The Impact of Periodontal Diseases on Alzheimer's Disease: A Literature Review

Year 2024, , 292 - 298, 22.05.2024

Ayla Ozturk

https://doi.org/10.33631/sabd.1266234

Abstract

Mounting evidence supports the link between Alzheimer's disease (AD), a neurodegenerative disease of the brain, and periodontitis, an inflammatory disease caused by bacteria attached to the tooth surface. It known that inflammation plays a vital role in the pathogenesis of both diseases with totally different clinical symptoms. Periodontitis can be defined as a low-grade systemic disease, considering that the level of pro-inflammatory cytokines and C-Reaktif protein in the systemic circulation is increased. Inflammation is also one of the important features of AD and forms the basis of the hypothesis that periodontitis may be a risk factor for AD. In inflammation theory, it has been suggested that the peripheral inflammatory process triggers amyloid plaque accumulation. Periodontitis can affect cognitive functions through various mechanisms. The mechanisms proposed in the literature are: a) Direct invasion of microorganism into the brain, b) Toxic products of the periodontal pathogens can reach the brain and have a toxic effect, c) the increase in subclinical doses of pro-inflammatory molecules in the systemic circulation during the host response to periodontitis and the long-term exposure of the brain to these molecules due to the chronic nature of periodontitis. Consistent with these theories, one of the major periodontal pathogens, Porphyromonas. gingivalis, has been detected in AD brains and cerebrospinal fluid. When administered orally to mice, P. gingivalis travels to the brain and induces neuroinflammation, amyloid plaque formation, and neurofibrillary tangles, which are pathological hallmarks of AD. The virulence factor of this pathogen, gingipain, has been shown to be elevated in the brain tissue of people with AD. Interestingly, the use of gingipain inhibitors, a P. gingivalis proteinase, in mice alleviates infection, decreases Amyloid beta 42 (Aβ42) peptide accumulation and neuroinflammation. The purpose of this review is to evaluate the link between periodontitis and AD and present the latest evidence explaining the relationship between both diseases.

Keywords

Alzheimer's Disease, Periodontitis, Inflammation, P. gingivalis

Periodontal Hastalıkların Alzheimer Hastalığı Üzerine Etkileri: Literatür Taraması

Abstract

Beynin nörodejeneratif bir hastalığı olan Alzheimer Hastalığı (AH) ile diş yüzeyine tutunan bakterilerin sebep olduğu lokal inflamatuar bir hastalık olan periodontitis arasında ilişkiyi gösteren çalışmaların sayısı giderek artmaktadır. Klinik bulguları birbirinden tamamen farklı olan bu iki hastalığın gelişim sürecinde inflamasyonun anahtar rol aldığı bilinmektedir. Periodontitis, sistemik dolaşımdaki proinflamatuar sitokinlerin ve C-reaktif protein seviyelerinin arttığı göz önüne alındığında, düşük dereceli bir sistemik hastalık olarak da tanımlanabilir. İnflamasyon AH’nın da önemli özelliklerinden biridir ve periodontitisin AH için risk faktörü olabileceği hipotezinin temelini oluşturur. İnflamasyon teorisinde periferal inflamatuar sürecin amiloid birikimini tetiklediği görüşü ileri sürülmüştür. Periodontitis AH’nı farklı mekanizmalarla etkileyebilir. Bu mekanizmalara örnek olarak, a) periodontal patojenlerin beyne direkt invazyonu veya b) periodontal patojenlerin toksik ürünlerinin beyne ulaşması ve bunların toksik etkileri, ya da c) periodontitis kaynaklı proinflamatuar moleküllerin sistemik dolaşımda sub-klinik dozda artması ve beynin bunlara uzun süre maruz kalması, literatürde ileri sürülmüştür. Bu teorilerle uyumlu olarak kilit periodontal patojenlerden biri olan Porphyromonas gingivalis AH’nın beyinlerinde, beyin omurilik sıvısında tespit edilmiştir. Yine farelere bu oral patojen verildiğinde beyine ulaştığı, AH’nın patolojik belirtileri olan nöroinflamasyon, amiloid plak oluşumu ve nörofibriler demetlerin ortaya çıkmasına sebep olduğu gözlemlenmiştir. Ayrıca AH olan bireylerin beyin dokularında bu patojenin virülans faktörü olan gingipainin arttığı gösterilmiştir. Farede gingipain inhibitörlerinin kullanılmasının enfeksiyonu hafiflettiği, Amyloid beta 42 (Aβ42) peptid birikimini ve nöroinflamasyonu azalttığı gösterilmiştir. Bu derlemenin amacı periodontitis ve AH arasındaki bağlantıyı gözden geçirerek her iki hastalık arasındaki ilişkiyi açıklayan en güncel kanıtları sunmaktır.

Keywords

Alzheimer hastalığı,, Periodontitis,, İnflamasyon,, P. gingivalis

References

• Seymour G, Ford P, Cullinan M, Leishman S, Yamazaki K. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect. 2007; 13: 3-10.
• Abbayya K, Puthanakar NY, Naduwinmani S, Chidambar Y. Association between periodontitis and Alzheimer's disease. N Am J Med Sci. 2015; 7(6): 241.
• Cerajewska T, Davies M, West N. Periodontitis: a potential risk factor for Alzheimer's disease. Br Dent J. 2015; 218(1): 29-34.
• Cestari JA, Fabri GM, Kalil J, Nitrini R, Jacob-Filho W, de Siqueira JT, et al. Oral Infections and Cytokine Levels in Patients with Alzheimer's Disease and Mild Cognitive Impairment Compared with Controls. J Alzheimers Dis. 2016; 52(4): 1479-85.
• Teeling J, Perry V. Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms. Neurosci. 2009; 158(3): 1062-73.
• Demmer RT, Papapanou PN. Epidemiologic patterns of chronic and aggressive periodontitis. Periodontol 2000. 2010; 53: 28-44.
• Armitage GC. The complete periodontal examination. Periodontol 2000. 2004; 34(1): 22-33.
• Eikelenboom P, Hoozemans JJ, Veerhuis R, van Exel E, Rozemuller AJ, van Gool WA. Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease. Alzheimers Res Ther. 2012; 4(3): 15.
• Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. Inflammation and Alzheimer's disease: possible role of periodontal diseases. Alzheimers Dement. 2008; 4(4): 242-50.
• Teixeira FB, Saito MT, Matheus FC, Prediger RD, Yamada ES, Maia CS, et al. Periodontitis and Alzheimer’s disease: a possible comorbidity between oral chronic inflammatory condition and neuroinflammation. Front Aging Neurosci. 2017; 9: 327.
• Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019; 5(1): eaau3333.
• Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016; 12(4): 459-509.
• Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, et al. Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimer's & Dementia. 2016; 12(3): 292-323.
• Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the "common" neurologic disorders? Neurology. 2007; 68(5): 326-37.
• Hardy J. Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal. J Alzheimers Dis. 2006; 9(3 Suppl): 151-3.
• Alzheimer A. Uber einen eigenartigen schweren Erkrankungsprozess der Hirninde. Neurologisches Centralblatt. 1906; 25: 1134.
• D’Aiuto F, Parkar M, Andreou G, Suvan J, Brett PM, Ready D, et al. Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers. J Dent Res. 2004; 83(2): 156-60.
• Ilievski V, Zuchowska PK, Green SJ, Toth PT, Ragozzino ME, Le K, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One. 2018; 13(10): e0204941.
• Sochocka M, Zwolińska K, Leszek J. The Infectious Etiology of Alzheimer's Disease. Curr Neuropharmacol. 2017; 5(7): 996-1009.
• Gosztyla ML, Brothers HM, Robinson SR. Alzheimer's Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence. J Alzheimers Dis. 2018; 62(4): 1495-506.
• Riviere G, Riviere KH, Smith KS. Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer's disease. Oral microbiol. immunol. 2002; 17(2): 113-8.
• Olsen I, and Singhrao SK. Can oral infection be a risk factor for Alzheimer's disease? J Oral Microbiol. 2015; 7: 29143.
• B. ÖDD. In: FB Ü ed. Periodontal ve Sistemik Hastalıklarda Mikrobiyal Etkileşim. Ankara, Türkiye: Türkiye Klinikleri; 2020: 49-54.
• 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. Alzheimer's Dis. 2013; 36(4): 665-77.
• Noble JM, Borrell LN, Papapanou PN, Elkind M, Scarmeas N, Wright CB. Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III. J Neurol. Neurosurg. Psychiatry. 2009; 80(11): 1206-11.
• Stein PS, Steffen MJ, Smith C, Jicha G, Ebersole JL, Abner E, et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease. Alzheimers Dement. 2012; 8(3): 196-203.
• Itzhaki RF, Lin W-R, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997; 349(9047): 241-44.
• Slots J. Update on human cytomegalovirus in destructive periodontal disease. Oral microbiol. immunol. 2004; 19(4): 217-23.
• Socransky SS. Dental biofilms: difficult therapeutic targets. Periodontol 2000. 2002; 28: 12-55.
• Aiello AE, Haan MN, Blythe L, Moore K, Gonzalez JM, Jagust W. The influence of latent viral infection on rate of cognitive decline over 4 years. J Am Geriatr Soc. 2006; 54(7): 1046-54.
• Strandberg TE, Pitkala KH, Linnavuori KH, Tilvis RS. Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke. 2003; 34(9): 2126-31.
• Itzhaki RF, Wozniak MA. Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders. Prog. Lipid Res. 2006; 45(1): 73-90.
• Cohen O, Reichenberg A, Perry C, Ginzberg D, Pollmächer T, Soreq H, et al. Endotoxin-induced changes in human working and declarative memory associate with cleavage of plasma "readthrough" acetylcholinesterase. J Mol Neurosci. 2003; 21(3): 199-212.
• Krabbe KS, Reichenberg A, Yirmiya R, Smed A, Pedersen BK, Bruunsgaard H. Low-dose endotoxemia and human neuropsychological functions. Brain Behav. Immun. 2005; 19(5): 453-60.
• Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001; 58(5): 445-52.
• Kamer AR, Pirraglia E, Tsui W, Rusinek H, Vallabhajosula S, Mosconi L, et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol Aging. 2015; 36(2): 627-33.
• D'Aiuto F, Graziani F, Tetè S, Gabriele M, Tonetti MS. Periodontitis: from local infection to systemic diseases. Int J Immunopathol Pharmacol. 2005; 18(3 Suppl): 1-11.
• Watts A, Crimmins EM, Gatz M. Inflammation as a potential mediator for the association between periodontal disease and Alzheimer’s disease. Neuropsychiatr. Dis. Treat. 2008; 4(5): 865.
• Maldonado A, Laugisch O, Bürgin W, Sculean A, Eick S. Clinical periodontal variables in patients with and without dementia—a systematic review and meta-analysis. Clin. Oral Investig. 2018; 22(7): 2463-74.
• Leira Y, Dominguez C, Seoane J, Seoane-Romero J, Pías-Peleteiro JM, Takkouche B, et al. Is periodontal disease associated with Alzheimer's disease? A systematic review with meta-analysis. Neuroepidemiology. 2017; 48(1-2): 21-31.
• Wu B, Fillenbaum GG, Plassman BL, Guo L. Association between oral health and cognitive status: a systematic review. J Am Geriatr Soc. 2016; 64(4): 739-51.
• Gatz M, Mortimer JA, Fratiglioni L, Johansson B, Berg S, Reynolds CA, et al. Potentially modifiable risk factors for dementia in identical twins. Alzheimers Dement. 2006; 2(2): 110-7.
• Kondo K, Niino M, Shido K. A case-control study of Alzheimer's disease in Japan--significance of life-styles. Dementia. 1994; 5(6): 314-26.
• Asher S, Stephen R, Mäntylä P, Suominen AL, Solomon A. Periodontal health, cognitive decline, and dementia: A systematic review and meta‐analysis of longitudinal studies. J Am Geriatr Soc. 2022; 70(9): 2695-709.
• Cebeci IA, Ozturk D, Dogan B, Bekiroglu N. Assessment of oral health in elders with and without Alzheimer’s Disease: A Cross-Sectional Study. Clin Exp Health Sci. 2021;11(4): 849-55.
• Guo H, Chang S, Pi X, Hua F, Jiang H, Liu C, et al. The effect of periodontitis on dementia and cognitive impairment: a meta-analysis. Int J Environ Res Public Health. 2021; 18(13): 6823.
• Ma K, Hasturk H, Carreras I, Dedeoglu A, Veeravalli J, Huang J, et al. Dementia and the risk of periodontitis: a population-based cohort study. J. Dent. Res. 2022; 101(3): 270-7.
• Ide M, Harris M, Stevens A, Sussams R, Hopkins V, Culliford D, et al. Periodontitis and cognitive decline in Alzheimer's disease. PLoS One. 2016; 11(3): e0151081.
• Chen C-K, Wu Y-T, Chang Y-C. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther. 2017; 9(1): 56.
• Stein PS, Desrosiers M, Donegan SJ, Yepes JF, Kryscio RJ. Tooth loss, dementia and neuropathology in the Nun study. J Am Dent Assoc. 2007; 138(10): 1314-22; quiz 81-2.
• Kaye EK, Valencia A, Baba N, Spiro III A, Dietrich T, Garcia RI. Tooth loss and periodontal disease predict poor cognitive function in older men. J Am Geriatr Soc. 2010; 58(4): 713-8.
• Yoneyama T, Yoshida M, Ohrui T, Mukaiyama H, Okamoto H, Hoshiba K, et al. Oral care reduces pneumonia in older patients in nursing homes. J Am Geriatr Soc. 2002; 50(3): 430-3.