Reciprocal Interactions Between Periodontal Disease and Alzheimer’s Disease: Implications for Mutual Triggering, Exacerbation, and Treatment Interventions—A Comprehensive Review of the Literature
Abstract
:1. Introduction
2. Methods
3. Discussion
3.1. Pathogenesis of AD
3.1.1. Amyloid and Tau Proteins
3.1.2. Neuroinflammation in AD
3.1.3. Synaptic Dysfunction in AD
3.1.4. Peripheral Inflammation and AD
3.2. Periodontitis and Alzheimer’s Disease Pathogenesis
3.3. Inflammatory Biomarkers Linking Periodontitis and Alzheimer’s Disease
3.4. Integrated Early Intervention Strategies for Alzheimer’s Disease and Periodontal Disease
3.5. Bidirectional Pathways in the Prevention of Alzheimer’s Disease and Periodontitis
3.5.1. Controlling the Bacterial Biofilm
3.5.2. Host Modulation Therapy
3.5.3. Assessing the Risk Factors
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Zhang, J.; Zhang, Y.; Wang, J.; Xia, Y.; Zhang, J.; Chen, L. Recent Advances in Alzheimer’s Disease: Mechanisms, Clinical Trials and New Drug Development Strategies. Signal Transduct. Target. Ther. 2024, 9, 211. [Google Scholar] [CrossRef]
- Knopman, D.S.; Amieva, H.; Petersen, R.C.; Chételat, G.; Holtzman, D.M.; Hyman, B.T.; Nixon, R.A.; Jones, D.T. Alzheimer Disease. Nat. Rev. Dis. Primers 2021, 7, 33. [Google Scholar] [CrossRef]
- Scheltens, P.; De Strooper, B.; Kivipelto, M.; Holstege, H.; Chételat, G.; Teunissen, C.E.; Cummings, J.; van der Flier, W.M. Alzheimer’s Disease. Lancet 2021, 397, 1577–1590. [Google Scholar] [CrossRef]
- Dementia. Available online: https://www.who.int/news-room/fact-sheets/detail/dementia (accessed on 14 September 2024).
- Dementia Statistics|Alzheimer’s Disease International (ADI). Available online: https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/ (accessed on 9 February 2025).
- Wimo, A.; Seeher, K.; Cataldi, R.; Cyhlarova, E.; Dielemann, J.L.; Frisell, O.; Guerchet, M.; Jönsson, L.; Malaha, A.K.; Nichols, E.; et al. The worldwide costs of dementia in 2019. Alzheimer’s Dement. 2023, 19, 2865–2873. [Google Scholar] [CrossRef]
- GBD 2019 Collaborators; Nichols, E.; Abd-Allah, F.; Abdoli, A.; Abosetugn, A.E.; Abrha, W.A.; Abualhasan, A.; Abu-Gharbieh, E.; Akinyemi, R.O.; Alahdab, F.; et al. Global mortality from dementia: Application of a new method and results from the Global Burden of Disease Study 2019. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2021, 7, e12200. [Google Scholar] [CrossRef]
- Hardy, J.A.; Higgins, G.A. Alzheimer’s Disease: The Amyloid Cascade Hypothesis. Science 1992, 256, 184–185. [Google Scholar] [CrossRef]
- Wu, D.T.; Cho, Y.W.; Spalti, M.D.; Bishara, M.; Nguyen, T.T. The Link between Periodontitis and Alzheimer’s Disease—Emerging Clinical Evidence. Dent. Rev. 2023, 3, 100062. [Google Scholar] [CrossRef]
- Sedghi, L.M.; Bacino, M.; Kapila, Y.L. Periodontal Disease: The Good, The Bad, and The Unknown. Front. Cell Infect. Microbiol. 2021, 11, 766944. [Google Scholar] [CrossRef]
- Nazir, M.A. Prevalence of Periodontal Disease, Its Association with Systemic Diseases and Prevention. Int. J. Health Sci. 2017, 11, 72. Available online: https://pubmed.ncbi.nlm.nih.gov/28539867/ (accessed on 21 May 2025). [PubMed]
- Eke, P.I.; Thornton-Evans, G.O.; Wei, L.; Borgnakke, W.S.; Dye, B.A.; Genco, R.J. Periodontitis in US Adults: National Health and Nutrition Examination Survey 2009–2014. J. Am. Dent. Assoc. 2018, 149, 576–588.e6. [Google Scholar] [CrossRef]
- From the Dental Archives: Miller 1891, pt. 1. Available online: https://websites.umich.edu/~pfa/denthist/articles/Miller1891.html (accessed on 12 September 2024).
- Liccardo, D.; Marzano, F.; Carraturo, F.; Guida, M.; Femminella, G.D.; Bencivenga, L.; Agrimi, J.; Addonizio, A.; Melino, I.; Valletta, A.; et al. Potential Bidirectional Relationship Between Periodontitis and Alzheimer’s Disease. Front. Physiol. 2020, 11, 683. [Google Scholar] [CrossRef]
- Kim, J.; Amar, S. Periodontal Disease and Systemic Conditions: A Bidirectional Relationship. Odontology 2006, 94, 10–21. [Google Scholar] [CrossRef]
- Arigbede, A.O.; Babatope, B.O.; Bamidele, M.K. Periodontitis and Systemic Diseases: A Literature Review. J. Indian Soc. Periodontol. 2012, 16, 487. [Google Scholar] [CrossRef]
- Bui, F.Q.; Almeida-da-Silva, C.L.C.; Huynh, B.; Trinh, A.; Liu, J.; Woodward, J.; Asadi, H.; Ojcius, D.M. Association between Periodontal Pathogens and Systemic Disease. Biomed. J. 2019, 42, 27–35. [Google Scholar] [CrossRef]
- Hajishengallis, G. Periodontitis: From Microbial Immune Subversion to Systemic Inflammation. Nat. Rev. Immunol. 2015, 15, 30–44. [Google Scholar] [CrossRef]
- Hajishengallis, G.; Chavakis, T. Local and Systemic Mechanisms Linking Periodontal Disease and Inflammatory Comorbidities. Nat. Rev. Immunol. 2021, 21, 426–440. [Google Scholar] [CrossRef]
- Kamer, A.R.; Craig, R.G.; Dasanayake, A.P.; Brys, M.; Glodzik-Sobanska, L.; de Leon, M.J. Inflammation and Alzheimer’s Disease: Possible Role of Periodontal Diseases. Alzheimer’s Dement. 2008, 4, 242–250. [Google Scholar] [CrossRef]
- Cekici, A.; Kantarci, A.; Hasturk, H.; Van Dyke, T.E. Inflammatory and Immune Pathways in the Pathogenesis of Periodontal Disease. Periodontol. 2000 2014, 64, 57–80. [Google Scholar] [CrossRef]
- Offenbacher, S.; Barros, S.P.; Beck, J.D. Rethinking Periodontal Inflammation. J. Periodontol. 2008, 79 (Suppl. S8), 1577–1584. [Google Scholar] [CrossRef]
- Ide, M.; Harris, M.; Stevens, A.; Sussams, R.; Hopkins, V.; Culliford, D.; Fuller, J.; Ibbett, P.; Raybould, R.; Thomas, R.; et al. Periodontitis and Cognitive Decline in Alzheimer’s Disease. PLoS ONE 2016, 11, e0151081. [Google Scholar] [CrossRef]
- Ryder, M.I. Porphyromonas gingivalis and Alzheimer Disease: Recent Findings and Potential Therapies. J. Periodontol. 2020, 91 (Suppl. S1), S45–S49. [Google Scholar] [CrossRef]
- Gaur, S.; Agnihotri, R. Alzheimer’s Disease and Chronic Periodontitis: Is There an Association? Geriatr. Gerontol. Int. 2015, 15, 391–404. [Google Scholar] [CrossRef]
- Rolim, T.d.S.; Fabri, G.M.C.; Nitrini, R.; Anghinah, R.; Teixeira, M.J.; de Siqueira, J.T.T.; Cesari, J.A.F.; de Siqueira, S.R.D.T. Evaluation of Patients with Alzheimer’s Disease before and after Dental Treatment. Arq. Neuropsiquiatr. 2014, 72, 919–924. [Google Scholar] [CrossRef]
- Hajishengallis, G.; Chavakis, T.; Lambris, J.D. Current Understanding of Periodontal Disease Pathogenesis and Targets for Host-Modulation Therapy. Periodontol. 2000 2020, 84, 14. [Google Scholar] [CrossRef]
- Kinane, D.F.; Stathopoulou, P.G.; Papapanou, P.N. Periodontal Diseases. Nat. Rev. Dis. Primers 2017, 3, 17038. [Google Scholar] [CrossRef]
- Wu, Z.; Ni, J.; Liu, Y.; Teeling, J.L.; Takayama, F.; Collcutt, A.; Ibbett, P.; Nakanishi, H. Cathepsin B Plays a Critical Role in Inducing Alzheimer’s Disease-like Phenotypes Following Chronic Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis in Mice. Brain Behav. Immun. 2017, 65, 350–361. [Google Scholar] [CrossRef]
- Wang, R.P.H.; Ho, Y.S.; Leung, W.K.; Goto, T.; Chang, R.C.C. Systemic Inflammation Linking Chronic Periodontitis to Cognitive Decline. Brain Behav. Immun. 2019, 81, 63–73. [Google Scholar] [CrossRef]
- Sehar, U.; Rawat, P.; Reddy, A.P.; Kopel, J.; Reddy, P.H. Amyloid Beta in Aging and Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 12924. [Google Scholar] [CrossRef]
- Selkoe, D.J.; Hardy, J. The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years. EMBO Mol. Med. 2016, 8, 595–608. [Google Scholar] [CrossRef]
- Vassar, R.; Bennett, B.D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E.A.; Denis, P.; Teplow, D.B.; Ross, S.; Amarante, P.; Loeloff, R.; et al. Beta-Secretase Cleavage of Alzheimer’s Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE. Science 1999, 286, 735–741. [Google Scholar] [CrossRef]
- Haass, C.; Selkoe, D.J. Soluble Protein Oligomers in Neurodegeneration: Lessons from the Alzheimer’s Amyloid Beta-Peptide. Nat. Rev. Mol. Cell Biol. 2007, 8, 101–112. [Google Scholar] [CrossRef] [PubMed]
- Jarrett, J.T.; Berger, E.P.; Lansbury, P.T. The Carboxy Terminus of the Beta Amyloid Protein Is Critical for the Seeding of Amyloid Formation: Implications for the Pathogenesis of Alzheimer’s Disease. Biochemistry 1993, 32, 4693–4697. [Google Scholar] [CrossRef] [PubMed]
- Finder, V.H.; Glockshuber, R. Amyloid-Beta Aggregation. Neurodegener. Dis. 2007, 4, 13–27. [Google Scholar] [CrossRef]
- Lambert, M.P.; Barlow, A.K.; Chromy, B.A.; Edwards, C.; Freed, R.; Liosatos, M.; Morgan, T.E.; Rozovsky, I.; Trommer, B.; Viola, K.L.; et al. Diffusible, Nonfibrillar Ligands Derived from Abeta1-42 Are Potent Central Nervous System Neurotoxins. Proc. Natl. Acad. Sci. USA 1998, 95, 6448–6453. [Google Scholar] [CrossRef]
- Weingarten, M.D.; Lockwood, A.H.; Hwo, S.Y.; Kirschner, M.W. A Protein Factor Essential for Microtubule Assembly. Proc. Natl. Acad. Sci. USA 1975, 72, 1858–1862. [Google Scholar] [CrossRef]
- Wang, J.Z.; Liu, F. Microtubule-Associated Protein Tau in Development, Degeneration and Protection of Neurons. Prog. Neurobiol. 2008, 85, 148–175. [Google Scholar] [CrossRef] [PubMed]
- Buée, L.; Bussière, T.; Buée-Scherrer, V.; Delacourte, A.; Hof, P.R. Tau Protein Isoforms, Phosphorylation and Role in Neurodegenerative Disorders. Brain Res. Rev. 2000, 33, 95–130. [Google Scholar] [CrossRef]
- Ashton, N.J.; Brum, W.S.; Molfetta, G.D.; Benedet, A.L.; Arslan, B.; Jonaitis, E.; Langhough, R.E.; Cody, K.; Wilson, R.; Carlsson, C.M.; et al. Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology. JAMA Neurol. 2024, 81, 255–263. [Google Scholar] [CrossRef]
- Therriault, J.; Janelidze, S.; Benedet, A.L.; Ashton, N.J.; Arranz Martínez, J.; Gonzalez-Escalante, A.; Bellaver, B.; Alcolea, D.; Vrillon, A.; Karim, H.; et al. Diagnosis of Alzheimer’s Disease Using Plasma Biomarkers Adjusted to Clinical Probability. Nat. Aging 2024, 4, 1529–1537. [Google Scholar] [CrossRef]
- Iqbal, K.; Liu, F.; Gong, C.-X.; Grundke-Iqbal, I. Tau in Alzheimer Disease and Related Tauopathies. Curr. Alzheimer Res. 2010, 7, 656–664. Available online: https://pmc.ncbi.nlm.nih.gov/articles/PMC3090074/ (accessed on 21 May 2025). [CrossRef]
- Goedert, M.; Spillantini, M.G.; Potier, M.C.; Ulrich, J.; Crowther, R.A. Cloning and Sequencing of the CDNA Encoding an Isoform of Microtubule-Associated Protein Tau Containing Four Tandem Repeats: Differential Expression of Tau Protein MRNAs in Human Brain. EMBO J. 1989, 8, 393–399. [Google Scholar] [CrossRef] [PubMed]
- Grundke-Iqbal, I.; Iqbal, K.; Tung, Y.C.; Quinlan, M.; Wisniewski, H.M.; Binder, L.I. Abnormal Phosphorylation of the Microtubule-Associated Protein Tau (Tau) in Alzheimer Cytoskeletal Pathology. Proc. Natl. Acad. Sci. USA 1986, 83, 4913–4917. [Google Scholar] [CrossRef] [PubMed]
- Lee, V.M.Y.; Goedert, M.; Trojanowski, J.Q. Neurodegenerative Tauopathies. Annu. Rev. Neurosci. 2001, 24, 1121–1159. [Google Scholar] [CrossRef]
- Braak, H.; Braak, E. Neuropathological Stageing of Alzheimer-Related Changes. Acta Neuropathol. 1991, 82, 239–259. [Google Scholar] [CrossRef]
- Ittner, L.M.; Götz, J. Amyloid-β and Tau--a Toxic Pas de Deux in Alzheimer’s Disease. Nat. Rev. Neurosci. 2011, 12, 67–72. [Google Scholar] [CrossRef] [PubMed]
- Pooler, A.M.; Polydoro, M.; Maury, E.A.; Nicholls, S.B.; Reddy, S.M.; Wegmann, S.; William, C.; Saqran, L.; Cagsal-Getkin, O.; Pitstick, R.; et al. Amyloid Accelerates Tau Propagation and Toxicity in a Model of Early Alzheimer’s Disease. Acta Neuropathol. Commun. 2015, 3, 14. [Google Scholar] [CrossRef]
- Heneka, M.T.; Golenbock, D.T.; Latz, E. Innate Immunity in Alzheimer’s Disease. Nat. Immunol. 2015, 16, 229–236. [Google Scholar] [CrossRef]
- Prinz, M.; Tay, T.L.; Wolf, Y.; Jung, S. Microglia: Unique and Common Features with Other Tissue Macrophages. Acta Neuropathol. 2014, 128, 319–331. [Google Scholar] [CrossRef]
- De Strooper, B.; Karran, E. The Cellular Phase of Alzheimer’s Disease. Cell 2016, 164, 603–615. [Google Scholar] [CrossRef]
- Hickman, S.E.; Kingery, N.D.; Ohsumi, T.K.; Borowsky, M.L.; Wang, L.C.; Means, T.K.; El Khoury, J. The Microglial Sensome Revealed by Direct RNA Sequencing. Nat. Neurosci. 2013, 16, 1896–1905. [Google Scholar] [CrossRef]
- Tang, Y.; Le, W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol. Neurobiol. 2016, 53, 1181–1194. [Google Scholar] [CrossRef] [PubMed]
- Morales, I.; Jiménez, J.M.; Mancilla, M.; Maccioni, R.B. Tau Oligomers and Fibrils Induce Activation of Microglial Cells. J. Alzheimer’s Dis. 2013, 37, 849–856. [Google Scholar] [CrossRef] [PubMed]
- Asai, H.; Ikezu, S.; Tsunoda, S.; Medalla, M.; Luebke, J.; Haydar, T.; Wolozin, B.; Butovsky, O.; Kügler, S.; Ikezu, T. Depletion of Microglia and Inhibition of Exosome Synthesis Halt Tau Propagation. Nat. Neurosci. 2015, 18, 1584–1593. [Google Scholar] [CrossRef]
- Frost, B.; Diamond, M.I. Prion-like Mechanisms in Neurodegenerative Diseases. Nat. Rev. Neurosci. 2010, 11, 155–159. [Google Scholar] [CrossRef]
- Sofroniew, M.V.; Vinters, H.V. Astrocytes: Biology and Pathology. Acta Neuropathol. 2010, 119, 7–35. [Google Scholar] [CrossRef] [PubMed]
- Maragakis, N.J.; Rothstein, J.D. Mechanisms of Disease: Astrocytes in Neurodegenerative Disease. Nat. Clin. Pract. Neurol. 2006, 2, 679–689. [Google Scholar] [CrossRef]
- Verkhratsky, A. Glial Calcium Signaling in Physiology and Pathophysiology. Acta Pharmacol. Sin. 2006, 27, 773–780. [Google Scholar] [CrossRef]
- Hopp, S.C.; Lin, Y.; Oakley, D.; Roe, A.D.; Devos, S.L.; Hanlon, D.; Hyman, B.T. The Role of Microglia in Processing and Spreading of Bioactive Tau Seeds in Alzheimer’s Disease. J. Neuroinflamm. 2018, 15, 269. [Google Scholar] [CrossRef]
- Puangmalai, N.; Bhatt, N.; Montalbano, M.; Sengupta, U.; Gaikwad, S.; Ventura, F.; McAllen, S.; Ellsworth, A.; Garcia, S.; Kayed, R. Internalization Mechanisms of Brain-Derived Tau Oligomers from Patients with Alzheimer’s Disease, Progressive Supranuclear Palsy and Dementia with Lewy Bodies. Cell Death Dis. 2020, 11, 314. [Google Scholar] [CrossRef]
- Sidoryk-Wegrzynowicz, M.; Wegrzynowicz, M.; Lee, E.; Bowman, A.B.; Aschner, M. Role of Astrocytes in Brain Function and Disease. Toxicol. Pathol. 2011, 39, 115–123. [Google Scholar] [CrossRef]
- Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.C.; et al. NLRP3 Is Activated in Alzheimer’s Disease and Contributes to Pathology in APP/PS1 Mice. Nature 2013, 493, 674–678. [Google Scholar] [CrossRef]
- Selkoe, D.J. Alzheimer’s Disease Is a Synaptic Failure. Science 2002, 298, 789–791. [Google Scholar] [CrossRef] [PubMed]
- Shankar, G.M.; Li, S.; Mehta, T.H.; Garcia-Munoz, A.; Shepardson, N.E.; Smith, I.; Brett, F.M.; Farrell, M.A.; Rowan, M.J.; Lemere, C.A.; et al. Amyloid-Beta Protein Dimers Isolated Directly from Alzheimer’s Brains Impair Synaptic Plasticity and Memory. Nat. Med. 2008, 14, 837–842. [Google Scholar] [CrossRef] [PubMed]
- De Felice, F.G.; Velasco, P.T.; Lambert, M.P.; Viola, K.; Fernandez, S.J.; Ferreira, S.T.; Klein, W.L. Abeta Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-Aspartate Receptor-Dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine. J. Biol. Chem. 2007, 282, 11590–11601. [Google Scholar] [CrossRef] [PubMed]
- Snyder, E.M.; Nong, Y.; Almeida, C.G.; Paul, S.; Moran, T.; Choi, E.Y.; Nairn, A.C.; Salter, M.W.; Lombroso, P.J.; Gouras, G.K.; et al. Regulation of NMDA Receptor Trafficking by Amyloid-Beta. Nat. Neurosci. 2005, 8, 1051–1058. [Google Scholar] [CrossRef]
- Wang, Z.; Jackson, R.J.; Hong, W.; Taylor, W.M.; Corbett, G.T.; Moreno, A.; Liu, W.; Li, S.; Frosch, M.P.; Slutsky, I.; et al. Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP. J. Neurosci. 2017, 37, 11947–11966. [Google Scholar] [CrossRef]
- Bloom, G.S. Amyloid-β and Tau: The Trigger and Bullet in Alzheimer Disease Pathogenesis. JAMA Neurol. 2014, 71, 505–508. [Google Scholar] [CrossRef]
- Ross, F.M.; Allan, S.M.; Rothwell, N.J.; Verkhratsky, A. A Dual Role for Interleukin-1 in LTP in Mouse Hippocampal Slices. J. Neuroimmunol. 2003, 144, 61–67. [Google Scholar] [CrossRef]
- Khatri, A.; Prakash, O.; Agarwal, R.; Kushwaha, S. Systemic Inflammatory Markers and Their Association with Alzheimer’s Disease: A Cross-Sectional Analysis. Indian. J. Psychiatry 2024, 66, 287. [Google Scholar] [CrossRef]
- Kravitz, B.A.; Corrada, M.M.; Kawas, C.H. Elevated C-Reactive Protein Levels Are Associated with Prevalent Dementia in the Oldest-Old. Alzheimer’s Dement. 2009, 5, 318. [Google Scholar] [CrossRef]
- Lyra e Silva, N.M.; Gonçalves, R.A.; Pascoal, T.A.; Lima-Filho, R.A.S.; Resende, E. de P. F.; Vieira, E.L.M.; Teixeira, A.L.; de Souza, L.C.; Peny, J.A.; Fortuna, J.T.S.; et al. Pro-Inflammatory Interleukin-6 Signaling Links Cognitive Impairments and Peripheral Metabolic Alterations in Alzheimer’s Disease. Transl. Psychiatry 2021, 11, 251. [Google Scholar] [CrossRef] [PubMed]
- Meyle, J.; Chapple, I. Molecular Aspects of the Pathogenesis of Periodontitis. Periodontol. 2000 2015, 69, 7–17. [Google Scholar] [CrossRef] [PubMed]
- Gingivitis-StatPearls-NCBI Bookshelf. Available online: https://www.ncbi.nlm.nih.gov/books/NBK557422/ (accessed on 28 February 2025).
- Gil-Montoya, J.A.; Sanchez-Lara, I.; Carnero-Pardo, C.; Fornieles, F.; Montes, J.; Vilchez, R.; Burgos, J.S.; Gonzalez-Moles, M.A.; Barrios, R.; Bravo, M. Is Periodontitis a Risk Factor for Cognitive Impairment and Dementia? A Case-Control Study. J. Periodontol. 2015, 86, 244–253. [Google Scholar] [CrossRef] [PubMed]
- Tzeng, N.S.; Chung, C.H.; Yeh, C.B.; Huang, R.Y.; Yuh, D.Y.; Huang, S.Y.; Lu, R.B.; Chang, H.A.; Kao, Y.C.; Chiang, W.S.; et al. Are Chronic Periodontitis and Gingivitis Associated with Dementia? A Nationwide, Retrospective, Matched-Cohort Study in Taiwan. Neuroepidemiology 2016, 47, 82–93. [Google Scholar] [CrossRef]
- Chen, C.K.; Wu, Y.T.; Chang, Y.C. Association between Chronic Periodontitis and the R isk of Alzheimer’s Disease: A Retrospective, Population-Based, Matched-Cohort Study. Alzheimer’s Res. Ther. 2017, 9, 56. [Google Scholar] [CrossRef]
- Stein, P.S.; Desrosiers, M.; Donegan, S.J.; Yepes, J.F.; Kryscio, R.J. Tooth Loss, Dementia and Neuropathology in the Nun Study. J. Am. Dent. Assoc. 2007, 138, 1314–1322. [Google Scholar] [CrossRef]
- Rubinstein, T.; Brickman, A.M.; Cheng, B.; Burkett, S.; Park, H.; Annavajhala, M.K.; Uhlemann, A.C.; Andrews, H.; Gutierrez, J.; Paster, B.J.; et al. Periodontitis and Brain Magnetic Resonance Imaging Markers of Alzheimer’s Disease and Cognitive Aging. Alzheimer’s Dement. 2024, 20, 2191–2208. [Google Scholar] [CrossRef]
- Avula, H.; Chakravarthy, Y. Models of Periodontal Disease Pathogenesis: A Journey through Time. J. Indian Soc. Periodontol. 2022, 26, 204–212. [Google Scholar] [CrossRef]
- Perry, V.H.; Cunningham, C.; Holmes, C. Systemic Infections and Inflammation Affect Chronic Neurodegeneration. Nat. Rev. Immunol. 2007, 7, 161–167. [Google Scholar] [CrossRef]
- Holmes, C. Review: Systemic Inflammation and Alzheimer’s Disease. Neuropathol. Appl. Neurobiol. 2013, 39, 51–68. [Google Scholar] [CrossRef]
- Holmes, C.; Cunningham, C.; Zotova, E.; Woolford, J.; Dean, C.; Kerr, S.; Culliford, D.; Perry, V.H. Systemic Inflammation and Disease Progression in Alzheimer Disease. Neurology 2009, 73, 768–774. [Google Scholar] [CrossRef] [PubMed]
- Dominy, S.S.; Lynch, C.; Ermini, F.; Benedyk, M.; Marczyk, A.; Konradi, A.; Nguyen, M.; Haditsch, U.; Raha, D.; Griffin, C.; et al. Porphyromonas gingivalis in Alzheimer’s Disease Brains: Evidence for Disease Causation and Treatment with Small-Molecule Inhibitors. Sci. Adv. 2019, 5, eaau3333. [Google Scholar] [CrossRef] [PubMed]
- Itzhaki, R.F.; Wozniak, M.A. Herpes Simplex Virus Type 1, Apolipoprotein E, and Cholesterol: A Dangerous Liaison in Alzheimer’s Disease and Other Disorders. Prog. Lipid Res. 2006, 45, 73–90. [Google Scholar] [CrossRef]
- Siddiqui, H.; Eribe, E.R.; Singhrao, S.K.; Olsen, I. High Throughput Sequencing Detect Gingivitis And Periodontal Oral Bacteria In Alzheimer’s Disease Autopsy Brains. Neuro Res. 2019, 1, 3. [Google Scholar] [CrossRef]
- Emery, D.C.; Shoemark, D.K.; Batstone, T.E.; Waterfall, C.M.; Coghill, J.A.; Cerajewska, T.L.; Davies, M.; West, N.X.; Allen, S.J. 16S RRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer’s Post-Mortem Brain. Front. Aging Neurosci. 2017, 9, 195. [Google Scholar] [CrossRef]
- Kamer, A.R.; Pushalkar, S.; Gulivindala, D.; Butler, T.; Li, Y.; Annam, K.R.C.; Glodzik, L.; Ballman, K.V.; Corby, P.M.; Blennow, K.; et al. Periodontal dysbiosis associates with reduced CSF Aβ42 in cognitively normal elderly. Alzheimer’s Dement. 2021, 13, e12172. [Google Scholar] [CrossRef] [PubMed]
- Stamatovic, S.; Keep, R.; Andjelkovic, A. Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier. Curr. Neuropharmacol. 2008, 6, 179–192. [Google Scholar] [CrossRef]
- Wardlaw, J.M.; Benveniste, H.; Nedergaard, M.; Zlokovic, B.V.; Mestre, H.; Lee, H.; Doubal, F.N.; Brown, R.; Ramirez, J.; MacIntosh, B.J.; et al. Perivascular Spaces in the Brain: Anatomy, Physiology and Pathology. Nat. Rev. Neurol. 2020, 16, 137–153. [Google Scholar] [CrossRef]
- Ganong, W.F. Circumventricular Organs: Definition and Role in the Regulation of Endocrine and Autonomic Function. Clin. Exp. Pharmacol. Physiol. 2000, 27, 422–427. [Google Scholar] [CrossRef]
- Danielyan, L.; Schäfer, R.; von Ameln-Mayerhofer, A.; Buadze, M.; Geisler, J.; Klopfer, T.; Burkhardt, U.; Proksch, B.; Verleysdonk, S.; Ayturan, M.; et al. Intranasal Delivery of Cells to the Brain. Eur. J. Cell Biol. 2009, 88, 315–324. [Google Scholar] [CrossRef]
- Johnson, N.J.; Hanson, L.R.; Frey, W.H. Trigeminal Pathways Deliver a Low Molecular Weight Drug from the Nose to the Brain and Orofacial Structures. Mol. Pharm. 2010, 7, 884–893. [Google Scholar] [CrossRef] [PubMed]
- Riviere, G.; Riviere, K.H.; Smith, K.S. Molecular and Immunological Evidence of Oral Treponema in the Human Brain and Their Association with Alzheimer’s Disease. Oral. Microbiol. Immunol. 2002, 17, 113–118. [Google Scholar] [CrossRef] [PubMed]
- Singhrao, S.K.; Harding, A.; Poole, S.; Kesavalu, L.; Crean, S.J. Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer’s Disease. Mediat. Inflamm. 2015, 1, 137357. [Google Scholar] [CrossRef]
- Zheng, S.; Yu, S.; Fan, X.; Zhang, Y.; Sun, Y.; Lin, L.; Wang, H.; Pan, Y.; Li, C. Porphyromonas gingivalis Survival Skills: Immune Evasion. J. Periodontal Res. 2021, 56, 1007–1018. [Google Scholar] [CrossRef]
- Díaz-Zúñiga, J.; More, J.; Melgar-Rodríguez, S.; Jiménez-Unión, M.; Villalobos-Orchard, F.; Muñoz-Manríquez, C.; Monasterio, G.; Valdés, J.L.; Vernal, R.; Paula-Lima, A. Alzheimer’s Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent. Front. Immunol. 2020, 11, 1007–1018. [Google Scholar] [CrossRef]
- Ilievski, V.; Zuchowska, P.K.; Green, S.J.; Toth, P.T.; Ragozzino, M.E.; Le, K.; Aljewari, H.W.; O’Brien-Simpson, N.M.; Reynolds, E.C.; Watanabe, K. Chronic Oral Application of a Periodontal Pathogen Results in Brain Inflammation, Neurodegeneration and Amyloid Beta Production in Wild Type Mice. PLoS ONE 2018, 13, e0204941. [Google Scholar] [CrossRef] [PubMed]
- Poole, S.; Singhrao, S.K.; Chukkapalli, S.; Rivera, M.; Velsko, I.; Kesavalu, L.; Crean, S. Active Invasion of Porphyromonas gingivalis and Infection-Induced Complement Activation in ApoE-/- Mice Brains. J. Alzheimer’s Dis. 2015, 43, 67–80. [Google Scholar] [CrossRef]
- Nakanishi, H.; Nonaka, S.; Wu, Z. Microglial Cathepsin B and Porphyromonas gingivalis Gingipains as Potential Therapeutic Targets for Sporadic Alzheimer’s Disease. CNS Neurol. Disord. Drug Targets 2020, 19, 495–502. [Google Scholar] [CrossRef]
- Haditsch, U.; Roth, T.; Rodriguez, L.; Hancock, S.; Cecere, T.; Nguyen, M.; Arastu-Kapur, S.; Broce, S.; Raha, D.; Lynch, C.C.; et al. Alzheimer’s Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active Gingipains. J. Alzheimer’s Dis. 2020, 75, 1301–1317. [Google Scholar] [CrossRef]
- Sparks Stein, P.; Steffen, M.J.; Smith, C.; Jicha, G.; Ebersole, J.L.; Abner, E.; Dawson, D. Serum Antibodies to Periodontal Pathogens Are a Risk Factor for Alzheimer’s Disease. Alzheimer’s Dement. 2012, 8, 196–203. [Google Scholar] [CrossRef]
- Sabbagh, M.N.; Decourt, B. COR388 (Atuzaginstat): An Investigational Gingipain Inhibitor for the Treatment of Alzheimer Disease. Expert. Opin. Investig. Drugs 2022, 31, 987. [Google Scholar] [CrossRef] [PubMed]
- Tang, Z.; Cheng, X.; Su, X.; Wu, L.; Cai, Q.; Wu, H. Treponema Denticola Induces Alzheimer-Like Tau Hyperphosphorylation by Activating Hippocampal Neuroinflammation in Mice. J. Dent. Res. 2022, 101, 992–1001. [Google Scholar] [CrossRef] [PubMed]
- Kanagasingam, S.; Chukkapalli, S.S.; Welbury, R.; Singhrao, S.K. Porphyromonas gingivalis Is a Strong Risk Factor for Alzheimer’s Disease. J. Alzheimer’s Dis. Rep. 2020, 4, 501–511. [Google Scholar] [CrossRef]
- Olsen, I. Porphyromonas gingivalis-Induced Neuroinflammation in Alzheimer’s Disease. Front. Neurosci. 2021, 15, 691016. [Google Scholar] [CrossRef]
- Yamada, C.; Akkaoui, J.; Ho, A.; Duarte, C.; Deth, R.; Kawai, T.; Nichols, F.; Lakshmana, M.K.; Movila, A. Potential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen Porphyromonas gingivalis in the Pathogenesis of Alzheimer’s Disease. Front. Immunol. 2020, 11, 1. Available online: https://pubmed.ncbi.nlm.nih.gov/33329577/ (accessed on 21 May 2025). [CrossRef]
- Choe, K.; Park, J.S.; Park, H.Y.; Tahir, M.; Park, T.J.; Kim, M.O. Lupeol Protect against LPS-Induced Neuroinflammation and Amyloid Beta in Adult Mouse Hippocampus. Front. Nutr. 2024, 11, 1414696. [Google Scholar] [CrossRef]
- Godbout, J.P.; Chen, J.; Abraham, J.; Richwine, A.F.; Berg, B.M.; Kelley, K.W.; Johnson, R.W. Exaggerated Neuroinflammation and Sickness Behavior in Aged Mice Following Activation of the Peripheral Innate Immune System. FASEB J. 2005, 19, 1329–1331. [Google Scholar] [CrossRef] [PubMed]
- Zhan, X.; Stamova, B.; Sharp, F.R. Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review. Front. Aging Neurosci. 2018, 10, 42. [Google Scholar] [CrossRef]
- Poole, S.; Singhrao, S.K.; Kesavalu, L.; Curtis, M.A.; Crean, S.J. Determining the Presence of Periodontopathic Virulence Factors in Short-Term Postmortem Alzheimer’s Disease Brain Tissue. J. Alzheimer’s Dis. 2013, 36, 665–677. [Google Scholar] [CrossRef]
- Lee, J.W.; Lee, Y.K.; Yuk, D.Y.; Choi, D.Y.; Ban, S.B.; Oh, K.W.; Hong, J.T. Neuro-Inflammation Induced by Lipopolysaccharide Causes Cognitive Impairment through Enhancement of Beta-Amyloid Generation. J. Neuroinflamm. 2008, 5, 37. [Google Scholar] [CrossRef]
- Jaeger, L.B.; Dohgu, S.; Sultana, R.; Lynch, J.L.; Owen, J.B.; Erickson, M.A.; Shah, G.N.; Price, T.O.; Fleegal-Demotta, M.A.; Butterfiled, D.A.; et al. Lipopolysaccharide Alters the Blood-Brain Barrier Transport of Amyloid Beta Protein: A Mechanism for Inflammation in the Progression of Alzheimer’s Disease. Brain Behav. Immun. 2009, 23, 507–517. [Google Scholar] [CrossRef] [PubMed]
- Lee, D.C.; Rizer, J.; Selenica, M.L.B.; Reid, P.; Kraft, C.; Johnson, A.; Blair, L.; Gordon, M.N.; Dickey, C.A.; Morgan, D. LPS- Induced Inflammation Exacerbates Phospho-Tau Pathology in RTg4510 Mice. J. Neuroinflamm. 2010, 7, 56. [Google Scholar] [CrossRef]
- Rangarajan, M.; Aduse-Opoku, J.; Paramonov, N.A.; Hashim, A.; Curtis, M.A. Hemin Binding by Porphyromonas gingivalis Strains Is Dependent on the Presence of A-LPS. Mol. Oral. Microbiol. 2017, 32, 365–374. [Google Scholar] [CrossRef]
- Olsen, I.; Singhrao, S.K. Importance of Heterogeneity in Porhyromonas Gingivalis Lipopolysaccharide Lipid A in Tissue Specific Inflammatory Signalling. J. Oral. Microbiol. 2018, 10, 1440128. [Google Scholar] [CrossRef]
- Díaz-Zúñiga, J.; Muñoz, Y.; Melgar-Rodríguez, S.; More, J.; Bruna, B.; Lobos, P.; Monasterio, G.; Vernal, R.; Paula-Lima, A. Serotype b of Aggregatibacter Actinomycetemcomitans Triggers Pro-Inflammatory Responses and Amyloid Beta Secretion in Hippocampal Cells: A Novel Link between Periodontitis and Alzheimer’s Disease? J. Oral. Microbiol. 2019, 11, 1586423. [Google Scholar] [CrossRef]
- Hook, V.Y.H.; Kindy, M.; Reinheckel, T.; Peters, C.; Hook, G. Genetic Cathepsin B Deficiency Reduces β-Amyloid in Transgenic Mice Expressing Human Wild-Type Amyloid Precursor Protein. Biochem. Biophys. Res. Commun. 2009, 386, 284. [Google Scholar] [CrossRef]
- Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 Inflammasome Is Involved in the Innate Immune Response to Amyloid-Beta. Nat. Immunol. 2008, 9, 857–865. [Google Scholar] [CrossRef] [PubMed]
- Wu, Z.; Sun, L.; Hashioka, S.; Yu, S.; Schwab, C.; Okada, R.; Hayashi, Y.; McGeer, P.L.; Nakanishi, H. Differential Pathways for Interleukin-1β Production Activated by Chromogranin A and Amyloid β in Microglia. Neurobiol. Aging 2013, 34, 2715–2725. [Google Scholar] [CrossRef] [PubMed]
- Hook, G.; Reinheckel, T.; Ni, J.; Wu, Z.; Kindy, M.; Peters, C.; Hook, V. Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders. Pharmacol. Rev. 2022, 74, 600–629. [Google Scholar] [CrossRef]
- Kornman, K.S.; Page, R.C.; Tonetti, M.S. The Host Response to the Microbial Challenge in Periodontitis: Assembling the Players. Periodontol. 2000 1997, 14, 33–53. [Google Scholar] [CrossRef]
- Gomes-Filho, I.S.; Freitas Coelho, J.M.; da Cruz, S.S.; Passos, J.S.; Teixeira de Freitas, C.O.; Aragão Farias, N.S.; Amorim da Silva, R.; Silva Pereira, M.N.; Lima, T.L.; Barreto, M.L. Chronic Periodontitis and C-Reactive Protein Levels. J. Periodontol. 2011, 82, 969–978. [Google Scholar] [CrossRef] [PubMed]
- Koyama, A.; O’Brien, J.; Weuve, J.; Blacker, D.; Metti, A.L.; Yaffe, K. The Role of Peripheral Inflammatory Markers in Dementia and Alzheimer’s Disease: A Meta-Analysis. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68, 433–440. [Google Scholar] [CrossRef]
- Warren, K.N.; Beason-Held, L.L.; Carlson, O.; Egan, J.M.; An, Y.; Doshi, J.; Davatzikos, C.; Ferrucci, L.; Resnick, S.M. Elevated Markers of Inflammation Are Associated With Longitudinal Changes in Brain Function in Older Adults. J. Gerontol. A Biol. Sci. Med. Sci. 2018, 73, 770–778. [Google Scholar] [CrossRef] [PubMed]
- Kiddle, S.J.; Thambisetty, M.; Simmons, A.; Riddoch-Contreras, J.; Hye, A.; Westman, E.; Pike, I.; Ward, M.; Johnston, C.; Lupton, M.K.; et al. Plasma Based Markers of [11C] PiB-PET Brain Amyloid Burden. PLoS ONE 2012, 7, 44260. [Google Scholar] [CrossRef]
- Wang, R.P.H.; Huang, J.; Chan, K.W.Y.; Leung, W.K.; Goto, T.; Ho, Y.S.; Chang, R.C.C. IL-1β and TNF-α Play an Important Role in Modulating the Risk of Periodontitis and Alzheimer’s Disease. J. Neuroinflamm. 2023, 20, 71. [Google Scholar] [CrossRef]
- Gil Montoya, J.A.; Barrios, R.; Sanchez-Lara, I.; Ramos, P.; Carnero, C.; Fornieles, F.; Montes, J.; Santana, S.; Luna, J.d.D.; Gonzalez-Moles, M.A. Systemic Inflammatory Impact of Periodontitis on Cognitive Impairment. Gerodontology 2020, 37, 11–18. [Google Scholar] [CrossRef]
- Németh, H.; Toldi, J.; Vécsei, L. Kynurenines, Parkinson’s Disease and Other Neurodegenerative Disorders: Preclinical and Clinical Studies. J. Neural Transm. Suppl. 2006, 285–304. [Google Scholar] [CrossRef]
- Kurgan, Ş.; Önder, C.; Balcı, N.; Akdoğan, N.; Altıngöz, S.M.; Serdar, M.A.; Günhan, M. Influence of Periodontal Inflammation on Tryptophan-Kynurenine Metabolism: A Cross-Sectional Study. Clin. Oral. Investig. 2022, 26, 5721–5732. [Google Scholar] [CrossRef] [PubMed]
- Leblhuber, F.; Huemer, J.; Steiner, K.; Gostner, J.M.; Fuchs, D. Knock-on Effect of Periodontitis to the Pathogenesis of Alzheimer’s Disease? Wien. Klin. Wochenschr. 2020, 132, 493–498. [Google Scholar] [CrossRef]
- Olsen, I.; Singhrao, S.K. Can Oral Infection Be a Risk Factor for Alzheimer’s Disease? J. Oral. Microbiol. 2015, 7, 29143. [Google Scholar] [CrossRef]
- French, P.W. Unfolded P53 in Non-Neuronal Cells Supports Bacterial Etiology of Alzheimer’s Disease. Neural Regen. Res. 2022, 17, 2619–2622. [Google Scholar] [CrossRef] [PubMed]
- Piccirella, S.; Van Neste, L.; Fowler, C.; Masters, C.L.; Fripp, J.; Doecke, J.D.; Xiong, C.; Uberti, D.; Kinnon, P. A Conformational Variant of P53 (U-P53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer’s Disease. J. Prev. Alzheimer’s Dis. 2022, 9, 469–479. [Google Scholar] [CrossRef]
- Watabe-Rudolph, M.; Song, Z.; Lausser, L.; Schnack, C.; Begus-Nahrmann, Y.; Scheithauer, M.O.; Rettinger, G.; Otto, M.; Tumani, H.; Thal, D.R.; et al. Chitinase Enzyme Activity in CSF Is a Powerful Biomarker of Alzheimer Disease. Neurology 2012, 78, 569–577. [Google Scholar] [CrossRef] [PubMed]
- Castellani, R.J.; Perry, G.; Smith, M.A. The Role of Novel Chitin-like Polysaccharides in Alzheimer Disease. Neurotox. Res. 2007, 12, 269–274. [Google Scholar] [CrossRef]
- Kamer, A.R.; Craig, R.G.; Pirraglia, E.; Dasanayake, A.P.; Norman, R.G.; Boylan, R.J.; Nehorayoff, A.; Glodzik, L.; Brys, M.; de Leon, M.J. TNF-Alpha and Antibodies to Periodontal Bacteria Discriminate between Alzheimer’s Disease Patients and Normal Subjects. J. Neuroimmunol. 2009, 216, 92–97. [Google Scholar] [CrossRef] [PubMed]
- Noble, J.M.; Borrell, L.N.; Papapanou, P.N.; Elkind, M.S.V.; Scarmeas, N.; Wright, C.B. Periodontitis Is Associated with Cognitive Impairment among Older Adults: Analysis of NHANES-III. J. Neurol. Neurosurg. Psychiatry 2009, 80, 1206. [Google Scholar] [CrossRef]
- Al-Sharqi, A.J.; Abdulkareem, A. Microbiological and Salivary Biomarkers Successfully Predict Site-Specific and Whole-Mouth Outcomes of Nonsurgical Periodontal Treatment. J. Clin. Med. 2024, 13, 4256. [Google Scholar] [CrossRef]
- Loos, B.G. Systemic Markers of Inflammation in Periodontitis. J. Periodontol. 2005, 76, 2106–2115. [Google Scholar] [CrossRef]
- Papapanou, P.N. Systemic Effects of Periodontitis: Lessons Learned from Research on Atherosclerotic Vascular Disease and Adverse Pregnancy Outcomes. Int. Dent. J. 2015, 65, 283–291. [Google Scholar] [CrossRef]
- Thakkar, A.; Vora, A.; Kaur, G.; Akhtar, J. Dysbiosis and Alzheimer’s Disease: Role of Probiotics, Prebiotics and Synbiotics. Naunyn Schmiedebergs Arch. Pharmacol. 2023, 396, 2911–2923. [Google Scholar] [CrossRef]
- Rong, X.; Xiang, L.; Li, Y.; Yang, H.; Chen, W.; Li, L.; Liang, D.; Zhou, X. Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics. Front. Aging Neurosci. 2020, 12, 248. [Google Scholar] [CrossRef] [PubMed]
- Li, A.; Du, M.; Chen, Y.; Marks, L.A.M.; Visser, A.; Xu, S.; Tjakkes, G.H.E. Periodontitis and Cognitive Impairment in Older Adults: The Mediating Role of Mitochondrial Dysfunction. J. Periodontol. 2022, 93, 1302–1313. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Lv, J.; Bai, H.; Ren, L.; Yang, J.; Ding, Y.; Liu, C.; Chen, X. Periodontal Status and Saliva Metabolic Signature in Patients with Alzheimer’s Disease. J. Alzheimer’s Dis. 2023, 95, 603–613. [Google Scholar] [CrossRef] [PubMed]
- Qiu, C.; Zhou, W.; Shen, H.; Wang, J.; Tang, R.; Wang, T.; Xie, X.; Hong, B.; Ren, R.; Wang, G.; et al. Profiles of Subgingival Microbiomes and Gingival Crevicular Metabolic Signatures in Patients with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease. Alzheimer’s Res. Ther. 2024, 16, 41. [Google Scholar] [CrossRef] [PubMed]
- Li, R.; Wang, J.; Xiong, W.; Luo, Y.; Feng, H.; Zhou, H.; Peng, Y.; He, Y.; Ye, Q. The Oral-Brain Axis: Can Periodontal Pathogens Trigger the Onset and Progression of Alzheimer’s Disease? Front. Microbiol. 2024, 15, 1358179. [Google Scholar] [CrossRef]
- Lu, J.; Zhang, S.; Huang, Y.; Qian, J.; Tan, B.; Qian, X.; Zhuang, J.; Zou, X.; Li, Y.; Yan, F. Periodontitis-Related Salivary Microbiota Aggravates Alzheimer’s Disease via Gut-Brain Axis Crosstalk. Gut Microbes 2022, 14, 2126272. [Google Scholar] [CrossRef]
- Sait, A.M.; Day, P.J.R. Interconnections between the Gut Microbiome and Alzheimer’s Disease: Mechanisms and Therapeutic Potential. Int. J. Mol. Sci. 2024, 25, 8619. [Google Scholar] [CrossRef]
- Ma, Y.Y.; Li, X.; Yu, J.T.; Wang, Y.J. Therapeutics for Neurodegenerative Diseases by Targeting the Gut Microbiome: From Bench to Bedside. Transl. Neurodegener. 2024, 13, 12. [Google Scholar] [CrossRef]
- Martínez-García, M.; Hernández-Lemus, E. Periodontal Inflammation and Systemic Diseases: An Overview. Front. Physiol. 2021, 12, 709438. [Google Scholar] [CrossRef]
- Guo, H.; Chang, S.; Pi, X.; Hua, F.; Jiang, H.; Liu, C.; Du, M. The Effect of Periodontitis on Dementia and Cognitive Impairment: A Meta-Analysis. Int. J. Environ. Res. Public Health 2021, 18, 6823. [Google Scholar] [CrossRef]
- Chen, H.-L.; Wu, D.-R.; Lien, S.; Lin, C.-H. Association between periodontitis treatment and dementia in Taiwanese adults. Open Access BMC Oral Health 2023, 23, 969. [Google Scholar] [CrossRef] [PubMed]
- Harding, A.; Gonder, U.; Robinson, S.J.; Crean, S.J.; Singhrao, S.K. Exploring the Association between Alzheimer’s Disease, Oral Health, Microbial Endocrinology and Nutrition. Front. Aging Neurosci. 2017, 9, 398. [Google Scholar] [CrossRef] [PubMed]
- Schwahn, C.; Frenzel, S.; Holtfreter, B.; Van der Auwera, S.; Pink, C.; Bülow, R.; Friedrich, N.; Völzke, H.; Biffar, R.; Kocher, T.; et al. Effect of Periodontal Treatment on Preclinical Alzheimer’s Disease—Results of a Trial Emulation Approach. Alzheimer’s Dement. 2022, 18, 127–141. [Google Scholar] [CrossRef] [PubMed]
- Farsai, P.S. Cognitive Impairment in Older Adults and Oral Health Considerations: Treatment and Management. Dent. Clin. N. Am. 2021, 65, 345–360. [Google Scholar] [CrossRef]
- Brennan, L.J.; Strauss, J. Cognitive Impairment in Older Adults and Oral Health Considerations: Treatment and Management. Dent. Clin. N. Am. 2014, 58, 815–828. [Google Scholar] [CrossRef]
- Chalmers, J.; Pearson, A. Oral hygiene care for residents with dementia: A literature review. J. Adv. Nurs. 2005, 52, 410–419. [Google Scholar] [CrossRef]
- Rozas, N.S.; Sadowsky, J.M.; Jeter, C.B. Strategies to Improve Dental Health in Elderly Patients with Cognitive Impairment: A Systematic Review. J. Am. Dent. Assoc. 2017, 148, 236–245.e3. [Google Scholar] [CrossRef]
- Singhrao, S.K.; Olsen, I. Assessing the Role of Porphyromonas gingivalis in Periodontitis to Determine a Causative Relationship with Alzheimer’s Disease. J. Oral. Microbiol. 2019, 11, 1563405. [Google Scholar] [CrossRef]
- Kamer, A.R.; Fortea, J.O.; Videla, S.; Mayoral, A.; Janal, M.; Carmona-Iragui, M.; Benejam, B.; Craig, R.G.; Saxena, D.; Corby, P.; et al. Periodontal Disease’s Contribution to Alzheimer’s Disease Progression in Down Syndrome. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2016, 2, 49. [Google Scholar] [CrossRef]
- Harding, A.; Robinson, S.; Crean, S.; Singhrao, S.K. Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer’s Disease? J. Alzheimer’s Dis. 2017, 58, 337–348. [Google Scholar] [CrossRef]
- Harding, A.; Kanagasingam, S.; Welbury, R.; Singhrao, S.K. Periodontitis as a Risk Factor for Alzheimer’s Disease: The Experimental Journey So Far, with Hope of Therapy. Adv. Exp. Med. Biol. 2022, 1373, 241–260. [Google Scholar] [CrossRef] [PubMed]
- Cobb, C.M. Clinical Significance of Non-Surgical Periodontal Therapy: An Evidence-Based Perspective of Scaling and Root Planing. J. Clin. Periodontol. 2002, 29 (Suppl. S2), 22–32. [Google Scholar] [CrossRef]
- Haffajee, A.D.; Cugini, M.A.; Dibart, S.; Smith, C.; Kent, R.L., Jr.; Socransky, S.S. The Effect of SRP on the Clinical and Microbiological Parameters of Periodontal Diseases. J. Clin. Periodontol. 1997, 24, 324–334. [Google Scholar] [CrossRef]
- Drisko, C.H. Nonsurgical Periodontal Therapy. Periodontol. 2000 2001, 25, 77–88. [Google Scholar] [CrossRef] [PubMed]
- Zhang, M.; Mi, N.; Ying, Z.; Lin, X.; Jin, Y. Advances in the Prevention and Treatment of Alzheimer’s Disease Based on Oral Bacteria. Front. Psychiatry 2023, 14, 1291455. [Google Scholar] [CrossRef] [PubMed]
- Kwon, T.H.; Lamster, I.B.; Levin, L. Current Concepts in the Management of Periodontitis. Int. Dent. J. 2021, 71, 462–476. [Google Scholar] [CrossRef]
- Peters, R.; Poulter, R.; Warner, J.; Beckett, N.; Burch, L.; Bulpitt, C. Smoking, Dementia and Cognitive Decline in the Elderly, a Systematic Review. BMC Geriatr. 2008, 8, 36. [Google Scholar] [CrossRef]
- Shaik, M.; Ahmad, S.; Gan, S.; Abuzenadah, A.; Ahmad, E.; Tabrez, S.; Ahmed, F.; Kamal, M. How Do Periodontal Infections Affect the Onset and Progression of Alzheimer’s Disease? CNS Neurol. Disord. Drug Targets 2014, 13, 460–466. [Google Scholar] [CrossRef]
- Okamoto, N.; Morikawa, M.; Amano, N.; Yanagi, M.; Takasawa, S.; Kurumatani, N. Effects of Tooth Loss and the Apolipoprotein E ε4 Allele on Mild Memory Impairment in the Fujiwara-Kyo Study of Japan: A Nested Case-Control Study. J. Alzheimer’s Dis. 2017, 55, 575. [Google Scholar] [CrossRef]
Biomarker(s) | Sample Type | Reference | Year | Study Design | Number of Subjects | Key Finding/s |
---|---|---|---|---|---|---|
IL1-Ra | Blood | Gil Montoya, José Antonio et al. [130] | 2020 | Case–control study | Case (n = 171) and control (n = 131) | Among patients with periodontal disease and dementia, 70% had AD; 29 inflammatory biomarkers were analyzed. IL 1-Ra was significantly elevated in mild periodontitis (p < 0.018) and was associated with cognitive impairment (Crude OR = 2.92; 95% CI = 1.14 to 7.46). |
Cathepsin B | Blood | Rong, Xianfang et al. [145] | 2020 | Case–control study | Case (n = 23) and control (n = 45) | Compared with controls, patients with chronic periodontal disease demonstrated elevations in five biomarkers involved in AD pathogenesis, with cathepsin B being the most notable one (42% increase in periodontal disease compared to control, p < 0.01; and correlation with MME score, r = −0.874, p < 0.001). |
Periodontal bacterial antibodies | Blood | Sparks Stein, Pamela et al. [104] | 2012 | Retrospective study | 158 | Levels of antibodies against F. nucleatum and P. intermedia were higher in patients who developed AD (6.1 ± 0.4 in healthy controls vs. 10.0 ± 1.5 in chronic periodontitis; and 6.2 ± 0.4 in healthy controls vs. 15.9 ± 2.2 in chronic periodontitis, respectively. p < 0.0001). |
Neopterin and KYN | Blood | Leblhuber, Friedrich et al. [132] | 2020 | Clinical trial | 20 | Serum levels of neopterin and KYN, which are precursors of adaptive cell metabolites, were low in patients with periodontal disease and AD (positive for periodontal pathogen compared to control negative for periodontal pathogen; positive 6.14 ± 0.65 vs. negative 9.58 ± 0.73 nmol/L; U = 2.533, p < 0.01 for neopterin, and positive 1.64 ± 0.17 vs. negative: 2.16 ± 0.20; U = 1.980, p < 0.05 for KYN). |
Methylmalonic acid (MMA) | Blood | Li, An et al. [146] | 2022 | Cross-sectional study | 1883 | Serum MMA was correlated with lower scores of cognitive performance in patients with periodontal disease and cognitive impairment, including AD. (Fully adjusted weighted β coefficient (SE) for CERAD immediate recall −0.229 (0.023) and −0.331 (0.036) for Stage III and Stage IV periodontitis, respectively; p < 0.05. For Digit symbol substitution test, fully adjusted weighted β coefficient (SE) −0.139 (0.019) and −0.144 (0.031) for Stage III and Stage IV periodontitis, respectively; p < 0.05.) |
5-cyclohexadiene-1,2-diol, dodecanoic acid, Cis-3-(1-carboxy-ethyl)-3, and N,N-dimethylethanolamine N-oxide | Salivary | Yang, Yi et al. [147] | 2023 | Case–control study | Case (n = 30), control (n = 30) | Salivary biomarkers are potential candidates for AD screening in patients with periodontal disease (ROC value = 0.95). |
Galactinol, sn-glycerol 3-phosphoethanolamine, D-mannitol, 1 h-indole-1-pentanoic acid, 3-(1-naphthalenylcarbonyl)-, and L-iditol | Salivary | Qiu, Che et al. [148] | 2024 | Cross-sectional study | 64 | The levels of these periodontal pathogen’s metabolites in GCF were correlated with AD progression (for galactinol, AUC = 0.98 in AD vs. mild cognitive impairment/normal (aMCI/CN; for sn-glycerol 3-phosphoethanolamine, AUC = 0.98 in AD vs. aMCI and AUC = 0.99 in AD vs. CN). |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Gharaibeh, S.; Alsabbah, A.; Alloubani, A.; Gharaibeh, A. Reciprocal Interactions Between Periodontal Disease and Alzheimer’s Disease: Implications for Mutual Triggering, Exacerbation, and Treatment Interventions—A Comprehensive Review of the Literature. Neurol. Int. 2025, 17, 81. https://doi.org/10.3390/neurolint17060081
Gharaibeh S, Alsabbah A, Alloubani A, Gharaibeh A. Reciprocal Interactions Between Periodontal Disease and Alzheimer’s Disease: Implications for Mutual Triggering, Exacerbation, and Treatment Interventions—A Comprehensive Review of the Literature. Neurology International. 2025; 17(6):81. https://doi.org/10.3390/neurolint17060081
Chicago/Turabian StyleGharaibeh, Shatha, Alameen Alsabbah, Ahmad Alloubani, and Abeer Gharaibeh. 2025. "Reciprocal Interactions Between Periodontal Disease and Alzheimer’s Disease: Implications for Mutual Triggering, Exacerbation, and Treatment Interventions—A Comprehensive Review of the Literature" Neurology International 17, no. 6: 81. https://doi.org/10.3390/neurolint17060081
APA StyleGharaibeh, S., Alsabbah, A., Alloubani, A., & Gharaibeh, A. (2025). Reciprocal Interactions Between Periodontal Disease and Alzheimer’s Disease: Implications for Mutual Triggering, Exacerbation, and Treatment Interventions—A Comprehensive Review of the Literature. Neurology International, 17(6), 81. https://doi.org/10.3390/neurolint17060081