Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
Visit old site
Home Print this page Email this page Small font size Default font size Increase font size
Users Online: 2083

 Table of Contents  
Year : 2015  |  Volume : 7  |  Issue : 6  |  Page : 241-246

Association between periodontitis and Alzheimer's disease

1 Department of Periodontology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University, Karad, Satara, India
2 Department of Prosthodontics, Annasaheb Chudaman Patil Memorial Dental College, Dhule, Maharashtra, India
3 Department of Orthodontics, Maratha Mandal Dental College, Belgaum, Karnataka, India
4 Department of Oral and Maxillofacial Surgery, Annasaheb Chudaman Patil Memorial Dental College, Dhule, Maharashtra, India

Date of Web Publication25-Jun-2015

Correspondence Address:
Dr Keshava Abbayya
Department of Periodontology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University, Karad, Satara-415 110, Maharashtra
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1947-2714.159325

Rights and Permissions

Alzheimer's disease (AD) is a neurodegenerative disease which significantly increases with age. Its onset can be either early or late. AD is characterized by the salient inflammatory features, microglial activation, and increased levels of proinflammatory cytokines which contribute to the inflammatory status of the central nervous system (CNS). Whereas, periodontitis is a common oral infection associated with the gram negative anaerobic bacteria. Periodontitis can be marked as a "low-grade systemic disease" by release of proinflammatory cytokines into systemic circulation and elevation of C-reactive protein (CRP). Inflammation is known to play a pivotal role in both the disease process serving as a connecting link between periodontitis and AD. The present review throws a light on possible enigmatic link between AD and periodontitis. This review is designed by collecting data from PubMed database using key words like "Alzheimer's disease", "inflammation", "periodontitis", and "proinflammatory cytokines".

Keywords: Alzheimer′s disease, Inflammation, Periodontitis, Proinflammatory cytokines

How to cite this article:
Abbayya K, Puthanakar NY, Naduwinmani S, Chidambar Y S. Association between periodontitis and Alzheimer's disease. North Am J Med Sci 2015;7:241-6

How to cite this URL:
Abbayya K, Puthanakar NY, Naduwinmani S, Chidambar Y S. Association between periodontitis and Alzheimer's disease. North Am J Med Sci [serial online] 2015 [cited 2023 Feb 3];7:241-6. Available from: https://www.najms.org/text.asp?2015/7/6/241/159325

  Introduction Top

Alzheimer's disease (AD) is a fatal neurodegenerative disease associated with elderly age group and a major health problem in the geriatric subject's worldwide. The incidence of AD significantly increases with age, reaching almost 50% in subjects aged 85 years. [1] As the population ages and life span increases, the prevalence of AD will increase even further and is expected to affect around 14 million people in the next 50 years. A decrease in the prevalence of AD can be achieved by switching to newer treatment approaches which can be effective against probable risk factors for AD and can also delay the onset. [2]

AD could be either early or late onset. Early onset AD is thought to be genetically determined; whereas late onset or sporadic AD, which includes the majority of patients, is believed to be a result of interaction between genetic and environmental factors. Age is a major risk factor for AD. Other risk factors for late onset AD include family history, education, high fat diet, hypertension, diabetes, history of head trauma, and susceptibility genes such as apolipoprotein E (APOE). Among all these risk factors; age, family history, and APOE 4 allele are considered to be accepted risk factors. Periodontitis is also considered to be one of the probable risk factors for AD. It is a chronic inflammation of the tissue surrounding the teeth which is due to complex bacterial interaction, resulting in breakdown and loss of supporting structures around the teeth. The present review elucidates the enigmatic link between AD and periodontitis, showcasing the pathophysiology and possible implications of the association.

AD is characterized by the formation of extracellular amyloid β-peptide (AβP) plaques and intraneuronal neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein, leading to gradual loss of neuronal synapses and ultimately neuronal degeneration with diminution of essential neurotransmitters. [3] Genetic aberration causes increased expression of the amyloid precursor protein (APP) gene which could be a risk factor for late-onset of AD. It is also likely that APOE epsilon 4 (APOEε4) allele is genetically linked to majority of the AD cases.[4]

Pathogenesis of AD

AD has the tendency to induce inflammation, including Aβ-amyloid 1-42 peptide (Aβ42) found in senile plaques, hyperphosphorylated tau protein (P-Tau) comprising the NFTs, or components of degenerated neurons. [3] These pathologic changes in turn are likely to stimulate microglial cells. These microglial cells are protective in nature at low levels (concentration). They help in maintaining a homeostasis in the brain by acting as mononuclear phagocytes against any noxious injury within the central nervous system (CNS). In healthy individuals, microglial cells play a neuroprotective function by clearing the AβP plaques. [5] With advancing age and genetic predisposition, the normal neuroprotective capability of the microglial cells is compromised, resulting in persistence of chronic inflammatory response within the CNS. [6],[7] This results in microglial cells of the brain to direct their phenotypes to produce neurotoxic substances when they are exposed to the systemic inflammatory signals. Such response of the microglial cells contributes to the pathogenesis of AD instead of providing with a protective response to the systemic inflammatory signals. The induced microglial cells now referred to as "activated microglial cells" alters its morphology and secrete cell antigens, which in turn results in uncontrolled expression of proinflammatory factors. This uncontrolled expression of factor levels as in AD can induce neurodegeneration, suggesting that the expression of inflammatory molecules will contribute to the progression of the AD. [8]

Microglial cells in AD

The function of microglial cell is like a "double-edged sword" being either damaging or protective depending on the situation. [9],[10],[11] Stimulated/activated microglial cells produce proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and C-reactive protein (CRP). These elevated proinflammatory cytokines and CRP might then act via paracrine and/or autocrine pathways to stimulate glial cells to further produce additional Aβ42, P-Tau, and proinflammatory molecules. Thus, leading to a pathway where inflammatory mediators play a dual role by both stimulating glial cells and activating molecular pathways, resulting in neurodegeneration. [12] Senile plaques are associated with reactive astrocytes and activated microglial cells which react with antibodies against TNF-α, IL-1β, IL-6, CRP, and complement proteins. [3] TNF-α, IL-1β, and IL-6 are capable of stimulating the synthesis of Aβ42 and the phosphorylation of tau protein, and Aβ42 and P-Tau can in turn stimulate the production of TNF-α, IL-1α, and IL-6 by glial cells. [12],[13],[14]

Research studies have revealed the correlation between value of CRP and other systemic inflammatory markers in the onset of AD. Elevated levels of CRP increase the risk of developing AD in various populations. [15],[16] A case-control study of 1,050 subjects reported that higher levels of CRP increased the risk of developing AD 25 years later. [17],[18] The presence of a composite genotype characterized by the presence of IL-1α-889 and IL-1β + 3953 polymorphisms conferred an almost 11-fold increased risk of developing AD, presumably as a result of increased IL-1 levels. [19]

Mechanisms involved in spread of inflammation to brain

There are two mechanisms involved in the brain which causes an increase in proinflammatory molecules, that is, via systemic circulation and/or neural pathways. In the systemic circulation, proinflammatory molecules enter brain through areas which lack blood brain barrier (BBB). Alternatively these inflammatory molecules can also enter areas in brain with blood brain barrier through:

  1. Fenestrated capillaries of the BBB,
  2. Using cytokine-specific transporters,
  3. Increasing the permeability of BBB, or
  4. Endothelial cells of the brain are activated to produce cytokine-inducing signaling molecules such as nitric oxide or prostanoids.

As the proinflammatory molecules enter the brain, it leads to increase in the local proinflammatory cytokine pool or stimulation of glial cells to synthesize additional proinflammatory cytokines. Alternative pathway through which the cytokines derived from peripheral inflammatory sources might affect the brain is through neuronal pathway. [20] Peripheral cytokines have the capability to stimulate afferent fibers of peripheral nerves, resulting in increased levels of brain cytokines; similarly they can also utilize channels or compartments associated with peripheral nerves to enter the brain.

Other mechanism include the presence of receptors for CD14 present in the brain which can get activated by LPS derived from invasive bacteria or AD AβP, which in turn will activate CD14 cells. These CD14 cells are exposed to systemic circulation such as leptomeninges, circumventricular areas, and choroid plexus; thus increasing further brain cytokines and hypothetically contributing to the inflammatory burden of AD.

Microbiota in AD

The role of bacteria in the pathogenesis of AD is thought to be due to Chlamydia pneumoniae and spirochetes which is emphasized by certain studies conducted. The presence of Borrelia burgdorferi spirochetes were found in the blood and cerebrospinal fluid of patients with AD, and it was also observed that glial and neuronal cells exposed to B. burgdorferi synthesized βAPP and P-taus. [21]

Spirochetes and Treponema denticola are commonly isolated microorganisms in moderate to severe periodontitis. [22] These organisms are also detected in patients with AD suggesting that periodontopathic bacteria can invade the brain by systemic circulation as well as peripheral nerve pathways. Invasion of microorganisms through neuronal pathways is supported by presence of oral treponemas in the trigeminal ganglia. [23],[24] The presence of oral bacteria in systemic circulation is usually expected when heavy bacterial plaques are present. AβP, the main component of amyloid plaques is derived from APP by proteolytic cleavage. Studies support the hypothesis that APP and AβP are instrumental in the pathogenesis of AD. [25]

The stability of microtubules in neurons is maintained by associated tau protein. But hyperphosphorylation of tau takes place as a result of inflammation, oxidative stress, upregulation of tau kinases, and downregulation of phosphatases. [26] This hyperphosphorylated tau is insoluble with low affinity for microtubules, disrupting the microtubule stabilization, thus conducing to synaptic dysfunction and neurodegeneration.

AD was thought to be a disorder related to synthesis and decline in the degradation of AβP. But, with the introduction of "amyloid cascade hypothesis" impaired clearance of AβP is also stated as a cofactor with APP playing a pivotal role. [27]

Studies have shown that, chronic lipopolysaccharide (LPS)-induced neuroinflammation ensues in the elevated levels of intraneuronal AβP in transgenic mice. This may contribute to the deterioration of AD-affected brain. [28],[29],[30]

Periodontal Disease: As a low-grade systemic disease

Periodontal disease (PD) is a condition that causes inflammation and destruction of the gingiva (gums), alveolar bone, and other structures that support the teeth. The etiology of PD is complex involving the presence of pathogenic bacteria found in dental plaque evoking host immune response. PD is a common source of chronic systemic inflammation and immune reactions that result in loss of bone and soft tissue that supports teeth in the jaws. [31]

Periodontitis which is primarily a result of plaque exists in the form of biofilm and consists of numerous microorganisms. Characteristic features of periodontitis include, bleeding and purulent discharge from the gums, progressive deepening of gingival sulcus (referred as pocket formation), oral halitosis, spacing between the teeth, and mobility of teeth in advanced stages. The predominant periodontal pathogens involved in periodontitis are Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Fusobacterium nucleatum (Fn), Tannerella forsythensis (Tf), Eikenella corrodens (Ec), and Treponema denticola (Td). [32],[33]

The inflammatory process in periodontitis extends from the gingiva (gums) into deeper connective tissues, resulting in the loss of connective tissue and bone mainly through the activation of host-derived osteoclasts and matrix metalloproteinases (MMP). The connective tissue adjacent to the pocket epithelium is infiltrated with intense inflammatory cells consisting of polymorphonuclear leukocytes, monocyte/macrophages, T- and B-cells mediated by a multitude of cytokines and chemokines, and most of them produced by the inflammatory cells themselves. [34] This low grade inflammation is conceived to perturb the general systemic health and exasperate other systemic disorders. Therefore, chronic periodontitis can be a significant source of covert peripheral inflammation within the general population. [35] Thus, periodontitis can be marked as a "low-grade systemic disease".

Periodontitis is basically a result of inflammation caused due to wide array of pathogenic microorganisms [Figure 1]. These microorganisms release numerous proteolytic enzymes, resulting in destruction of soft and hard tissues supporting the teeth. Release of LPSs from the gram negative bacteria results in the expression of proinflammatory factors/cytokines like IL-1α and -1β, IL-6, TNF-α, prostanoids, MMP, and by the host tissue cells (neutrophils and monocytes); ultimately paving way to more destruction of periodontal tissues. Hence, host response plays a role of diabolical "dual role" leading to self-destruction, due to the exaggerated expression of tissue proteolytic enzymes. [36]
Figure 1: Pathogenesis of periodontitis

Click here to view

Microorganisms involved in periodontitis can elicit systemic effects through various mechanisms [Figure 2].
Figure 2: Systemic outcomes due to periodontal diseases

Click here to view

  • Periodontal bacteria and their products could be aspirated, which could induce pulmonary pathology.
  • Periodontal pathogens have the capability to gain access to systemic circulation and subsequently colonize different distant anatomic sites in the body. For example, periodontal bacteria have been implicated in several systemic diseases including endocarditis and brain abscesses [Figure 3].
    Figure 3: Possible pathway between periodontal infection and AD

    Click here to view
  • Periodontal bacteria and their products can disseminate through systemic circulation in pregnant woman inducing inflammatory changes and resulting in preterm low birth weight infants.
  • Chronic adult periodontitis has been associated with several conditions including increased risk of atherosclerotic complications, myocardial infarction, stroke, poorly controlled diabetes mellitus, and possibly with AD. [37]
  • The host response also plays a vital role in inducing systemic effects by producing a multitude of inflammatory mediators including cytokines (against the periodontal microbiota) that gain access to the systemic circulation.

The isolation of periodontal microbiota from various samples obtained from respiratory tract, atheromatous plaque in the heart, brain, vaginal smears, and also from patients suffering from rheumatoid arthritis reveals a possible association of periodontitis with systemic diseases.

AD and periodontitis - A correlation

Inflammation is known to play a pivotal role in this process. It is proposed that periodontitis can lead to progression of AD by two probable mechanisms.

Two mechanisms have been put forth to explain the association of periodontitis and AD.

  1. According to the first mechanism, periodontopathic microorganisms and the host response cause an increase in the levels of proinflammatory cytokines. This results in an array of cytokines and pro-inflammatory agents that are spurted out in systemic circulation leading to systemic inflammatory burden resulting in a state of systemic/peripheral inflammation. These proinflammatory molecules are capable of compromising the BBB and entering the cerebral regions. This leads to priming/activation of microglial cells and the adverse repercussions leading to neuronal damage.
  2. The second mechanism is thought to be due to invasion of brain by microorganisms present in the dental plaque biofilm. The microorganisms in the dental plaque can enter brain either through blood stream or via peripheral nerves. These microorganisms and their products elicit an inflammatory mechanism within the CNS. It is generally accepted with appreciable evidence that presence of inflammation in the CNS results in cognitive impairment, such as that seen in AD. This inflammatory impairment is attributed to cytokine arbitrated interactions between neurons and glial cells. Cytokines released due to inflammation include IL family, TNF-α, transforming growth factor-β, and chemokines (monocyte chemotactic protein, IL-8, macrophage migration inhibitory factor, and monokine induced by γ-interferon) that have also been implicated as serum and plasma biomarkers for pathogenesis of AD. [38] Cytokines which are released (especially TNF-α) during inflammation play a major role in neurodegenerative disease. TNF-α exaggerates the inflammatory process resulting in gliosis, demyelination, BBB deterioration, and cell death. Thus, TNF-α plays a very important role in the neurodegenerative process. [39],[40] Anti-inflammatory agents indicated during any inflammatory conditions markedly reduce the effects of these cytokines and other proinflammatory molecules. Studies conducted on mice models have revealed salutary effects of anti-inflammatory agents in the amelioration of neuroinflammation and amyloid plaque deposition. Alongside, there is also a significant reduction in the levels of IL-1β and glial fibrillary acidic protein levels in mice treated with nonsteroidal anti-inflammatory agent. [41],[42]

The role of anti-inflammatory agents has been studied by Alzheimer's disease Anti-inflammatory Prevention Trial (ADAPT) and hypothesized that the beneficial effect of anti-inflammatory drugs is evident only in the early, asymptomatic, phases of the disease. In individuals with AD, elevated IL-1β predicted rates of cognitive decline. [43] Patients with elevated markers preceding a baseline levels showed a greater rate of cognitive decline over a 2-month follow-up period than those who did not have elevated levels prior to baseline. Similarly, dementia is also considered to be a complex disorder associated with an interaction between genetics and diseases related to systemic inflammation. Elevated blood inflammatory markers predict risk for dementia and incidence of cognitive impairment. Cross-sectional and longitudinal studies have revealed dementia in subjects with poor oral health. Thus, Periodontitis which leads to the presence of inflammatory molecules in systemic circulation is thought to be a definite risk factor for developing a variety of systemic diseases including AD. [42]

  Conclusion Top

Inflammation could serve as a connecting link between periodontitis and AD. However; in the literature, there are no animal studies specifically addressing the causal relationship of periodontal inflammation to AD. Since periodontitis has a tendency to infiltrate the systemic circulation with inflammatory mediators and result in systemic disease outcome; thus, it would always be advisable and better option to prevent periodontal disease progression to prevent further systemic outcomes.

  References Top

Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al., Alzheimer's Disease International. Global prevalence of dementia: A Delphi consensus study. Lancet 2005;366:2112-7.  Back to cited text no. 1
Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanskad L, de Leon MJ. Inflammation and Alzheimer's disease: Possible role of periodontal diseases. Alzheimers Dement 2008;4:242-50.  Back to cited text no. 2
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421.  Back to cited text no. 3
Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: Back to the future. Neuron 2010;68:270-81.  Back to cited text no. 4
Fetler L, Amigorena S. Neuroscience. Brain under surveillance: The microglia patrol. Science 2005;309:392-3.  Back to cited text no. 5
Schram MT, Euser SM, de Craen AJ, Witteman JC, Frolich M, Hofman A, et al. Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc 2007;55: 708-16.  Back to cited text no. 6
Arosio B, Trabattoni D, Galimberti L, Bucciarelli P, Fasano F, Calabresi C, et al. Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer's disease. Neurobiol Aging 2004;25:1009-15.  Back to cited text no. 7
von Bernhardi R, Eugenin J. Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors. Brain Res 2004;1025:186-93.  Back to cited text no. 8
Weitz TM, Town T. Microglia in Alzheimer's disease: It's all about context. Int J Alzheimers Dis 2012;2012:314185.  Back to cited text no. 9
Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 2007;7:161-7.  Back to cited text no. 10
Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci 2005;25:8843-53.  Back to cited text no. 11
McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 2001;22:799-809.  Back to cited text no. 12
Konsman JP, Drukarch B, Van Dam AM. (Peri) vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci (Lond) 2007;112:1-25.  Back to cited text no. 13
Gosselin D, Rivest S. Role of IL-1 and TNF in the brain: Twenty years of progress on a Dr. Jekyll/Mr Hyde duality of the innate immune system. Brain Behav Immun 2007;21:281-9.  Back to cited text no. 14
Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, et al. Inflammatory proteins in plasma and the risk of dementia: The rotterdam study. Arch Neurol 2004;61:668-72.  Back to cited text no. 15
Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004;292:2237-42.  Back to cited text no. 16
Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: A 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 2002;52:168-74.  Back to cited text no. 17
Kalman J, Juhasz A, Laird G, Dickens P, Jardanhazy T, Rimanóczy A, et al. Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease. Acta Neurol Scand 1997;96:236-40.  Back to cited text no. 18
Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilcock G, MacGowan S, et al. Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann Neurol 2000;47:365-8.  Back to cited text no. 19
Dantzer R, Konsman JP, Bluthe RM, Kelley KW. Neural and humoral pathways of communication from the immune system to the brain: Parallel or convergent? Auton Neurosci 2000;85:60-5.  Back to cited text no. 20
Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, et al. Beta-amyloid deposition and Alzheimer's type changes induced by Borrelia spirochetes. Neurobiol Aging 2006;27:228-36.  Back to cited text no. 21
Ellen RP, Galimanas VB. Spirochetes at the forefront of periodontal infections. Periodontol 2000. 2005;38:13-32.  Back to cited text no. 22
Riviere 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.  Back to cited text no. 23
Foschi F, Izard J, Sasaki H, Sambri V, Prati C, Muller R, et al. Treponema denticola in disseminating endodontic infections. J Dent Res 2006;85:761-5.  Back to cited text no. 24
Galimberti D, Scarpini E. Progress in Alzheimer's disease. J Neurol 2012;259:201-11.  Back to cited text no. 25
Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inflammation and Alzheimer's disease. Arch Pharm Res 2010;33:1539-56.  Back to cited text no. 26
Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P. Alzheimer culprits: Cellular crossroads and interplay. Cell Signal 2012;24:1831-40.  Back to cited text no. 27
Miller AJ, Luheshi GN, Rothwell NJ, Hopkins SJ. Local cytokine induction by LPS in the rat air pouch and its relationship to the febrile response. Am J Physiol 1997;272:R857-61.  Back to cited text no. 28
Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 2008;5:37.  Back to cited text no. 29
Tan ZS, Seshadri S. Inflammation in the Alzheimer's disease cascade: Culprit or innocent bystander? Alzheimers Res Ther 2010;2:6.  Back to cited text no. 30
Garcia RI, Henshaw MM, Krall EA. Relationship between periodontal disease and systemic health. Periodontol 2000. 2001;25:21-36.  Back to cited text no. 31
Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontol 2000. 2005;38:135-87.  Back to cited text no. 32
Filoche S, Wong L, Sissons CH. Oral biofilms: Emerging concepts in microbial ecology. J Dent Res 2010;89:8-18.  Back to cited text no. 33
Taubman MA, Valverde P, Han X, Kawai T. Immune response: The key to bone resorption in periodontal disease. J Periodontol 2005;76:2033-41.  Back to cited text no. 34
D'Aiuto F, Graziani F, Tetè S, Gabriele M, Tonetti MS. Periodontitis: From local infection to systemic diseases. Int J Immunopathol Pharmacol 2005;18:1-11.  Back to cited text no. 35
Preshaw PM, Taylor JJ. How has research into cytokine interactions and their role in driving immune responses impacted our understanding of periodontitis? J Clin Periodontol 2011;38:60-84.  Back to cited text no. 36
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: 110-7.  Back to cited text no. 37
Lee KS, Chung JH, Choi TK, Suh SY, Oh BH, Hong CH. Peripheral cytokines and chemokines in Alzheimer's disease. Dement Geriatr Cogn Disord 2009;28:281-7.  Back to cited text no. 38
Park KM, Bowers WJ. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 2010;22:977-83.  Back to cited text no. 39
Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 2012;7:42-59.  Back to cited text no. 40
Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, et al. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 2003;23:7504-9.  Back to cited text no. 41
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, et al. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 2005;128:1442-53.  Back to cited text no. 42
Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2003;74:788-9.  Back to cited text no. 43


  [Figure 1], [Figure 2], [Figure 3]

This article has been cited by
1 Identification of a Czc-like operon of the periodontal pathobiont P. gingivalis involved in metal ion efflux
A.F. Gains, D.W. Lambert, G.P. Stafford
Anaerobe. 2023; : 102696
[Pubmed] | [DOI]
2 The link between periodontitis and Alzheimer's disease – emerging clinical evidence
David T. Wu, Ye Won Cho, Matthew D. Spalti, Mark Bishara, Thomas T. Nguyen
Dentistry Review. 2023; 3(1): 100062
[Pubmed] | [DOI]
3 Fusobacterium nucleatum and its associated systemic diseases: epidemiologic studies and possible mechanisms
Zixin Fan, Pengzhou Tang, Cheng Li, Qi Yang, Yan Xu, Chuan Su, Lu Li
Journal of Oral Microbiology. 2023; 15(1)
[Pubmed] | [DOI]
4 Dementia Prevention in Clinical Practice
Kellyann Niotis, Kiarra Akiyoshi, Caroline Carlton, Richard Isaacson
Seminars in Neurology. 2022;
[Pubmed] | [DOI]
5 Purification, crystallization and crystallographic analysis of the PorX response regulator associated with the type IX secretion system
Anshu Saran, Nuwani Weerasinghe, Christopher J. Thibodeaux, Natalie Zeytuni
Acta Crystallographica Section F Structural Biology Communications. 2022; 78(10): 354
[Pubmed] | [DOI]
6 Periodontal microorganisms and Alzheimer disease – A causative relationship?
Gert Jungbauer, Alexandra Stähli, Xilei Zhu, Lavinia Auber Alberi, Anton Sculean, Sigrun Eick
Periodontology 2000. 2022;
[Pubmed] | [DOI]
7 Neuroimmune contributions to Alzheimer’s disease: a focus on human data
Verena Haage, Philip L. De Jager
Molecular Psychiatry. 2022;
[Pubmed] | [DOI]
8 The Role of Gut Microbiota in the Pathogenesis of Alzheimer’s Disease
Shaoqiang Sun, Jingwei Mao, Yingde Wang
Journal of Biomaterials and Tissue Engineering. 2022; 12(12): 2483
[Pubmed] | [DOI]
9 When the infectious environment meets the AD brain
Tal Ganz, Nina Fainstein, Tamir Ben-Hur
Molecular Neurodegeneration. 2022; 17(1)
[Pubmed] | [DOI]
10 The Periodontal Pathogen Fusobacterium nucleatum Exacerbates Alzheimer’s Pathogenesis via Specific Pathways
Hongle Wu, Wei Qiu, Xiaofang Zhu, Xiangfen Li, Zhongcong Xie, Isabel Carreras, Alpaslan Dedeoglu, Thomas Van Dyke, Yiping W. Han, Nadeem Karimbux, Qisheng Tu, Lei Cheng, Jake Chen
Frontiers in Aging Neuroscience. 2022; 14
[Pubmed] | [DOI]
11 Implications of Microorganisms in Alzheimer’s Disease
Pardeep Yadav, Yeon-Hee Lee, Hrithika Panday, Shubham Kant, Neha Bajwa, Ritika Parashar, Saurabh Kumar Jha, Niraj Kumar Jha, Parma Nand, Sang-Soo Lee, Abhimanyu Kumar Jha
Current Issues in Molecular Biology. 2022; 44(10): 4584
[Pubmed] | [DOI]
12 Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies
Arkadiusz Dziedzic
International Journal of Molecular Sciences. 2022; 23(23): 15320
[Pubmed] | [DOI]
13 Do Oral Pathogens Inhabit the Eye and Play a Role in Ocular Diseases?
Pachiappan Arjunan, Radhika Swaminathan
Journal of Clinical Medicine. 2022; 11(10): 2938
[Pubmed] | [DOI]
14 Does Dementia Have a Microbial Cause?
Remi L. Landry, Monica E. Embers
NeuroSci. 2022; 3(2): 262
[Pubmed] | [DOI]
15 Memory Impairment, Pro-Inflammatory Host Response and Brain Histopathologic Severity in Rats Infected with K. pneumoniae or P. aeruginosa Meningitis
Bassma H. Elwakil, Basant A. Bakr, Mohammed M. Aljeldah, Nourhan S. Shehata, Yahya H. Shahin, Zakia A. Olama, Maria Augustyniak, Mourad A. M. Aboul-Soud, Abeer El Wakil
Pathogens. 2022; 11(8): 933
[Pubmed] | [DOI]
16 Infection of Porphyromonas gingivalis in Alzheimer’s Disease and the Suppression of Immunity
CitraFeriana Putri, EndangWiniati Bachtiar
Dental Hypotheses. 2021; 12(4): 174
[Pubmed] | [DOI]
17 Young at Gut—Turning Back the Clock with the Gut Microbiome
Harish Narasimhan,Clarissa C. Ren,Sharvari Deshpande,Kristyn E. Sylvia
Microorganisms. 2021; 9(3): 555
[Pubmed] | [DOI]
18 Nutrition as a Key Modifiable Factor for Periodontitis and Main Chronic Diseases
Prescilla Martinon,Laurie Fraticelli,Agnes Giboreau,Claude Dussart,Denis Bourgeois,Florence Carrouel
Journal of Clinical Medicine. 2021; 10(2): 197
[Pubmed] | [DOI]
19 Exploring the Connection between Porphyromonas gingivalis and Neurodegenerative Diseases: A Pilot Quantitative Study on the Bacterium Abundance in Oral Cavity and the Amount of Antibodies in Serum
Raffaella Franciotti,Pamela Pignatelli,Claudia Carrarini,Federica Maria Romei,Martina Mastrippolito,Antonella Gentile,Rosa Mancinelli,Stefania Fulle,Adriano Piattelli,Marco Onofrj,Maria Cristina Curia
Biomolecules. 2021; 11(6): 845
[Pubmed] | [DOI]
20 Porphyromonas Gingivalis as a Risk Factor to Alzheimer’s Disease: A Systematic Review
Abdelrahman Elwishahy, Khatia Antia, Sneha Bhusari, Nkorika Chiamaka Ilechukwu, Olaf Horstick, Volker Winkler
Journal of Alzheimer's Disease Reports. 2021; 5(1): 721
[Pubmed] | [DOI]
21 The Association of Periodontitis and Alzheimer’s Disease: How to Hit Two Birds with One Stone
Tom Werber, Zsofia Bata, Eniko Szabo Vaszine, Dalida Borbala Berente, Anita Kamondi, Andras Attila Horvath
Journal of Alzheimer's Disease. 2021; 84(1): 1
[Pubmed] | [DOI]
22 Associations between depression and gingivitis among adolescents resident in semi-urban South-West Nigeria
Morenike Oluwatoyin Folayan,Maha El Tantawi,Nneka Maureen Chukwumah,Michael Alade,Boladale Mapayi,Olakunle Oginni,Olaniyi Arowolo,Nadia A. Sam-Agudu
BMC Oral Health. 2021; 21(1)
[Pubmed] | [DOI]
23 Assessment of common infections and incident dementia using UK primary and secondary care data: a historical cohort study
Rutendo Muzambi,Krishnan Bhaskaran,Liam Smeeth,Carol Brayne,Nish Chaturvedi,Charlotte Warren-Gash
The Lancet Healthy Longevity. 2021;
[Pubmed] | [DOI]
24 Dose-Response Meta-Analysis on Tooth Loss With the Risk of Cognitive Impairment and Dementia
Xiang Qi,Zheng Zhu,Brenda L. Plassman,Bei Wu
Journal of the American Medical Directors Association. 2021;
[Pubmed] | [DOI]
25 Pathophysiological association between periodontal disease and Alzheimeræs disease: Importance of periodontal health in the elderly
Natnael Teshome Desta
Journal of Oral Biosciences. 2021;
[Pubmed] | [DOI]
26 Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer’s pathology: Insights and therapeutic approaches from periphery
Rahat Ullah,Tae Ju Park,Xu Huang,Myeong Ok Kim
Ageing Research Reviews. 2021; 71: 101451
[Pubmed] | [DOI]
27 One-step, wash-free, bead-based immunoassay employing bound-free phase detection
Benita Johannsen,Michal Karpíšek,Desirée Baumgartner,Vanessa Klein,Nagihan Bostanci,Nils Paust,Susanna M. Früh,Roland Zengerle,Konstantinos Mitsakakis
Analytica Chimica Acta. 2021; : 338280
[Pubmed] | [DOI]
28 Shared Molecular Mechanisms between Alzheimer’s Disease and Periodontitis Revealed by Transcriptomic Analysis
Jieqi Jin,Mengkai Guang,Anthony Chukwunonso Ogbuehi,Simin Li,Kai Zhang,Yihong Ma,Aneesha Acharya,Bihan Guo,Zongwu Peng,Xiangqiong Liu,Yupei Deng,Zhaobi Fang,Xiongjie Zhu,Shiting Hua,Cong Li,Rainer Haak,Dirk Ziebolz,Gerhard Schmalz,Lei Liu,Baohua Xu,Juan Yang,Xiaofeng Huang
BioMed Research International. 2021; 2021: 1
[Pubmed] | [DOI]
29 Clinical significance of ragA , ragB , and PG0982 genes in Porphyromonas gingivalis isolates from periodontitis patients
Kübra Bunte,Christina Kuhn,Carolin Walther,Ulrike Peters,Ghazal Aarabi,Ralf Smeets,Thomas Beikler
European Journal of Oral Sciences. 2021;
[Pubmed] | [DOI]
30 Implication of thyroid function in periodontitis: a nationwide population-based study
Eyun Song, Min Jeong Park, Jung A. Kim, Eun Roh, Ji Hee Yu, Nam Hoon Kim, Hye Jin Yoo, Ji A. Seo, Sin Gon Kim, Nan Hee Kim, Sei Hyun Baik, Kyung Mook Choi
Scientific Reports. 2021; 11(1)
[Pubmed] | [DOI]
31 Effect of cranberry juice deacidification on its antibacterial activity against periodontal pathogens and its anti-inflammatory properties in an oral epithelial cell model
Geneviève Pellerin,Laurent Bazinet,Daniel Grenier
Food & Function. 2021;
[Pubmed] | [DOI]
32 Can chronic oral inflammation and masticatory dysfunction contribute to cognitive impairment?
Matthew R. Nangle,Nithin Manchery
Current Opinion in Psychiatry. 2020; 33(2): 156
[Pubmed] | [DOI]
33 Eye on the Enigmatic Link: Dysbiotic Oral Pathogens in Ocular Diseases; The Flip Side
Pachiappan Arjunan
International Reviews of Immunology. 2020; : 1
[Pubmed] | [DOI]
34 Risk of dementia in patients with periodontitis and related protective factors: A nationwide retrospective cohort study
Chia-Yen Lee,Chuen-Chau Chang,Chao-Shun Lin,Chun-Chieh Yeh,Chaur-Jong Hu,Ching-Zong Wu,Ta-Liang Chen,Chien-Chang Liao
Journal of Clinical Periodontology. 2020;
[Pubmed] | [DOI]
35 Targeting Infectious Agents as a Therapeutic Strategy in Alzheimer’s Disease
Tamàs Fülöp,Usma Munawara,Anis Larbi,Mathieu Desroches,Serafim Rodrigues,Michele Catanzaro,Andrea Guidolin,Abdelouahed Khalil,François Bernier,Annelise E. Barron,Katsuiku Hirokawa,Pascale B. Beauregard,David Dumoulin,Jean-Philippe Bellenger,Jacek M. Witkowski,Eric Frost
CNS Drugs. 2020;
[Pubmed] | [DOI]
36 Detecting dental problem related brain disease using intelligent bacterial optimized associative deep neural network
Nourelhoda M. Mahmoud,H. Fouad,Omar Alsadon,Ahmed M. Soliman
Cluster Computing. 2020;
[Pubmed] | [DOI]
37 Environmental Toxins and Alzheimer’s Disease Progression
Maryam Vasefi,Ehsan Ghabolian-Zare,Hamzah Abedelwahab,Anthony Osu
Neurochemistry International. 2020; : 104852
[Pubmed] | [DOI]
38 Sodium Butyrate and Indole-3-propionic Acid Prevent the Increase of Cytokines and Kynurenine Levels in LPS-induced Human Primary Astrocytes
Michelle L Garcez, Vanessa X Tan, Benjamin Heng, Gilles J Guillemin
International Journal of Tryptophan Research. 2020; 13: 1178646920
[Pubmed] | [DOI]
39 Do epigenetic changes caused by commensal microbiota contribute to development of ocular disease? A review of evidence
Ashima Nayyar,Sofya Gindina,Arturo Barron,Yan Hu,John Danias
Human Genomics. 2020; 14(1)
[Pubmed] | [DOI]
40 Infectious agents as a risk factor for Alzheimer’s disease
S. V. Vorobyev,K. V. Shalepo,E. V. Spasibova,A. M. Savicheva,A. N. Grigor’ev
Journal Infectology. 2020; 12(1): 5
[Pubmed] | [DOI]
41 Analgesic and Neuroprotective Effects of Electroacupuncture in a Dental Pulp Injury Model—A Basic Research
Sharmely Sharon Ballon Romero,Yu-Chen Lee,Lih-Jyh Fuh,Hsin-Yi Chung,Shih-Ya Hung,Yi-Hung Chen
International Journal of Molecular Sciences. 2020; 21(7): 2628
[Pubmed] | [DOI]
42 The Viral Hypothesis in Alzheimer’s Disease: Novel Insights and Pathogen-Based Biomarkers
Sean X Naughton,Urdhva Raval,Giulio M. Pasinetti
Journal of Personalized Medicine. 2020; 10(3): 74
[Pubmed] | [DOI]
43 Severe periodontitis with tooth loss as a modifiable risk factor for the development of Alzheimer, vascular, and mixed dementia: National Health Insurance Service-National Health Screening Retrospective Cohort 2002–2015
Do-hyung Kim,Seong-Nyum Jeong,Jae-Hong Lee
Journal of Periodontal & Implant Science. 2020; 50
[Pubmed] | [DOI]
44 Infection-Induced Systemic Inflammation Is a Potential Driver of Alzheimeræs Disease Progression
Vijayasree V. Giridharan,Faisal Masud,Fabricia Petronilho,Felipe Dal-Pizzol,Tatiana Barichello
Frontiers in Aging Neuroscience. 2019; 11
[Pubmed] | [DOI]
45 Apelin-APJ axis inhibits TNF-alpha-mediated expression of genes involved in the inflammatory response in periodontal ligament cells
Gyuseok Lee,Won-Hyun Song,Su-Jin Kim,Young-Gwon Kim,Je-Hwang Ryu
International Journal of Oral Biology. 2019; 44(4): 182
[Pubmed] | [DOI]
46 Association of Chronic Periodontitis on Alzheimeræs Disease or Vascular Dementia
Seulggie Choi,Kyuwoong Kim,Jooyoung Chang,Sung Min Kim,Seon Jip Kim,Hyun-Jae Cho,Sang Min Park
Journal of the American Geriatrics Society. 2019;
[Pubmed] | [DOI]
47 Lactobacillus helveticus SBT2171 upregulates the expression of ß-defensin and ameliorates periodontal disease caused by Porphyromonas gingivalis
Eiji Kobatake,Ryoki Kobayashi,Toshihide Kabuki,Tomoko Kurita-Ochiai
Microbiology and Immunology. 2019;
[Pubmed] | [DOI]
48 Chronic oral infection: An emerging risk factor of cerebral small vessel disease
Ghazal Aarabi,Götz Thomalla,Guido Heydecke,Udo Seedorf
Oral Diseases. 2018;
[Pubmed] | [DOI]
49 Genetic Relationship Between IL-6 rs1800796 Polymorphism and Susceptibility to Periodontitis
Bo Zhao,Xiaoqian Li,Ronghua Li
Immunological Investigations. 2018; : 1
[Pubmed] | [DOI]
50 Photoacoustic imaging for monitoring periodontal health: A first human study
Colman Moore,Yuting Bai,Ali Hariri,Joan B. Sanchez,Ching-Yu Lin,Sreenivas Koka,Parish Sedghizadeh,Casey Chen,Jesse V. Jokerst
Photoacoustics. 2018; 12: 67
[Pubmed] | [DOI]
51 The Possibility of an Infectious Etiology of Alzheimer Disease
Ghulam M. Ashraf,Vadim V. Tarasov,Alfiya Makhmutov?,Vladimir N. Chubarev,Marco Avila-Rodriguez,Sergey O. Bachurin,Gjumrakch Aliev
Molecular Neurobiology. 2018;
[Pubmed] | [DOI]
52 Oral health in Alzheimer’s disease: a multicenter case-control study
F. Aragón,M. A. Zea-Sevilla,J. Montero,P. Sancho,R. Corral,C. Tejedor,B. Frades-Payo,V. Paredes-Gallardo,A. Albaladejo
Clinical Oral Investigations. 2018;
[Pubmed] | [DOI]
53 Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review
Xinhua Zhan,Boryana Stamova,Frank R. Sharp
Frontiers in Aging Neuroscience. 2018; 10
[Pubmed] | [DOI]
54 Quantification by qPCR of Pathobionts in Chronic Periodontitis: Development of Predictive Models of Disease Severity at Site-Specific Level
Inmaculada Tomás,Alba Regueira-Iglesias,Maria López,Nora Arias-Bujanda,Lourdes Novoa,Carlos Balsa-Castro,Maria Tomás
Frontiers in Microbiology. 2017; 8
[Pubmed] | [DOI]
55 Periodontitis and Alzheimer’s Disease: A Possible Comorbidity between Oral Chronic Inflammatory Condition and Neuroinflammation
Francisco B. Teixeira,Miki T. Saito,Filipe C. Matheus,Rui D. Prediger,Elizabeth S. Yamada,Cristiane S. F. Maia,Rafael R. Lima
Frontiers in Aging Neuroscience. 2017; 9
[Pubmed] | [DOI]
56 In vivo and In vitro Identification of Endocannabinoid Signaling in Periodontal Tissues and Their Potential Role in Local Pathophysiology
Anna Konermann,Andreas Jäger,Stefanie A. E. Held,P. Brossart,Anne Schmöle
Cellular and Molecular Neurobiology. 2017;
[Pubmed] | [DOI]
57 Melatonin and periodontal tissues: Molecular and clinical perspectives
Agata Rita Carpentieri,María Elena Peralta Lopez,Javier Aguilar,Verónica Mariana Solá
Pharmacological Research. 2017; 125: 224
[Pubmed] | [DOI]
58 A systemic view of Alzheimer disease — insights from amyloid-ß metabolism beyond the brain
Jun Wang,Ben J. Gu,Colin L. Masters,Yan-Jiang Wang
Nature Reviews Neurology. 2017; 13(10): 612
[Pubmed] | [DOI]
59 Cytokine-based Predictive Models to Estimate the Probability of Chronic Periodontitis: Development of Diagnostic Nomograms
I. Tomás,N. Arias-Bujanda,M. Alonso-Sampedro,M. A. Casares-de-Cal,C. Sánchez-Sellero,D. Suárez-Quintanilla,C. Balsa-Castro
Scientific Reports. 2017; 7(1)
[Pubmed] | [DOI]
60 Periodontal disease and women’s health
Maria Luisa Martelli,Maria Luisa Brandi,Marialaura Martelli,Piero Nobili,Enzo Medico,Francesco Martelli
Current Medical Research and Opinion. 2017; : 1
[Pubmed] | [DOI]
61 Are Chronic Periodontitis and Gingivitis Associated with Dementia? A Nationwide, Retrospective, Matched-Cohort Study in Taiwan
Nian-Sheng Tzeng, Chi-Hsiang Chung, Chin-Bin Yeh, Ren-Yeong Huang, Da-Yo Yuh, San-Yuan Huang, Ru-Band Lu, Hsin-An Chang, Yu-Chen Kao, Wei-Shan Chiang, Yu-Ching Chou, Wu-Chien Chien
Neuroepidemiology. 2016; 47(2): 82
[Pubmed] | [DOI]
62 Procaine Inhibits Osteo/Odontogenesis through Wnt/ß-Catenin Inactivation
Carmen Herencia,Juan Miguel Diaz-Tocados,Lidia Jurado,Addy Montes de Oca,Maria Encarnación Rodríguez-Ortiz,Carmen Martín-Alonso,Julio M. Martínez-Moreno,Noemi Vergara,Mariano Rodríguez,Yolanda Almadén,Juan R. Muñoz-Castañeda,Rajeev Samant
PLOS ONE. 2016; 11(6): e0156788
[Pubmed] | [DOI]
63 Alzheimeræs disease lymphocytes: potential for biomarkers?
Urszula Wojda
Biomarkers in Medicine. 2016; 10(1): 1
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Article Figures

 Article Access Statistics
    PDF Downloaded1806    
    Comments [Add]    
    Cited by others 63    

Recommend this journal