665-77. doi: 10.3233/JAD-121918. PMID: 23666172.
[vi] Alzheimer’s Society. Understanding Dementia Risk. Accessed April 24. https://www.alzheimers.org.uk/about-dementia/managing-the-risk-of-dementia/understanding-dementia-risk
[vii] World Health Organisation. Dementia. Accessed April 24. https://www.who.int/news-room/fact-sheets/detail/dementia
[viii] Chen CK, Wu YT, Chang YC (2017) Association between chronic periodontitis and the risk of Alzheimer’s disease: A retrospective, population-based matched-cohort study. Alzheimers Res Ther 9, 56.
[ix] Lin JW, Chang CH, Caffrey JL (2020) Examining the association between oral health status and dementia: A nationwide nested case-controlled study. Exp Biol Med 245(3), 231-244
[x] Gil-Montoya JA, Barrios R, Santana S (2017) Association between periodontitis and amyloid peptide in elderly people with and without cognitive impairment. J Periodontol 88, 1051-1058
[xi] Kanagasingam S, von Ruhland C, Welbury R, Singhrao SK. Ex vivo Detection of Amyloid-β in Naturally Formed Oral Biofilm. J Alzheimers Dis Rep. 2022 Dec 16;6(1):757-773. doi: 10.3233/ADR-220076. PMID: 36721488; PMCID: PMC9837734.
[xii] Kanagasingam S, von Ruhland C, Welbury R, Singhrao SK. Antimicrobial, Polarizing Light, and Paired Helical Filament Properties of Fragmented Tau Peptides of Selected Putative Gingipains. J Alzheimers Dis. 2022;89(4):1279-1291. doi: 10.3233/JAD-220486. PMID: 36031895.
[xiii] Kanagasingam S, von Ruhland C, Welbury R, Chukkapalli SS, Singhrao SK. Porphyromonas gingivalis Conditioned Medium Induces Amyloidogenic Processing of the Amyloid-β Protein Precursor upon in vitro Infection of SH-SY5Y Cells. J Alzheimers Dis Rep. 2022 Sep 20;6(1):577-587. doi: 10.3233/ADR-220029. PMID: 36275415; PMCID: PMC9535609.
