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In 2019, widely publicized findings indicated that bacteria commonly thought to be a key pathogen in periodontitis, Porphyromonas gingivalis, also have a role in Alzheimer's disease; enzymes (gingipains) secreted by P. gingivalis were identified in the brain tissues of individuals with pathology and symptoms of Alzheimer's disease at higher levels than in the brains of individuals without such symptoms.1 An additional 10-year, prospective cohort study found that in a group of 262,349 older Korean adults, periodontitis at baseline increased the risk of developing Alzheimer's disease by 6% and all dementias by 5% over the study period.2 These reports have sparked interest in the potential role of periodontal diseases in development of Alzheimer's and other dementias. It is, however, important to note that the data examining a potential bacterial initiator for dementia use a cross-sectional analysis of tissues and that gingipains were found in 96% of all tissues assessed. These reports build on prior animal studies that have indicated that chronic oral application of P. gingivalis or the gingipains it produces increase the production of amyloid beta, a component of the amyloid plaques whose accumulation contributes to Alzheimer's disease.3 Although prospective trials are necessary to identify causation or common disease pathways, recent reports have speculated that periodontal health may be critical in this population.
Previous research has indicated that patients with periodontal disease are up to 70% more likely to present with Alzheimer's disease than those who are periodontally healthy.4,5 This association may be attributable to poorer oral hygiene over time due to deficits associated with dementia, dementia patients' resistance to caregiver delivery of oral care, medication-induced xerostomia, or other challenges associated with suboptimal biofilm removal and disruption for patients with dementia, leading to larger dental plaque masses or more pathologic intraoral bacteria. Additionally, shifts within oral biofilm, particularly subgingivally, can lead to dysbiosis, resulting in increased overall host response and destruction of soft and hard tissue.6 It has also been hypothesized that this interaction may be mediated by inflammation, the periodontal microbiome, and the immune reactions to those pathogens.7,8 The elderly population (individuals older than 65 years) in the United States is expected to nearly double from 43.1 million in 2014 to 83.7 million by the year 2050.9 Currently, more than 5 million adults, approximately 13.9% of older adults in the United States, have dementia.10 Additionally, the rate of total edentulism for all Americans is dropping and is expected to reach as low as 2.6% by 2050, which, accounting for estimations of population growth and aging, represents a 30% decrease in overall edentulism.11 Consequently, many more individuals with dementia, who require care for their activities of daily living, will be dentate, and thus oral hygiene will become a more integral part of caring for individuals with dementia. Adding to this challenge, medications for dementia often increase symptoms of xerostomia, and higher caries rates are seen in patients with dementia; these factors are particularly evident in patients with moderate to severe disease and those who reside in residential nursing care facilities.12,13 This "grey tsunami" of an aging population and increased tooth retention will require protocols not only to minimize periodontal inflammation, but also to allow effective oral home care for patients with dementia, while minimizing their behaviors that are resistant to care, and improved nonsurgical interventions for patients with caries or periodontal diseases.14-16 Despite these efforts, surgical approaches, including provision of dental care with sedation or anesthesia, may be required.
Epidemiology and Classification of Dementia
Dementia is not a natural consequence of aging, and it is not simply extreme forgetfulness. It is a generally progressive chronic syndrome in which patients experience a deterioration in memory, thinking, behavior, and the ability to perform everyday activities.17 Dementia is described in the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) as:
A syndrome due to disease of the brain, usually of a chronic or progressive nature, in which there is a disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement. Consciousness is not clouded. The impairments of cognitive function are commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior, or motivation. This syndrome occurs in Alzheimer's disease, in cerebrovascular disease, and in other conditions primarily or secondarily affecting the brain.18
Nearly 10 million individuals are diagnosed with new cases of dementia each year worldwide, and that number is expected to increase with increasing life expectancy.17 In 2015, the economic costs in the United States associated with dementia were approximately $818 billion.17
Prevalence and Distribution of Patients With Dementia
Dementia rates are growing at an alarming proportion in all regions of the world and are related to population aging.19 Neurologic conditions, including dementia, were estimated by the Global Burden of Disease Study 2010 as the third leading cause of years lived with disability at a global level.20
The prevalence of dementia increases dramatically in the older members of the elderly population. Approximately 2% to 3% of those aged 70 to 75 years are affected with dementia, whereas 20% to 25% of individuals 85 years or older have some form of the disease.21 Data tracking prevalence in individuals older than 85 years is limited; therefore, it is not clear whether dementia prevalence continues to increase or stabilizes in those individuals.22 Particularly in very old age (older than 90 years), women have slightly greater probability to develop dementia than men, mainly due to an age-adjusted increased risk of Alzheimer's disease (relative risk = 1.3).23
Common Causes of Dementia
Alzheimer's disease is the most common form of dementia, causing approximately two-thirds of all cases of dementia. Other major forms are vascular dementia (affecting up to 20% of patients with dementia), dementia with Lewy bodies (approximately 15% of all dementia cases), and frontotemporal dementia (less than 5% of dementia cases).24 The boundaries between different forms of dementia are indistinct, and mixed forms, as well as dementia as a comorbidity with other diseases, may coexist.17 Additionally, less common forms of dementia include Parkinson's disease dementia, Huntington's disease, Creutzfeldt-Jakob disease and other prion diseases, dementia in HIV/AIDS, traumatic brain injury, and Wernicke-Korsakoff syndrome (which includes dementia from alcohol abuse).25
Risk factors for dementia are multifactorial and vary throughout life. Educational attainment early in life (eg, high number of years spent in education) is associated with a reduced likelihood of developing dementia; a higher level of education may delay the onset of dementia later in life.26 Additionally, hypertension, type 2 diabetes mellitus, hyperlipidemia, cognitive activity, social activity, exercise, alcohol use, diet, and smoking have been associated with dementia development.26,27 Late-onset Alzheimer's, the most common form of dementia, is thought to be a multifactorial disease in which development of the condition likely includes a combination of genetic, lifestyle, and environmental factors. Genetically, a polymorphism of the apolipoprotein E (APOE) gene, specifically APOE ɛ4 on chromosome 19, increases an individual's risk for developing late-onset Alzheimer's.28 This gene and other genes are implicated in the risk of development of Alzheimer's disease, including increasing the production of presenilin and ß-amyloid precursor protein, and have been shown to enhance deposition of ß-amyloid proteins, which are main components of plaques found in the brains of individuals who have Alzheimer's.29 Although the normal function of ß-amyloid is not well understood,30 it has been shown to be elevated in response to microbial activity and inflammation.31,32 ß-amyloid is a purported causative agent in several common dementias, including Alzheimer's disease and Lewy body dementia,33,34 and amyloid levels have been correlated with Alzheimer's disease onset.35 In addition to these genetic risk factors, epigenetic alterations of the genome (modification of the genome to turn genes off) may involve a role of environmental and lifestyle factors to influence gene expression and ameliorate or potentiate underlying genetic risk factors.36 Finally, recent studies have identified breakdown of the blood-brain barrier, including increased permeability, microbleeds, impaired nutrient transport, and impaired clearing of neurotoxins, as a mechanism for introduction of neurotoxic substances into the brain in neurodegenerative diseases, potentially including bacteria and bacterial by-products.37
Cognitive Impairment Classifications
Dementia symptoms generally vary in severity and progress over time from no impairment to very severe dementia. Both the Global Deterioration Scale/Reisberg Scale and the Functional Assessment Staging Test assign seven stages to the progression of dementia (Table 1).38
Proposed Mechanisms of Interaction Between Periodontal Disease and Dementia
Impaired cognitive function has been associated with worsening oral health parameters, including caries rates and periodontal clinical parameters, in cross-sectional studies.39-41 Epidemiologic studies have also shown that individuals with increased systemic inflammation, including elevated pro-inflammatory markers and cardiovascular diseases, have a higher risk of developing dementia and more rapid progression of dementia symptoms over time.42-44 Periodontal diseases are initiated by bacterial biofilm, which induces a localized inflammatory response that may result in periodontal pocket formation, alveolar bone resorption, and ultimately tooth loss.45,46 This local inflammatory process has been demonstrated to increase in both local and systemic pro-inflammatory markers, which can contribute to the overall systemic burden of inflammation.47,48 When present, destruction of the local periodontal tissues results in loss of integrity of the pocket lining epithelium. Bacteria, bacterial by-products, and the inflammatory mediators produced locally in response to the biofilm initiation can find their way through the ulcerated epithelium and be spread hematologically to distant sites in the body.49 Both the elevated systemic inflammatory state and oral bacteria and their by-products associated with periodontitis have been linked to dementia.1-3,50-52
Additionally, patients with dementia and their caregivers must manage delivery of preventive oral hygiene measures, which can be increasingly difficult as dementia severity increases.53,54 Due to the large number of individuals affected by both periodontal disease55 and dementia9 and the progressive nature of both diseases, understanding the potential role that dental healthcare providers can play in improving oral health to reduce dementia risk and the implementation of treatment strategies for promotion of optimal oral health for patients with dementia should be emphasized.
Periodontitis has been linked to cognitive impairment and dementia after controlling for confounding factors such as age, sex, and educational attainment.5,39,40,56-60 Progression of periodontal disease is associated with dysbiosis and elevated chronic inflammation, and dementia and Alzheimer's disease have been linked to periodontal disease through both inflammatory and bacterial mechanisms.40,51,52,61-66 Periodontal disease has also been linked to increased systemic and neurological markers of Alzheimer's disease.40,67,68
Common Pathways of Immune Response and Inflammatory State
Chronic inflammation is correlated with the onset and progression of Alzheimer's disease, and it has been postulated that chronic inflammation and neuronal aging induce stress and neuropathologic changes.69 In this model, chronic inflammation primes the microglia and induces a hyperreactive state, which then results in a failure to clear misfolded or damaged neuronal proteins and enhances the aggregation of neuronal proteins associated with dementia, such as Aß1-42.70,71 Similarly, periodontal tissue breakdown seen in periodontitis is a result of host inflammatory response to bacterial stimuli. Periodontal tissue breakdown is mediated by pro-inflammatory cytokines and mediators such as interleukin-1ß, interleukin-6, tumor necrosis factor-α, prostaglandin E2, receptor activator of nuclear factor kapp B ligand, and matrix metalloproteinases. These pro-inflammatory mediators interact with bacteria and the surrounding tissues. The heterogeneity among individuals in this response can influence disease susceptibility and severity.72 Additionally, periodontal disease severity is correlated with increased levels of pro-inflammatory mediators systemically.72-74 Because inflammation may influence the progression of disease in both periodontitis and dementia, one mechanism of interaction between periodontitis and dementia may include increased levels of inflammation and their influence on neuronal function.
Microbial Interactions Between Periodontal Disease and Dementia
Oral bacteria and their by-products have been found in brain tissue1-3,7,66; increased levels of serum antibodies to periodontopathogenic bacteria have been found in patients with Alzheimer's disease and dementia.44,51,66 These bacteria may enter the brain through several pathways: 1) bacteremias allow bacteria within the bloodstream, and degradation of the blood-brain barrier is seen in advanced age, chronic infection, and inflammation; 2) direct access to the brain may be gained through perivascular spaces, and 3) bacteria may pass into the brain through olfactory or trigeminal nerve pathways.75 In addition to the bacteria themselves, influence on the brain by bacterial by-products including virulence factors such as lipopolysaccharide, capsular material, proteolytic enzymes, and gingipains may contribute to progression of dementia.1-3,44,56,76,77 Finally, epigenetic alterations of the host genome as a result of exposure to bacteria or their by-products may alter gene expression and influence the risk conferred by those genes. Bacteria and their by-products have been shown to increase DNA methylation and histone acetylation, which has been indicated in the development of periodontal disease, cancers, and other diseases.78,79
Oral hygiene status in elderly dentate patients has also been associated with development of dementia.80 Alteration of the oral microbiome may in some cases be achieved through oral hygiene interventions, which then can alter serum levels of microorganisms and change a potential pathway for bacteria and their by-products to cross the blood-brain barrier.1,3,81 Improved oral hygiene delivery is associated with decreases in dental diseases in these populations, although further study is necessary to establish ideal interventions and identify patients in whom additional interventions may be necessary.82,83 Optimizing oral health through nonsurgical and surgical means has been suggested as an intervention to reduce the direct and indirect influences of oral bacteria and their by-products on the brain and their potential influence on cognitive decline.84
Part II
The second part of this article, available online at idh.cdeworld.com, addresses oral hygiene in patients with dementia, including delivery of oral home care by primary caregivers and adjunctive therapies to improve oral health in patients with dementia. Also covered is interdisciplinary care for individuals in residential nursing facilities.
Delivery of preventive and minimally invasive care for periodontitis and caries within a nursing home environment is challenging, but simple interventions and coordination between interdisciplinary healthcare providers can improve outcomes for patients.
About the Authors
Maria L. Geisinger, DDS, MS
Professor
University of Alabama at Birmingham
Department of Periodontology
Hussein S. Basma, DDS, DESS, MS
Assistant Professor
University of Alabama at Birmingham
Department of Periodontology
References
1. Dominy SS, Lynch C, Ermini F, 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. doi: 10.1126/sciadv.aau3333.
2. Choi S, Kim K, Chang J, et al. Association of chronic periodontitis on Alzheimer's disease or vascular dementia. J Am Geriatr Soc. 2019;67(6):1234-1239.
3. Ilievski V, Zuchowska PK, Green SJ, 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.
4. Chen CK, Wu YT, Chang YC. 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.
5. Leira Y, Dominguez C, Seoane J, et al. Is periodontal disease associated with Alzheimer's disease? A systematic review with meta-analysis. Neuroepidemiology. 2017;48(1-2):21-31.
6. Meyle J, Chapple I. Molecular aspects of the pathogenesis of periodontitis. Periodontol 2000.2015;69(1):7-17.
7. Kamer AR, Dasanayake AP, Craig RG, et al. Alzheimer's disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis. J Alzheimers Dis. 2008;13(4):437-449.
8. Kamer AR, Craig RG, Dasanayake AP, et al. Inflammation and Alzheimer's disease: possible role of periodontal diseases. Alzheimers Dement. 2008;4(4):242-250.
9. United States Census Bureau. Fueled by aging baby boomers, nation's older population to nearly double in the next 20 years, census bureau reports. United States Census Bureau website. https://www.census.gov/newsroom/press-releases/2014/cb14-84.html. Published May 6, 2014. Accessed March 26, 2019.
10. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1-2):125-132.
11. Slade GD, Akinkugbe AA, Sanders AE. Projections of U.S. edentulism prevalence following 5 decades of decline. J Dent Res. 2014;93(10):959-965.
12. Zenthöfer A, Baumgart D, Cabrera T, et al. Poor dental hygiene and periodontal health in nursing home residents with dementia: an observational study. Odontology. 2017;105(2):208-213.
13. Zimmerman S, Austin S, Cohen L, et al. Readily identifiable risk factors of nursing home residents' oral hygiene: dementia, hospice, and length of stay. J Am Geriatr Soc. 2017;65(11):2516-2521.
14. Jablonski RA, Kolanowski A, Therrien B, et al. Reducing care-resistant behaviors during oral hygiene in persons with dementia. BMC Oral Health. 2011;11:30-39.
15. Jablonski RA, Kolanowski AM, Azuero A, et al. Randomised clinical trial: efficacy of strategies to provide oral hygiene activities to nursing home residents with dementia who resist mouth care. Gerodontology. 2018;35(4):365-375.
16. Jablonski RA, Winstead V, Azuero A, et al. Feasibility of providing safe mouth care and collecting oral and fecal microbiome samples from nursing home residents with dysphagia: proof of concept study. J Gerontol Nurs. 2017;43(9):9-15.
17. World Health Organization. Dementia. World Health Organization website. http://www.who.int/news-room/fact-sheets/detail/dementia. Published September 19, 2019. Accessed December 11, 2019.
18. World Health Organization. International Statistical Classification of Diseases and Related Health Problems 10th Revision. World Health Organization website. https://icd.who.int/browse10/2016/en. Accessed December 11, 2019.
19. Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol. 2008;7(9):812-826.
20. Horton R. GBD 2010: understanding disease, injury, and risk. Lancet. 2012;380(9859):2053-2054.
21. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366(9503):2112-2117.
22. Forette F, Boller F. Hypertension and the risk of dementia in the elderly. Am J Med. 1991;90(3A):14S-19S.
23. World Health Organization. The world health report 2002 - reducing risks, promoting healthy life. World Health Organization website. https://www.who.int/whr/2002/en/. Accessed December 11, 2019.
24. Alzheimer's Research UK. Different types of dementia. Alzheimer's Research UK website. https://www.dementiastatistics.org/statistics/different-types-of-dementia/. Reviewed May 7, 2018. Accessed December 11, 2019.
25. Dementia Care Center. Lesser known and rare types of dementia. Dementia Care Central website. https://www.dementiacarecentral.com/aboutdementia/othertypes/. Updated August 22, 2018. Accessed December 11, 2019.
26. Hughes TF, Ganguli M. Modifiable midlife risk factors for late-life cognitive impairment and dementia. Curr Psychiatry Rev. 2009;5(2):73-92.
27. Alzheimer's Society. Alzheimer's disease. Alzheimer's Society website. https://www.alzheimers.org.uk/site/scripts/download_info.php?downloadID=1093. Accessed December 11, 2019.
28. Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med. 1995;333(19):1242-1247.
29. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2016;18(5):421-430.
30. Hiltunen M, van Groen T, Jolkkonen J. Functional roles of amyloid-beta protein precursor and amyloid-beta peptides: evidence from experimental studies. J Alzheimers Dis.2009;18(2):401-412.
31. Kagan BL, Jang H, Capone R, et al. Antimicrobial properties of amyloid peptides. Mol Pharm.2012;9(4):708-717.
32. Li H, Liu CC, Zheng H, Huang TY. Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer's disease -conformist, nonconformist, and realistic prospects for AD pathogenesis. Transl Neurodegener.2018;7:34.
33. Sadigh-Eteghad S, Sabermarouf B, Majdi A, et al. Amyloid-beta: a crucial factor in Alzheimer's disease. Med Princ Pract.2015;24(1):1-10.
34. Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet.2015;386(10004):1683-1697.
35. Schirinzi T, Di Lazzaro G, Sancesario GM, et al. Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer's disease. J Neural Transm (Vienna).2017;124(12):1621-1625.
36. Daniilidou M, Koutroumani M, Tsolaki M. Epigenetic mechanisms in Alzheimer's disease. Curr Med Chem. 2011;18(12):1751-1756.
37. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133-150.
38. Dementia Care Central. Stages of Alzheimer's & dementia: durations & scales used to measure progression: GDS, FAST & CDR. Dementia Care Central website. https://www.dementiacarecentral.com/aboutdementia/facts/stages/. Updated September 1, 2018. Accessed December 11, 2019.
39. Noble JM, Scarmeas N, Papapanou PN. Poor oral health as a chronic, potentially modifiable dementia risk factor: review of the literature. Curr Neurol Neurosci Rep. 2013;13(10):384.
40. Nilsson H, Berglund J, Renvert S. Tooth loss and cognitive functions among older adults. Acta Odontol Scand. 2014;72(8):639-644.
41. Gil-Montoya JA, Sanchez-Lara I, Carnero-Pardo C, et al. Is periodontitis a risk factor for cognitive impairment and dementia? A case-control study. J Periodontol. 2015;86(2):244-253.
42. Schmidt R, Schmidt H, Curb JD, et al. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia aging study. Ann Neurol. 2002;52(2):168-174.
43. Engelhart MJ, Geerlings MI, Meijer J, et al. Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. Arch Neurol. 2004;61(5):668-672.
44. Kravitz BA, Corrada MM, Kawas CH. Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old. Alzheimers Dement. 2009;5(4):318-323.
45. Flemmig TF. Periodontitis. Ann Periodontol. 1999;4(1):32-38.
46. Page RC, Schroeder HE. Pathogenesis of inflammatory periodontal disease. A summary of current work. Lab Invest. 1976;34(3):235-249.
47. Hasturk H, Kantarci A. Activation and resolution of periodontal inflammation and its systemic impact. Periodontol 2000.2015;69(1):255-273.
48. Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers.2017; 3:17038.
49. Kumar PS. From focal sepsis to periodontal medicine: a century of exploring the role of oral microbiome in systemic disease. J Physiol.2017;595(2):465-476.
50. Feres M, Teles F, Teles R, et al. The subgingival periodontal microbiota of the aging mouth. Periodontol 2000. 2016;72(1):30-53.
51. Noble JM, Scarmeas N, Celenti RS, et al. Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease. PLoS One. 2014;9(12):e114959.
52. Laugisch O, Johnen A, Maldonado A, et al. Periodontal pathogens and associated intrathecal antibodies in early stages of Alzheimer's disease. J Alzheimers Dis. 2018;66(1):105-114.
53. Volicer L, Van der Steen JT, Frijters DH. Modifiable factors related to abusive behaviors in nursing home residents with dementia. J Am Med Dir Assoc. 2009;10(9):617-622.
54. Ishii S, Streim JE, Saliba D. Potentially reversible resident factors associated with rejection of care behaviors. J Am Geriatr Soc. 2010;58(9):1693-1700.
55. Eke PI, Dye BA, Wei L, et al. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 2012;91(1):914-920.
56. Holmer J, Eriksdotter M, Schultzberg M, et al. Association between periodontitis and risk of Alzheimer's disease, mild cognitive impairment and subjective cognitive decline: a case-control study. J Clin Periodontol. 2018;45(11):1287-1298.
57. Gusman DJR, Mello-Neto JM, Alves BES, et al. Periodontal disease severity in subjects with dementia: a systematic review and meta-analysis. Arch Gerontol Geriatr. 2018;76:147-159.
58. Maldonado A, Laugisch O, Bürgin W, et al. Clinical periodontal variables in patients with and without dementia-a systematic review and meta-analysis. Clin Oral Invest. 2018;22(7):2463-2474.
59. Tonsekar PP, Jiang SS, Yue G. Periodontal disease, tooth loss and dementia: is there a link? A systematic review. Gerodontology. 2017;34(2):151-163.
60. Miklossy J. Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation. 2011;8:90.
61. Moll van Charante EP, Richard E, Eurelings LS, et al., Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet. 2016;388(10046):797-805.
62. 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(2):113-118.
63. Kamer AR, Craig RG, Pirraglia E, et al. TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects. J Neuroimmunol. 2009;216(1-2):92-97.
64. Noble JM, Borrell LN, Papapanou PN, et al. Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III. J Neurol Neurosurg Psychiatry. 2009;80(11):1206-1211.
65. Poole S, Singhrao SK, Kesavalu L, et al. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue. J Alzheimers Dis. 2013;36(4):665-677.
66. Kamer AR, Pirraglia E, Tsui W, et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol Aging. 2015;36(2):627-633.
67. Singharao SK, Chukkapalli S, Poole S, Velsko I, Crean SJ, Kesavalu L. Chronic Porphyromonas gingivalis infection accelerates the occurrence of age-related granules in ApoE-/- mice brains. J Oral Microbiol. 2017;9(1):1270602.
68. Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat Rev Neurol. 2013;9(1):25-34.
69. Lim SL, Rodriguez-Ortiz CJ, Kitazawa M. Infection, systemic inflammation, and Alzheimer's disease. Microbes Infect. 2015;17(8):549-556.
70. Venegas C, Kumar S, Franklin BS, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017;552(7685):355-361.
71. Kinane DF, Preshaw PM, Loos BG; Working Group 2 of Seventh European Workshop on Periodontology. Host-response: understanding the cellular and molecular mechanisms of host-microbial interactions--consensus of the Seventh European Workshop on Periodontology. J Clin Periodontol. 2011;38(Suppl 11):44-48.
72. Loos BG. Systemic markers of inflammation in periodontitis. J Periodontol. 2005;76(11 Suppl):2106-2115.
73. Noack B, Genco RJ, Trevisan M, et al. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol. 2001;72(9):1221-1227.
74. Loos BG, Craandijk J, Hoek FJ, et al. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol. 2000;71(10):1528-1534.
75. Olsen I, Singhrao SK. Can oral infection be a risk factor for Alzheimer's disease? J Oral Microbiol. 2015;7:29143.
76. Holt SC, Ebersole JL, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia: the "red complex", a prototype polybacterial pathogenic consortium in periodontitis. Periodontol 2000. 2005;38:72-122.
77. Guo Y, Nguyen KA, Potempa J. Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon's knife to a meat chopper-like brutal degradation of proteins. Periodontol 2000. 2010;54(1):15-44.
78. Martins MD, Jiao Y, Larsson L, et al. Epigenetic modifications of histones in periodontal disease. J Dent Res. 2016;95(2):215-222.
79. Kang MK, Mehrazarin S, Park NH, Wang CY. Epigenetic gene regulation by histone demethylases: emerging role in oncogenesis and inflammation. Oral Dis. 2017;23(6):709-720.
80. Paganini-Hill A, White SC, Atchison KA. Dentition, dental health habits, and dementia: the Leisure World Cohort Study. J Am Geriatr Soc. 2012;60(8):1556-1563.
81. Kato T, Yamazaki K, Nakajima M, et al. Oral administration of Porphyromonas gingivalis alters the gut microbiome and serum metabolome. mSphere. 2018;3(5). pii: e00460-18. doi: 10.1128/mSphere.00460-18.
82. Rozas NS, Sadowsky JM, Jeter CB. Strategies to improve dental health in elderly patients with cognitive impairment: a systematic review. J Am Dent Assoc. 2017;148(4):236-245.e3. doi: 10.1016/j.adaj.2016.12.022.
83. Ellefsen B, Holm-Pedersen P, Morse DE, et al. Assessing caries increments in elderly patients with and without dementia: a one-year follow-up study. J Am Dent Assoc. 2009;140(11):1392-1400.
84. Harding A, Robinson S, Crean S, Singhrao SK. Can better management of periodontal disease delay the onset and progression of Alzheimer's disease? J Alzheimers Dis. 2017;58(2):337-348.
