{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:41:46Z","timestamp":1791265306799,"version":"4.1.0"},"reference-count":99,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Alzheimer\u2019s Disease (AD) is a complex neurodegenerative disease and remains the most common form of dementia. The pathological features include amyloid (A\u03b2) accumulation, neurofibrillary tangles (NFTs), neural and synaptic loss, microglial cell activation, and an increased blood\u2013brain barrier permeability. One longstanding hypothesis suggests that a microbial etiology is key to AD initiation. Among the various periodontal microorganisms, Porphyromonas gingivalis has been considered the keystone agent to potentially correlate with AD, due to its influence on systemic inflammation. P. gingivalis together with Treponema denticola and Tannerella forsythia belong to the red complex consortium of bacteria advocated to sustain periodontitis within a local dysbiosis and a host response alteration. Since the implication of P. gingivalis in the pathogenesis of AD, evidence has emerged of T. denticola clusters in some AD brain tissue sections. This narrative review explored the potential mode of spirochetes entry into the AD brain for tracing pathology. Spirochetes are slow-growing bacteria, which can hide within ganglia for many years. It is this feature in combination with the ability of these bacteria to evade the hosts\u2019 immune responses that may account for a long lag phase between infection and plausible AD disease symptoms. As the locus coeruleus has direct connection between the trigeminal nuclei to periodontal free nerve endings and proprioceptors with the central nervous system, it is plausible that they could initiate AD pathology from this anatomical region.<\/jats:p>","DOI":"10.3390\/ijerph19159386","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T23:37:29Z","timestamp":1659310649000},"page":"9386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["The Mechanistic Pathways of Periodontal Pathogens Entering the Brain: The Potential Role of Treponema denticola in Tracing Alzheimer\u2019s Disease Pathology"],"prefix":"10.3390","volume":"19","author":[{"given":"Flavio","family":"Pisani","sequence":"first","affiliation":[{"name":"School of Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Pisani","sequence":"additional","affiliation":[{"name":"Neurology and Neurorehabilitation Unit, I.R.C.C.S. \u201cSanta Lucia\u201d Foundation, Via Ardeatina, 306-00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Arcangeli","sequence":"additional","affiliation":[{"name":"Azienda Sanitaria Locale ASLRM1, Geriatric Department, Regina Margherita Hospital, Via Emilio Morosini, 30-00153 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Harding","sequence":"additional","affiliation":[{"name":"Dementia and Neurodegenerative Disease Research Group, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston PR1 2HE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simarjit Kaur","family":"Singhrao","sequence":"additional","affiliation":[{"name":"Dementia and Neurodegenerative Disease Research Group, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston PR1 2HE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1177\/00220345211043461","article-title":"Periodontitis and Dementia: A Bidirectional Relationship?","volume":"101","author":"Harding","year":"2022","journal-title":"J. Dent. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1128\/JB.183.12.3770-3783.2001","article-title":"Bacterial diversity in human subgingival plaque","volume":"183","author":"Paster","year":"2001","journal-title":"J. Bacteriol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eaau3333","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in Alzheimer\u2019s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/1742-2094-8-90","article-title":"Alzheimer\u2019s disease\u2014A neurospirochetosis. Analysis of the evidence following Koch\u2019s and Hill\u2019s criteria","volume":"8","author":"Miklossy","year":"2011","journal-title":"J. Neuroinflammation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"665","DOI":"10.3233\/JAD-121918","article-title":"Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer\u2019s disease brain tissue","volume":"36","author":"Poole","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1046\/j.0902-0055.2001.00100.x","article-title":"Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer\u2019s disease","volume":"17","author":"Riviere","year":"2002","journal-title":"Oral Microbiol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3233\/ADR-200250","article-title":"Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer\u2019s Disease","volume":"4","author":"Kanagasingam","year":"2020","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_8","first-page":"220345221076772","article-title":"Treponema denticola Induces Alzheimer-Like Tau Hyperphosphorylation by Activating Hippocampal Neuroinflammation in Mice","volume":"22","author":"Tang","year":"2022","journal-title":"J. Dent. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","article-title":"Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years","volume":"70","author":"Braak","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease","volume":"8","author":"Hyman","year":"2012","journal-title":"Alzheimers Dement."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a028035","DOI":"10.1101\/cshperspect.a028035","article-title":"Pathology of Neurodegenerative Diseases","volume":"9","author":"Dugger","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4044","DOI":"10.1073\/pnas.83.11.4044","article-title":"Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease","volume":"83","author":"Kosik","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1006\/exnr.2002.8014","article-title":"Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer\u2019s disease","volume":"177","author":"Ghoshal","year":"2002","journal-title":"Exp. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/j.1532-5415.2010.02788.x","article-title":"Tooth loss and periodontal disease predict poor cognitive function in older men","volume":"58","author":"Kaye","year":"2010","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"777","DOI":"10.3233\/JAD-141665","article-title":"Association between tooth loss and the development of mild memory impairment in the elderly: The Fujiwara-kyo Study","volume":"44","author":"Okamoto","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1177\/0022034509357881","article-title":"Tooth loss, apolipoprotein E, and decline in delayed word recall","volume":"89","author":"Stein","year":"2010","journal-title":"J. Dent. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"371","DOI":"10.3233\/JAD-2008-13403","article-title":"Chlamydophila pneumoniae and the etiology of late-onset Alzheimer\u2019s disease","volume":"13","author":"Balin","year":"2008","journal-title":"J. Alzheimers Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/BF02893605","article-title":"Die presbyophrene Demenz, deren anatomische Grundlage und klinische Abgrenzung","volume":"3","author":"Fischer","year":"1910","journal-title":"Z. Ges. Neurol. Psychiat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"979","DOI":"10.3233\/JAD-160152","article-title":"Microbes and Alzheimer\u2019s Disease","volume":"51","author":"Itzhaki","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0046-8177(87)80252-6","article-title":"Concurrent neocortical borreliosis and Alzheimer\u2019s disease","volume":"18","author":"MacDonald","year":"1987","journal-title":"Hum. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1097\/00001756-199307000-00002","article-title":"Alzheimer\u2019s disease\u2014A spirochetosis?","volume":"4","author":"Miklossy","year":"1993","journal-title":"Neuroreport"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29143","DOI":"10.3402\/jom.v7.29143","article-title":"Can oral infection be a risk factor for Alzheimer\u2019s disease?","volume":"7","author":"Olsen","year":"2015","journal-title":"J. Oral Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1080\/14787210.2020.1729741","article-title":"Is Alzheimer\u2019s disease a polymicrobial host microbiome dysbiosis?","volume":"18","author":"Singhrao","year":"2020","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_25","first-page":"S68","article-title":"Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"45","author":"Chapple","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_26","first-page":"72","article-title":"Prevalence of periodontal disease, its association with systemic diseases and prevention","volume":"11","author":"Nazir","year":"2017","journal-title":"Int. J. Health Sci."},{"key":"ref_27","first-page":"2146160","article-title":"Global prevalence of periodontal disease and lack of its surveillance","volume":"28","author":"Nazir","year":"2020","journal-title":"Sci. World J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/prd.12337","article-title":"A public health approach for prevention of periodontal disease","volume":"84","author":"Janakiram","year":"2020","journal-title":"Periodontology 2000"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1177\/0022034517693566","article-title":"Global, regional, and national prevalence, incidence, and disability-adjusted life years for oral conditions for 195 countries, 1990\u20132015: A systematic analysis for the global burden of diseases, injuries, and risk factors","volume":"96","author":"Kassebaum","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_30","unstructured":"Eaton, K.A., and Ower, P. (2015). The diseased root surface in periodontitis. Practical Periodontics, Elsevier Health Sciences."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1177\/0022034514552491","article-title":"Global burden of severe periodontitis in 1990\u20132010: A systematic review and meta-regression","volume":"93","author":"Kassebaum","year":"2014","journal-title":"J. Dent. Res."},{"key":"ref_32","unstructured":"British Society of Periodontology (2022, July 26). The Good Practitioner\u2019s Guide to Periodontology. Available online: https:\/\/www.bsperio.org.uk\/assets\/downloads\/good_practitioners_guide_2016.pdf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1111\/jcpe.12366","article-title":"Primary prevention of Periodontitis: Managing gingivitis","volume":"42","author":"Chapple","year":"2015","journal-title":"J. Clin. Periodontol."},{"key":"ref_34","unstructured":"White, D., Pitts, N., Steele, J., Sadler, K., Chadwick, B., and Disease and Related Disorders\u2014A Report from the Adult Dental Health Survey 2009 (2022, July 26). The Health and Social Care Information Centre. Available online: https:\/\/files.digital.nhs.uk\/publicationimport\/pub01xxx\/pub01086\/adul-dent-heal-surv-summ-them-the2-2009-rep4.pdf."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1111\/jcpe.12350","article-title":"Risk factor assessment tools for the prevention of periodontitis progression a systematic review","volume":"42","author":"Lang","year":"2015","journal-title":"J. Clin. Periodontol."},{"key":"ref_36","first-page":"7","article-title":"Periodontal risk assessment (PRA) for patients in supportive periodontal therapy (SPT)","volume":"1","author":"Lang","year":"2003","journal-title":"Oral Health Prev. Dent."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/j.1600-051X.2011.01849.x","article-title":"Five-year change of periodontal diseases in the Study of Health in Pomerania (SHIP)","volume":"39","author":"Holtfreter","year":"2012","journal-title":"J. Clin. Periodontol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41577-020-00488-6","article-title":"Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities","volume":"21","author":"Hajishengallis","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","unstructured":"Public Health England (2022, July 26). Delivering Better Oral Health: An Evidence-Based Toolkit For Prevention, Available online: https:\/\/assets.publishing.service.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/605266\/Delivering_better_oral_health.pdf."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1007\/s00784-020-03764-w","article-title":"Relationship of Porphyromonas gingivalis and Alzheimer\u2019s disease: A systematic review of preclinical studies","volume":"25","author":"Costa","year":"2021","journal-title":"Clin. Oral Investig."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Franciotti, R., Pignatelli, P., Carrarini, C., Romei, F.M., Mastrippolito, M., Gentile, A., Mancinelli, R., Fulle, S., Piattelli, A., and Onofrj, M. (2021). 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. Biomolecules, 11.","DOI":"10.3390\/biom11060845"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.14219\/jada.archive.2007.0046","article-title":"Tooth loss, dementia and neuropathology in the Nun study","volume":"138","author":"Stein","year":"2007","journal-title":"J. Am. Dent. Assoc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/prd.12296","article-title":"The role of the microbiota in periodontal disease","volume":"83","author":"Curtis","year":"2020","journal-title":"Periodontology 2000"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nrmicro2873","article-title":"The keystone-pathogen hypothesis","volume":"10","author":"Hajishengallis","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/j.2041-1014.2012.00663.x","article-title":"Beyond the red complex and into more complexity: The polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology","volume":"27","author":"Hajishengallis","year":"2012","journal-title":"Mol. Oral Microbiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/j.1600-051X.1998.tb02419.x","article-title":"Microbial complexes in subgingival plaque","volume":"25","author":"Socransky","year":"1998","journal-title":"J. Clin. Periodontol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1902\/jop.1982.53.9.550","article-title":"Relationship between the percentage of subgingival spirochetes and the severity of periodontal disease","volume":"53","author":"Armitage","year":"1982","journal-title":"J. Periodontol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1177\/0022034512453589","article-title":"Porphyromonas gingivalis as a potential community activist for disease","volume":"91","author":"Darveau","year":"2012","journal-title":"J. Dent. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1128\/AEM.02712-14","article-title":"Dysbiosis and alterations in predicted functions of the subgingival microbiome in chronic periodontitis","volume":"81","author":"Kirst","year":"2015","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1128\/IAI.66.4.1660-1665.1998","article-title":"Local chemokine paralysis, a novel pathogenic mechanism for Porphyromonas gingivalis","volume":"66","author":"Darveau","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_51","first-page":"421","article-title":"Subgingival Microbiome Shifts and Community Dynamics in Periodontal Diseases","volume":"44","author":"Diaz","year":"2016","journal-title":"J. Calif. Dent. Assoc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.chom.2011.10.006","article-title":"Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement","volume":"10","author":"Hajishengallis","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"359","DOI":"10.3233\/JAD-170304","article-title":"Cerebral oxidative stress and microvasculature defects in TNF-\u03b1 expressing transgenic and Porphyromonas gingivalis-infected ApoE-\/- mice","volume":"60","author":"Rokad","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1177\/0022034510385242","article-title":"Virulence factors of the oral spirochete Treponema denticola","volume":"90","author":"Dashper","year":"2011","journal-title":"J. Dent. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1902\/jop.2008.080139","article-title":"Transcriptomes in healthy and diseased gingival tissues","volume":"79","author":"Demmer","year":"2008","journal-title":"J. Periodontol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1600-0757.2005.00113.x","article-title":"Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia: The \u201cred complex\u201d, a prototype polybacterial pathogenic consortium in periodontitis","volume":"38","author":"Holt","year":"2005","journal-title":"Periodontology 2000"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.femsle.2005.07.019","article-title":"Synergistic biofilm formation by Treponema denticola and Porphyromonas gingivalis","volume":"250","author":"Yamada","year":"2005","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Dashper, S.G., Chen, Y.Y., Crawford, S., Slakeski, N., and Reynolds, E.C. (2013). Porphyromonas gingivalis and Treponema denticola synergistic polymicrobial biofilm development. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071727"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/j.2041-1014.2011.00612.x","article-title":"Synergistic virulence of Porphyromonas gingivalis and Treponema denticola in a murine periodontitis model","volume":"26","author":"Orth","year":"2011","journal-title":"Mol. Oral Microbiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/omi.12004","article-title":"Treponema denticola improves adhesive capacities of Porphyromonas gingivalis","volume":"28","author":"Meuric","year":"2013","journal-title":"Mol. Oral Microbiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3389\/fcimb.2019.00432","article-title":"The Role of Treponema denticola Motility in Synergistic Biofilm Formation with Porphyromonas gingivalis","volume":"9","author":"Ng","year":"2019","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13088","DOI":"10.1073\/pnas.1200791109","article-title":"Bacterial swimmers that infiltrate and take over the biofilm matrix","volume":"109","author":"Houry","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3653","DOI":"10.1128\/IAI.67.7.3653-3656.1999","article-title":"Development of a system for expressing heterologous genes in the oral spirochete Treponema denticola and its use in expression of the Treponema pallidum flaA gene","volume":"67","author":"Chi","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/j.1399-302X.1993.tb00567.x","article-title":"Viscosity-dependent locomotion of oral spirochetes","volume":"8","author":"Klitorinos","year":"1993","journal-title":"Oral Microbiol. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"30028","DOI":"10.1038\/srep30028","article-title":"Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer\u2019s disease","volume":"6","author":"Minter","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/341226a0","article-title":"Amyloid beta-protein deposition in tissues other than brain in Alzheimer\u2019s disease","volume":"341","author":"Joachim","year":"1989","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Flemming, H.-C., Neu, T.R., and Wingender, J. (2017). Amyloids\u2014A neglected child of the slime. The Perfect Slime, Microbial Extracellular Polymeric Substances (EPS), IWA Publishing.","DOI":"10.2166\/9781780407425"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fnagi.2017.00195","article-title":"16S rRNA next generation sequencing analysis shows bacteria in Alzheimer\u2019s post-mortem brain","volume":"20","author":"Emery","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3","DOI":"10.35702\/nrj.10003","article-title":"High Throughput Sequencing Detects Gingivitis and Periodontal Oral Bacteria in Alzheimer\u2019s Disease Autopsy Brains","volume":"1","author":"Siddiqui","year":"2019","journal-title":"Neuro Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"122","DOI":"10.4103\/jomfp.JOMFP_304_18","article-title":"Oral microbiome: Unveiling the fundamentals","volume":"23","author":"Deo","year":"2019","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jalz.2011.04.006","article-title":"Serum antibodies to periodontal pathogens are a risk factor for Alzheimer\u2019s disease","volume":"8","author":"Steffen","year":"2012","journal-title":"Alzheimers Dement."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"110393","DOI":"10.1016\/j.mehy.2020.110393","article-title":"Low levels of salivary lactoferrin may affect oral dysbiosis and contribute to Alzheimer\u2019s disease: A hypothesis","volume":"146","author":"Olsen","year":"2021","journal-title":"Med. Hypotheses"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"100956","DOI":"10.1016\/j.arr.2019.100956","article-title":"Olfactory dysfunction in the pathophysiological continuum of dementia","volume":"55","author":"Bathini","year":"2019","journal-title":"Ageing Res. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/10454411920040010101","article-title":"Central connections of trigeminal primary afferent neurons: Topographical and functional considerations","volume":"4","author":"Capra","year":"1992","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cne.902440102","article-title":"Oral and facial representation in the trigeminal principal and rostral spinal nuclei of the cat","volume":"244","author":"Shigenaga","year":"1986","journal-title":"J. Comp. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0006-8993(90)91632-Q","article-title":"Morphology of central terminations of low-threshold trigeminal primary afferents from facial skin in the cat--intra-axonal staining with HRP","volume":"523","author":"Shigenaga","year":"1990","journal-title":"Brain Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0006-8993(91)90011-J","article-title":"Monosynaptic connections between neurons of trigeminal mesencephalic nucleus and jaw-closing motoneurons in the rat: An intracellular horseradish peroxidase labelling study","volume":"559","author":"Luo","year":"1991","journal-title":"Brain Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0003-9969(83)90032-8","article-title":"The occurrence of a lamellated nerve terminal in the periodontal ligament of the rat incisor","volume":"28","author":"Berkovitz","year":"1983","journal-title":"Arch. Oral Biol."},{"key":"ref_79","first-page":"117","article-title":"The structure of physiologically located periodontal ligament mechanoreceptors of the cat canine tooth","volume":"167","author":"Millar","year":"1989","journal-title":"J. Anat."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1113\/jphysiol.1978.sp012353","article-title":"The projection of jaw elevator muscle spindle afferents to fifth nerve motoneurones in the cat","volume":"279","author":"Appenteng","year":"1978","journal-title":"J. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1152\/jn.1982.47.2.151","article-title":"Behavior of cutaneous mechanoreceptors recorded in mandibular division of Gasserian ganglion of the rabbit during movements of lower jaw","volume":"47","author":"Appenteng","year":"1982","journal-title":"J. Neurophysiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0006-8993(89)90119-4","article-title":"Physiological and morphological characteristics of periodontal mesencephalic trigeminal neurons in the cat\u2014Intra-axonal staining with HRP","volume":"505","author":"Shigenaga","year":"1989","journal-title":"Brain Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.tics.2016.01.001","article-title":"The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain","volume":"20","author":"Mather","year":"2016","journal-title":"Trends Cogn. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jalz.2016.06.2362","article-title":"Locus coeruleus volume and cell population changes during Alzheimer\u2019s disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery","volume":"13","author":"Theofilas","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s00401-020-02248-1","article-title":"The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer\u2019s disease","volume":"141","author":"Matchett","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.neures.2010.06.012","article-title":"The locus coeruleus projects to the mesencephalic trigeminal nucleus in rats","volume":"68","author":"Takahashi","year":"2010","journal-title":"Neurosci. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40478-017-0411-2","article-title":"Locus coeruleus cellular and molecular pathology during the progression of Alzheimer\u2019s disease","volume":"5","author":"Kelly","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1111\/j.1600-051X.2009.01426.x","article-title":"Tooth loss and cognitive impairment","volume":"36","author":"Grabe","year":"2009","journal-title":"J. Clin. Periodontol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.3233\/JAD-200257","article-title":"Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer\u2019s Disease in 3\u00d7Tg-AD Model Mice","volume":"76","author":"Goto","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1007\/s12031-021-01827-5","article-title":"Oral Treponema denticola Infection Induces A\u03b21-40 and A\u03b21-42 Accumulation in the Hippocampus of C57BL\/6 Mice","volume":"71","author":"Su","year":"2021","journal-title":"J. Mol. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3389\/fnagi.2015.00046","article-title":"Historic evidence to support a causal relationship between spirochetal infections and Alzheimer\u2019s disease","volume":"7","author":"Miklossy","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1679\/aohc.53.259","article-title":"Nerve terminals in human periodontal ligament as demonstrated by immunohistochemistry for neurofilament protein (NFP) and S-100 protein","volume":"53","author":"Maeda","year":"1990","journal-title":"Arch. Histol. Cytol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"205","DOI":"10.2119\/2007-00091.Rupprecht","article-title":"The pathogenesis of lyme neuroborreliosis: From infection to inflammation","volume":"14","author":"Rupprecht","year":"2008","journal-title":"Mol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1016\/j.neubiorev.2013.07.001","article-title":"A revised limbic system model for memory, emotion and behaviour","volume":"37","author":"Catani","year":"2013","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s00234-021-02783-y","article-title":"Gray matter volume reduction with different disease duration in trigeminal neuralgia","volume":"64","author":"Shen","year":"2022","journal-title":"Neuroradiology."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12929-019-0524-y","article-title":"Alzheimer\u2019s disease: Risk factors and potentially protective measures","volume":"26","author":"Silva","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12974-017-1052-x","article-title":"Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL\/6 mice","volume":"15","author":"Zhang","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.bbi.2004.01.004","article-title":"The influence of systemic inflammation on inflammation in the brain: Implications for chronic neurodegenerative disease","volume":"18","author":"Perry","year":"2004","journal-title":"Brain Behav. Immun."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1016\/j.jalz.2018.06.2857","article-title":"Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults","volume":"14","author":"Bowman","year":"2018","journal-title":"Alzheimers Dement."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/15\/9386\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:17Z","timestamp":1760140817000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/15\/9386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,31]]},"references-count":99,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijerph19159386"],"URL":"https:\/\/doi.org\/10.3390\/ijerph19159386","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,31]]}}}