Indian Journal of Oral Sciences

REVIEW ARTICLE
Year
: 2016  |  Volume : 7  |  Issue : 2  |  Page : 74--78

Association between periodontitis and Alzheimer's disease: Does the link exist?


Ravi Prakash Popat1, Neeta V Bhavsar2, Parita Ravi Popat1,  
1 Private Practitioner, Vadodara, Gujarat, India
2 Department of Periodontology, Government Dental College, Ahmedabad, Gujarat, India

Correspondence Address:
Ravi Prakash Popat
30-Basera Park, Near Rani Tower, Kalawad Road, Rajkot - 360 005, Gujarat
India

Abstract

The relationship between oral and systemic health has remained a matter of debate since the early 1900s. In recent years, concept of DQfocal infection,DQ systemic effect from oral microorganism, gained much attention. Based on the theory of DQfocal infection,DQ periodontitis is linked with various systemic conditions such as diabetes, cardiovascular disease, preterm birth/low-birth-weight infants, and aspiration pneumonia. In this review, we discuss the association between periodontitis and AlzheimerSQs disease.



How to cite this article:
Popat RP, Bhavsar NV, Popat PR. Association between periodontitis and Alzheimer's disease: Does the link exist?.Indian J Oral Sci 2016;7:74-78


How to cite this URL:
Popat RP, Bhavsar NV, Popat PR. Association between periodontitis and Alzheimer's disease: Does the link exist?. Indian J Oral Sci [serial online] 2016 [cited 2017 May 25 ];7:74-78
Available from: http://www.indjos.com/text.asp?2016/7/2/74/194202


Full Text

 Introduction



The relationship between oral and systemic health has remained a matter of debate since the early 1900s. In recent years, concept of "focal infection," systemic effect from oral microorganism, gained much attention. Furthermore, Offenbacher introduced term "Periodontal Medicine" in 1996 at World Workshop in Periodontics to validate relationship between periodontal and systemic disease and its biological plausibility.[1] It was also proposed that periodontitis may affect the host's susceptibility to systemic disease in three ways - by shared risk factors, by subgingival biofilms acting as reservoirs of Gram-negative bacteria, and through the periodontium acting as a reservoir of inflammatory mediators.[2] Recently, supportive evidence is available linking periodontal disease with various systemic conditions such as diabetes, cardiovascular disease, preterm birth/low-birth-weight infants, and aspiration pneumonia.[3],[4] In the present literature, an attempt is made to show association between periodontitis and Alzheimer's disease (AD).

 Alzheimer's Disease



AD is the most common neurodegenerative disease that causes dementia in the elderly. It is characterized by the gradual deterioration of memory and other cognitive functions, which eventually leads to a complete incapacity and death. The most important risk factors for AD are old age and a positive family history. The frequency of AD increases with each decade of adult life, reaching 20-40% of the population over the age of 85. A positive family history of dementia suggests a genetic cause of AD.[5],[6]

It has three consistent neuropathologic hallmarks: Plaques of amyloid beta (Aβ) protein (amyloid plaques), neurofibrillary tangles (NFTs), and neuronal degeneration. Senile plaques are mainly composed of Aβ peptide that is produced from proteolytic cleavage of the transmembrane amyloid precursor protein (APP). NFTs are formed by arrays of paired helical filaments structures, which contain mainly self-aggregated hyperphosphorylated tau, a multifunctional protein involved in microtubule assembly and stabilization. A distinguishing feature of AD is that the plaques and NFTs are localized to areas in the brain corresponding to the clinical symptoms. Although the development of plaques and NFTs eventually leads to a noticeable clinical condition, the process is thought to start years before the initial onset of symptoms (preclinical AD). While the specific factors involved in the etiology and pathogenesis of AD are not well characterized, inflammation is thought to play important role in pathogenesis of AD.[7]

 Periodontitis



Periodontitis is a multifactorial infectious disease of the supporting structures of the teeth, characterized by destruction of the supporting alveolar bone and connective tissue.[8] Although dental plaque is currently considered to be primary etiological factor, development of periodontal disease is modified by host response, genetics, and environmental factors.[9],[10],[11] More than 400 species of microorganisms are found in subgingival plaque. While bacterial involvement in periodontal diseases is well recognized, periodontal diseases are not caused by one organism; however, multiple pathogenic organisms are responsible for periodontal breakdown. Oral microorganisms such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia (formerly, Bacteroides forsythus), Treponema denticola, and Eikenella corrodens have been found to be associated with periodontitis.[12]

In the presence of the microbial challenge, the susceptible host responds with an immediate inflammatory and immune response to control the challenge. The initial host response comprises an innate recognition of microbial components - lipopolysaccharides (LPS), bacterial DNA - by host cells of the gingiva and the subsequent production of inflammatory mediators, such as eicosanoids, reactive oxygen species (ROS), matrix metalloproteinases, chemokines, and cytokines which are directly responsible for pathogenesis of periodontal diseases.[13] Periodontitis had shown to induce systemic inflammatory response. From the available literature, it was proven that a total number of leukocytes, plasma cytokines, and C-reactive protein (CRP) are higher among subjects having periodontitis as compared to healthy controls.[14]

 Association between Alzheimer's disease and periodontitis



On the basis of the contribution of periodontitis to systemic inflammation and the potential role of inflammation in the etiology and progression of AD, chronic periodontitis can be proposed as a risk factor in the incidence and progression of AD. Following factors can be considered as a link between them.

Periodontal pathogens

The cell walls of Gram-negative periodontal pathogens contain LPS. Various animal studies showed that bacterial LPS stimulate certain inflammatory cytokines such as that are associated with microglial activation and altered processing of APP.[15],[16] Further, various periodontal pathogens such as A. actinomycetemcomitans, P. gingivalis or/and T. forsythia, and T. denticola are linked with AD by various extents. The mechanism by which periodontal bacteria have access to the brain is not known. However, the mechanisms described for other bacteria such as access via systemic circulation are possible. Bacteremia of oral origin occurs quite frequently during dental and nondental manipulations. Other way the bacteria may reach the brain is via peripheral nerves.[17] Treponema species have been detected more frequently in the trigeminal ganglia, brainstem, and cortex of human brain, and AD donors than controls, suggesting that oral bacteria are capable of invading brain tissue perhaps via peripheral nerve fibers.[18]

A recent study showed the presence of LPS of P. gingivalis, a potential periodontopathogen, in brains of an individual with AD.[19] Elevated plasma IgG antibodies to periodontal bacteria (A. actinomycetemcomitans, P. gingivalis, or/and T. forsythia) found in individual with AD compared to normal controls.[20] Furthermore, elevated serum antibody IgG to Fusobacterium nucleatum and Prevotella intermedia in subjects with AD had found before development of AD as compared to controls.[21] It further supports possible role periodontal pathogens in pathogenesis of AD.

Viruses could also contribute directly to AD pathology. Herpes simplex virus (HSV) has glycoproteins that are very similar in amino acid sequences to Aβ and tau protein and may aggregate as Aβ. HSV may also impact the processing of APP. The production of Aβ may be increased as a result of altered APP processing or may also result directly from HSV infection.[22] It is interesting to note that increased virus isolates, in particular herpes group viruses, at sites with periodontal breakdown. Herpes viruses, including Epstein-Barr virus and cytomegalovirus, occur at high copy counts in periodontitis and may interact synergistically with periodontopathic bacteria in the etiology of the disease. Herpes virus active periodontal infections may impair local host defenses and thus increase the aggressiveness of resident periodontopathic bacteria. The bacteria, in turn, may augment the virulence of the herpes viruses.[23],[24]

Systemic inflammation

As described previously, the interaction between periodontopathic bacteria and host response results in locally increased production of inflammatory molecules including interleukin (IL)-1 β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and CRP.[14] In severe or extensive Parkinson's disease, these proinflammatory molecules may also induce systemic inflammation and therefore may access the brain via systemic circulation. Proinflammatory molecules derived locally from periodontal tissue may also stimulate trigeminal nerve fibers, leading to increased brain cytokines.[25]

There are several mechanisms through which systemic inflammation might contribute to pathogenesis in AD. These include priming of microglia, dysregulation of APP and Aβ processing and metabolism, activation of microglia in response to Aβ, and neurotoxic loop or vicious cycle in which immune response intended to be neuroprotective leads to exacerbation of the process.[22]

Both acute and chronic systemic inflammations, associated with increases in serum TNF-α, are associated with an increase in cognitive decline in AD.[26] TNF-α was significantly increased in AD subjects compared to healthy controls.[21]

Vascular changes

Oral bacteria including Streptococcus sanguis and P. gingivalis have been shown to result in the expression of platelet aggregation proteins that may play a role in the formation of atheromas and thrombi. High levels of atherosclerosis have been found to increase the risk of cognitive decline independent of other factors. Vascular changes in the brain may also contribute to the formation of AD pathology. Platelets are a primary source of APP and platelet aggregation associated with cerebrovascular pathology may increase the production of Aβ in the brain. In endothelial cells, Aβ causes the secretion of inflammatory proteins which upregulate the production of APP.[22]

Oxidative stress

Oxidative stress has negative effects in relation to periodontitis because of the increase in proinflammatory cytokines which leads to periodontal destruction. ROS are generated predominantly by polymorphonuclear leukocytes during an inflammatory response, which lead to degradation of extracellular matrix components.[27],[28] Growing evidence has demonstrated that oxidative stress is an important factor contributing to the initiation and progression of AD. The excessive ROS may be generated from mechanisms such as mitochondrial dysfunction and/or aberrant accumulation of transition metals while the abnormal accumulation of Aβ and tau proteins appears to promote the redox imbalance. The resulted oxidative stress has been implicated in Aβ- or tau-induced neurotoxicity. In addition, evidence has suggested that oxidative stress may augment the production and aggregation of Aβ and facilitate the phosphorylation and polymerization of tau, thus forming a vicious cycle that promotes the initiation and progression of AD.[29]

The proposed link of association among periodontitis and AD through above-mentioned risk factors is shown in [Figure 1].{Figure 1}

 Current Evidence



Various cross-sectional and longitudinal evidences are available linking periodontitis and AD. Gatz et al.[30] showed strong association between tooth loss and AD in monozygotic twins with controlled genetic factors. In fact, the twins having tooth loss was 5.5 times more likely to develop AD later in life compared to his/her sibling. Stein et al.[31] in a prospective follow-up study showed that participants with the fewest teeth had the highest risk of prevalence and incidence of dementia. Kim et al.[32] in a cross-sectional study of 686 community residents aged 65 or over without dementia followed over 2.4 years in Korean community found that having fewer teeth may be a marker of risk for dementia and AD. This might be explained either by specific nutritional deficits or by other side effects of periodontal disease.

Syrjälä et al.[33] in health examination survey of 2320 persons 55 years or older in Finland showed that cognitively impaired subjects among older adults in Finland have more carious teeth, are more often edentulous without using a denture, and have poorer denture hygiene than cognitively healthy persons. Yu and Kuo[34] in a population-based cross-sectional study of 803 older adults with age 60 years or older showed that higher cognitive function was associated with lower odds of periodontal disease in noninstitutionalized older adults. Wu[35] in National Health and Nutrition Examination Survey (NHANES, 1999-2002) of 1984 older adults with age 60 years or older showed that community-dwelling elders with lower cognitive function scores have greater deterioration of oral health. Stewart et al.[36] in NHANES survey of oral health and cognitive function showed that poor oral health is associated with worse cognitive function throughout adult life.

Okamoto et al. (2010)[37] examined 3061 community residents aged 65 years or older who had a score of 24 or more on the mini-mental state examination found that tooth loss is associated with mild memory impairment in later life after adjustment for sex, age, and level of education (odds ratio 1.71). Kaye et al.[38] in a longitudinal prospective study of 597 dentate men, aged 28-70 years at the study baseline, who have been followed up to 32 years showed that risk of cognitive decline in older men increases as more teeth are lost. Periodontal disease and caries, major reasons for tooth loss, are also related to cognitive decline. Kamer et al.[39] showed older adults with periodontal inflammation (PI) or many missing teeth would show impaired cognition compared to subjects without PI or with few missing teeth, and among subjects with PI, those with many missing teeth would show impaired cognition compared to those with few missing teeth.

 Conclusion



This literature review described possible association between periodontitis and AD and possible potential link between them. Although various cross-sectional and longitudinal evidences are available linking periodontitis and AD, there is lack of direct evidence linking periodontitis and AD. There is also lack of clinical evidence showing beneficial role of periodontal intervention on reducing risk of development of AD. Further researches are required to prove causal association between periodontitis and AD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Offenbacher S. Periodontal diseases: Pathogenesis. Ann Periodontol 1996;1:821-78.
2Page RC. The pathobiology of periodontal diseases may affect systemic diseases: Inversion of a paradigm. Ann Periodontol 1998;3:108-20.
3Pizzo G, Guiglia R, Lo Russo L, Campisi G. Dentistry and internal medicine: From the focal infection theory to the periodontal medicine concept. Eur J Intern Med 2010;21:496-502.
4Cullinan MP, Seymour GJ. Periodontal disease and systemic illness: Will the evidence ever be enough? Periodontol 2000 2013;62:271-86.
5Querfurth HW, LaFerla FM. Alzheimer′s disease. N Engl J Med 2010;362:329-44.
6Bird TD, Miller BL. Dementia. In: Fauci AS, editor. Harrison′s Principal of Internal Medicine. 17 th ed. New York (NY): McGraw-Hill Companies; 2008. p. 2536-48.
7Jackson-Siegal J. Our current understanding of the pathophysiology of Alzheimer′s disease. Adv Study Pharm 2005;2:126-35.
8Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal diseases. Periodontol 2000 1994;5:78-111.
9Berglundh T, Donati M. Aspects of adaptive host response in periodontitis. J Clin Periodontol 2005;32 Suppl 6:87-107.
10Shapira L, Wilensky A, Kinane DF. Effect of genetic variability on the inflammatory response to periodontal infection. J Clin Periodontol 2005;32 Suppl 6:72-86.
11Heitz-Mayfield LJ. Disease progression: Identification of high-risk groups and individuals for periodontitis. J Clin Periodontol 2005;32 Suppl 6:196-209.
12Feng Z, Weinberg A. Role of bacteria in health and disease of periodontal tissues. Periodontol 2000 2006;40:50-76.
13Garlet GP. The role of chemokines and cytokines in the pathogenesis of periodontal and periapical lesions: Current concepts. In: Khatami, editor. Inflammation, Chronic Diseases and Cancer - Cell and Molecular Biology, Immunology and Clinical Bases. 1 st ed. Rijeka, Croatia: InTech Publishers; 2012. p. 219-64.
14Loos BG. Systemic markers of inflammation in periodontitis. J Periodontol 2005;76 11 Suppl: 2106-15.
15Shapira L, Takashiba S, Amar S, Van Dyke TE. Porphyromonas gingivalis lipopolysaccharide stimulation of human monocytes: Dependence on serum and CD14 receptor. Oral Microbiol Immunol 1994;9:112-7.
16Shapira L, Ayalon S, Brenner T. Effects of Porphyromonas gingivalis on the central nervous system: Activation of glial cells and exacerbation of experimental autoimmune encephalomyelitis. J Periodontol 2002;73:511-6.
17Kamer AR, Dasanayake AP, Craig RG, Glodzik-Sobanska L, Bry M, de Leon MJ. Alzheimer′s disease and peripheral infections: The possible contribution from periodontal infections, model and hypothesis. J Alzheimers Dis 2008;13:437-49.
18Riviere GR, 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;17:113-8.
19Poole 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;36:665-77.
20Sparks Stein P, 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;8:196-203.
21Kamer AR, Craig RG, Pirraglia E, Dasanayake AP, Norman RG, Boylan RJ, et al. TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer′s disease patients and normal subjects. J Neuroimmunol 2009;216:92-7.
22Watts A, Crimmins EM, Gatz M. Inflammation as a potential mediator for the association between periodontal disease and Alzheimer′s disease. Neuropsychiatr Dis Treat 2008;4:865-76.
23Slots J. Human viruses in periodontitis. Periodontol 2000 2010;53:89-110.
24Slots J. Herpesvirus periodontitis: Infection beyond biofilm. J Calif Dent Assoc 2011;39:393-9.
25Romeo HE, Tio DL, Rahman SU, Chiappelli F, Taylor AN. The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: Relevance to neuroimmune surveillance of the oral cavity. J Neuroimmunol 2001;115:91-100.
26Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 2009;73:768-74.
27Chapple IL. Reactive oxygen species and antioxidants in inflammatory diseases. J Clin Periodontol 1997;24:287-96.
28Dahiya P, Kamal R, Gupta R, Bhardwaj R, Chaudhary K, Kaur S. Reactive oxygen species in periodontitis. J Indian Soc Periodontol 2013;17:411-6.
29Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer′s disease. Oxid Med Cell Longev, vol. 2013, Article ID 316523, 10 pages, 2013. doi: 10.1155/2013/316523
30Gatz 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;2:110-7.
31Stein PS, Desrosiers M, Donegan SJ, Yepes JF, Kryscio RJ. Tooth loss, dementia and neuropathology in the Nun study. J Am Dent Assoc 2007;138:1314-22.
32Kim JM, Stewart R, Prince M, Kim SW, Yang SJ, Shin IS, et al. Dental health, nutritional status and recent-onset dementia in a Korean community population. Int J Geriatr Psychiatry 2007;22:850-5.
33Syrjälä AM, Ylöstalo P, Sulkava R, Knuuttila M. Relationship between cognitive impairment and oral health: Results of the Health 2000 Health Examination Survey in Finland. Acta Odontol Scand 2007;65:103-8.
34Yu YH, Kuo HK. Association between cognitive function and periodontal disease in older adults. J Am Geriatr Soc 2008;56:1693-7.
35Wu B, Plassman BL, Crout RJ, Liang J. Cognitive function and oral health among community-dwelling older adults. J Gerontol A Biol Sci Med Sci 2008;63:495-500.
36Stewart R, Sabbah W, Tsakos G, D′Aiuto F, Watt RG. Oral health and cognitive function in the Third National Health and Nutrition Examination Survey (NHANES III). Psychosom Med 2008;70:936-41.
37Okamoto N, Morikawa M, Okamoto K, Habu N, Hazaki K, Harano A, et al. Tooth loss is associated with mild memory impairment in the elderly: The Fujiwara-kyo study. Brain Res 2010;1349:68-75.
38Kaye EK, Valencia A, Baba N, Spiro A 3 rd , Dietrich T, Garcia RI. Tooth loss and periodontal disease predict poor cognitive function in older men. J Am Geriatr Soc 2010;58:713-8.
39Kamer AR, Morse DE, Holm-Pedersen P, Mortensen EL, Avlund K. Periodontal inflammation in relation to cognitive function in an older adult Danish population. J Alzheimers Dis 2012;28:613-24.