Investigating the association between periodontal disease and Alzheimer's disease: a scoping review

Investigating the association between periodontal disease and Alzheimer's disease: a scoping review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Investigating the association between periodontal disease and Alzheimer's disease: a scoping review Xiaocui Zhang, Diemeng Chang, Yanli Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4199610/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The objective of this study was to evaluate and present evidence from animal and human clinical studies on associations between periodontal disease (PD) and Alzheimer's disease (AD), and to suggest potential mechanisms that might explain such associations. Methods An electronic search was conducted of PubMed, Embase and Cochrane Central Register of Controlled Trials for articles published from 2004to 2024 in the English language. From the initial search, 357 full-text studies were assessed for eligibility. After excluding studies for technical and study limitations, a total of 39 studies were included in the summary tables and additional studies were included in the review to support evidence. Results A total of 39 studies on the correlation between periodontal disease (PD) and Alzheimer 's disease (AD) were included in this study. Among them, 22 articles were related studies, and 20 studies showed that there was a correlation between PD and AD. 15 articles were related to mechanism research, and the research showed that PD is associated with brain Aβ and tau protein aggregation, the inflammatory response caused by PD is closely related to AD and P. gingivalis is closely related to the development of AD. Two latest treatment studies, studies have shown that gingipain inhibitors could be valuable for treating Pg brain colonization and neurodegeneration in AD and nisin abrogation of brain microbiome dysbiosis induces beneficial effects on AD-like pathogenic changes and neuroinfammation. Conclusions This scoping review shows that periodontal disease (PD) is associated with the progression of Alzheimer 's disease (AD). PD has been proposed as a potentially modifiable etiological factor for AD, which opens up new therapeutic strategies for the prevention or management of AD. periodontal disease Alzheimer's disease scoping review 1. Background Alzheimer 's disease (AD) is the most common type of dementia, accounting for 60–80% of all dementia cases [ 1 ] . It is estimated that the number of dementia patients in the world will reach 74.7 million by 2030, and the number of deaths caused by AD will increase by more than 40% [ 2 ] . In addition, the economic burden of disease caused by AD is also serious. In 2019, the total cost of AD and other types of dementia patients was as high as USD 2900 billion [ 3 ] . Mild cognitive impairment (MCI) is a concept proposed by Petersen et al.in 1995, which is defined as a condition in which cognitive function is lower than expected due to physiological aging. It is an intermediate state between normal cognition and pre-dementia. It has also been identified as the first clinical stage of AD [ 4 ] . The ability to carry out daily activities in the MCI state is still normal. Systematic review found that 32% of MCI cases will be converted to AD within 5 years [ 5 ] . However, this process is reversible [ 6 ] . Interventions that eliminate related risk factors or enhance preventive factors in patients with MCI can effectively prevent AD [ 7 ] . Therefore, controlling the development of MCI is important for AD prevention. Periodontal disease (PD) is an inflammatory injury of periodontal protection and supporting tissues caused by pathogenic bacteria or plaque biofilm, mainly including gingival disease and periodontitis. The survey results of Eke et al. showed that about 64% of adults over 65 years old had chronic moderate to severe periodontitis [ 8 ] . PD is not only a common chronic inflammatory oral disease, but also can lead to stroke, major depression, diabetes, chronic kidney disease, dyslipidemia and other systemic diseases [ 9 , 10 ] . Nowadays, people are paying more and more attention to the relationship between periodontal disease and AD or MCI. Periodontal disease seems to be related to AD and MCI. At present, there is an urgent need to determine the modifiable factors of AD risk in the absence of cure methods. This scoping review compiled and evaluated recent evidence from clinical human studies that assessed associations between PD and AD and potential mechanisms for such associations. Specifcally, a scoping review was undertaken to establish areas in which evidence on associations between PD and AD is available. 2. Methods 2.1 Data sources Two independent investigators (Xiaocui Zhang & Diemeng Chang) independently searched PubMed, Cochrane library, and EMBASE databases in february 2024 in PubMed, Embase and Cochrane Central Register for Controlled Trials. Results were limited to articles published from 2004 to 2024 in the English language. 2.2 Search strategy The following search strategy in PubMed utilized both keyword terms in the title and abstract felds as well as Medical Subject Headings (MeSH) to identify possible qualifying articles: ((((("Periodontal Diseases"[Mesh]) OR (Disease, Periodontal[Title/Abstract]) OR (Diseases, Periodontal[Title/Abstract])) OR (Periodontal Disease[Title/Abstract])) OR (Parodontosis[Title/Abstract])) OR (Parodontoses[Title/Abstract])) OR (Pyorrhea Alveolaris[Title/Abstract]) AND (((((((((((((((((((((((((((((((((("Alzheimer Disease"[Mesh]) OR (Alzheimer Dementia[Title/Abstract]) OR (Alzheimer Dementias[Title/Abstract])) OR (Dementia, Alzheimer[Title/Abstract])) OR (Alzheimer's disease[Title/Abstract])) OR (Dementia, Senile[Title/Abstract])) OR (Senile Dementia[Title/Abstract])) OR (Dementia, Alzheimer Type[Title/Abstract])) OR (Alzheimer Type Dementia[Title/Abstract])) OR (Alzheimer-Type Dementia (ATD[Title/Abstract]))) OR (Alzheimer Type Dementia (ATD[Title/Abstract]))) OR (Dementia, Alzheimer-Type (ATD[Title/Abstract]))) OR (Alzheimer Type Senile Dementia[Title/Abstract])) OR (Primary Senile Degenerative Dementia[Title/Abstract])) OR (Dementia, Primary Senile Degenerative[Title/Abstract])) OR (Alzheimer Sclerosis[Title/Abstract])) OR (Sclerosis, Alzheimer[Title/Abstract])) OR (Alzheimer Syndrome[Title/Abstract])) OR (Alzheimer's diseases[Title/Abstract])) OR (Alzheimer Diseases[Title/Abstract])) OR (Alzheimers Diseases[Title/Abstract])) OR (Senile Dementia, Alzheimer Type[Title/Abstract])) OR (Acute Confusional Senile Dementia[Title/Abstract])) OR (Senile Dementia, Acute Confusional[Title/Abstract])) OR (Dementia, Presenile[Title/Abstract])) OR (Presenile Dementia[Title/Abstract])) OR (Alzheimer Disease, Late Onset[Title/Abstract])) OR (Late Onset Alzheimer Disease[Title/Abstract])) OR (Alzheimer's disease, Focal Onset[Title/Abstract])) OR (Focal Onset Alzheimer's disease[Title/Abstract])) OR (Familial Alzheimer Disease (FAD[Title/Abstract]))) OR (Alzheimer Disease, Familial (FAD[Title/Abstract]))) OR (Familial Alzheimer Diseases (FAD[Title/Abstract]))) OR (Alzheimer Disease, Early Onset[Title/Abstract])) OR (Early Onset Alzheimer Disease[Title/Abstract])) OR (Presenile Alzheimer Dementia[Title/Abstract]). This search was translated and updated for Embase and Cochrane Central Register of Controlled Trials accordingly [11] . 2.3 Data fltering Search results were then saved and exported into EndNote, a bibliographic software program, to store, organize, and manage all results [12] . After removal of duplicates, titles were examined by one author (Xiaocui Zhang) and articles unrelated to PD and AD were removed. For retained articles, clinical human and animal studies were included where associations between PD and AD were explored or a potential mechanism was elucidated. And systematic and retrospective reviews were excluded. After title-based fltering, their eligibility was assessed by abstract-based fltering by two authors (Xiaocui Zhang and Diemeng Chang). After the evaluation, we resolved the differences between the two reviewers (Xiaocui Zhang and Diemeng Chang) through discussion with the third reviewer (Yanli Wu). When articles were on the topic of associations between PD and AD. The reference lists of included studies were hand searched and citations of all included studies were checked to ensure search completeness [12] . Individual studies were tabulated and brief description of the following parameters were provided: name of frst author, year of publication, number of participants, country of study participants, study design, study population (human or animal), objective of the study, outcomes including statistical parameters and conclusions (Tables 1-3). 3. Results The initial search yielded 761 results. After deduplication, 603 articles were further evaluated, of which 246 studies were excluded for systematic and retrospective reviews. The remaining 357 full-text articles were assessed, and after excluding studies where PD and/or AD was not the primary variable of interest, 39 studies were included in the summary tables. 21 studies explored the correlation between PD and AD through clinical research (Table 1). 16 studies explored the potential mechanism of the correlation between PD and AD, within 6 clinical studies, 7 animal studies and 3 cell researches (Table 2). 2 animal studies reported the treatment progress based on the potential mechanism of the correlation between PD and AD (Table 3). 4. Discussion 4.1 The correlation between PD and AD Most studies have shown that PD is associated with AD [ 9 , 13 – 24 ] . A 10-year cohort study found that the risk of AD in PD patients was 1.707 times higher than that without PD patients [ 25 ] . The results of a 13-year retrospective cohort study showed that the risk of AD in PD patients was 1.667 times higher than that without PD patients [ 13 ] . Another 10-year retrospective cohort study showed that the risk of AD in PD patients was 1.05 times higher than that without PD patients [ 9 ] . In addition, studies have shown that PD is also associated with MCI in the preclinical stage of AD [ 14 , 26 ] . Kamer AR and Na HS found that plasma TNF-alpha, antibodies against periodontal bacteria and potential periodontal pathogens were elevated in AD patients compared with normal controls [ 27 – 29 ] . Besides, Sparks Stein P found that in the years before the cognitive impairment, subjects had elevated antibodies to periodontal bacteria [ 30 ] . At the same time, studies have shown that the risk of PD in AD patients increased [ 20 , 31 ] . But a bidirectional mendelian randomization study invovled 117386 European patients showed that PD is not the cause of AD development [ 32 ] . And a cross-sectional study showed that clusters of IgG antibodies against periodontal microorganisms did not predict AD mortality [ 33 ] . In general, the general trend of most studies investigating the cross-sectional or longitudinal association between PD and AD suggests that there is a positive correlation between these two disease processes. 4.2 Potential mechanisms on PD and AD AD is a progressive neurodegenerative disease, neuropathologically characterised by intracerebral, extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles (NFTs). The cause of sporadic AD, and the pathophysiological mechanisms involved, remain major unanswered questions in medical science. At present, the three major hypotheses for the initiation and progression of AD mainly include: the β-amyloid hypothesis [ 34 ] , the microbiome-infection hypothesis [ 35 ] , and the inflammation-host response hypothesis [ 36 ] 4.2.1 PD is associated with brain Aβ and tau protein aggregation According to the amyloid hypothesis, abnormal accumulation of Aβ in certain brain regions can lead to neuronal dysfunction and subsequent neuronal death. Aβ deposition comes from amyloid precursor protein (APP), which is selectively cleaved into amyloid proteins of different lengths by a series of enzymes (mainly secretory enzymes). The Aβ plaques formed by these proteins in the brain can induce a local inflammatory response mainly driven by microglia, leading to the proliferation of microglia and the release of inflammatory mediators, which in turn damages neuronal cells, interneuronal cells and blood-brain barrier [ 37 ] . In addition, this inflammatory response, together with the microbiota that can penetrate the blood-brain barrier, induces tau protein phosphorylation and cleavage [ 38 ] . The lysed tau protein fragment can form neurofibrillary tangles (NFTs) and cause toxicity to neuronal cells, leading to neuronal cell death and brain region atrophy [ 39 ] . For example, existing studies have shown that PD is related to the aggregation of Aβ and tau protein in the brain. Kubota T et al. [ 40 ] speculated that periodontitis is involved in the synthesis and accumulation of Aβ in the brain, leading to the occurrence of AD. The results of Kamer AR et al. [ 41 ] confirmed the relevant speculation, and the results showed that the disappearance of periodontal attachment ≥ 3 mm was related to the increase of Aβ load. The results of cell research carried out by Díaz-Zúñiga J et al. showed that stimulating microglia with aggregatibacter actinomycetemcomitans, the most aggressive form of PD, will increase extracellular Aβ levels [ 42 ] . Animal studies carried out by Ilievski V and Qian X et al.showed that Aβ protein accumulation was higher in PD mice [ 43 , 44 ] . Besides, Ilievski V et al. found that APP and beta-site APP cleaving enzyme 1 gene expression were increased in PD mice, and phospho-Tau protein was detected and NFTs were evident in PD mice but not in the nomal mice [ 43 ] . 4.2.2 The inflammatory response caused by PD is closely related to AD Current proposals on how PD may promote the progression of AD. PD have been proposed to promote AD pathology by two mechanisms. Firstly, PD may impact the central nervous system indirectly by provoking microbiota-gut-brain axis disorders in the alimentary tract. This induces chronic systemic inflammation which subsequently extends to the brain adding to the load of neuroinflammation. The animal experimental study carried out by Li X et al. found that PD mice exhibited significant dysbiosis of the oral and gut microbiota, disruption of the intestinal barrier and blood-brain barrier [ 30 ] . The animal experimental study carried out by Lu J et al. found that AD-related pathologies in PD mice were consistent with gut microbial dysbiosis, intestinal proinflammatory responses, intestinal barrier impairment, and subsequent exacerbation of systemic inflammation [ 45 ] . Secondly, discontinuous sites within inflamed periodontal pocket epithelia allow periodontal bacteria to invade adjacent primary afferent nerves and blood vessels, along which they escape the oral cavity and directly access the brain, leading to brain infection. 4.2.3 P.gingivalis is closely related to the development of AD Although a number of oral bacteria have been associated with the neuropathology of AD we here focus on P. gingivalis (Pg) as this bacterium is by far the best studied and a major bacterial pathobiont that emerges as part of a subgingival pathogenic polymicrobial community during periodontitis. Poole S et al. found that lipopolysaccharide (LPS) from Pg could be detected in brain tissue samples of AD patients after death, while the samples of patients without cognitive impairment were negative [ 46 ] .Natsu Sato d et al. 's cell research found that interleukin-6 (IL-6) and C-C motif chemokine ligand 2 produced upon Pg LPS stimulation may contribute to the inflammatory reactions in brain endothelial cells and subsequent neurological disorders such as AD [ 47 ] . Yamada C et al. 's cell research found that Pg phosphoglycerol dihydroceramide ceramide promotes amyloidogenesis and hyperphosphorylation [ 48 ] . Dominy SS et al. proposed that increased Pg DNA levels in saliva and cerebrospinal fluid are associated with AD [ 49 ] . 4.3 The correlation between PD treatment management and AD For AD treatment, there are currently no approved drug treatments or other interventions with disease modification or regeneration characteristics, and the available drugs have mild and transient effects [ 50 ] . Effective treatment of AD needs to start earlier in the event chain, that is from the actual loss of cognitive function to the 'upstream'. These will include effective intervention and prevention of the occurrence and development of AD before advanced cognitive decline. Low levels of systemic inflammation and peripheral infectious diseases, including PD, have been proposed as potentially modifiable etiological factors of AD, which in turn opens up new therapeutic strategies for the prevention or management of AD [ 49 ] . With the potential link between PD and AD and other forms of dementia, reducing the load of oral microbiome and the inflammatory response to this microbiome is not only essential for the treatment of PD in patients with cognitive impairment, but also may be beneficial to reduce the incidence, severity and rate of cognitive decline. Many studies have directly or indirectly demonstrated the benefits of periodontal treatment in preventing the occurrence and development of AD. Schwahn C et al. [ 14 ] proposed that periodontal treatment had a favorable effect on AD-related brain atrophy. Saito M et al. [ 23 ] proposed that receiving periodontal treatment on many days had a low risk of AD. Recent animal experiment suggested that gingipain inhibitors could be valuable for treating Pg brain colonization and neurodegeneration in AD [ 49 ] . And Zhao C et al. proposed that nisin abrogation of brain microbiome dysbiosis induces beneficial effects on AD-like pathogenic changes and neuroinfammation, and thereby may serve as a potential therapeutic for periodontal–dysbiosis-related AD [ 51 ] . 5. Conclusion In summary, PD and AD are closely related and may be risk factors for each other. On the one hand, AD patients do not pay attention to oral hygiene, and with the progress of cognitive impairment, daily oral care is not sufficient, resulting in poor periodontal status than non-AD patients, and the probability of PD is higher. On the other hand, PD spreads to the brain through periodontal pathogens and inflammatory mediators to activate microglia and induce neuroinflammation, thereby promoting the formation and development of AD. The risk of AD in patients with PS is higher than that in patients without PD. In addition, studies have shown that PD is also associated with MCI in the preclinical stage of AD [ 14 , 26 ] . Unlike AD, MCI is reversible, and studies have shown that about 20% of MCI patients' cognitive function improves over time [ 2 ] . Therefore, PD has been proposed as a potentially modifiable etiological factor for AD, which opens up new therapeutic strategies for the prevention or management of AD. Many studies have demonstrated the benefits of periodontal treatment in preventing the occurrence and development of AD [ 14 ] [ 23 ] . Animal studies showed gingipain inhibition reduced the bacterial load of an established Pg brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus [ 45 ] . And Nisin treatment signifcantly decreased the mRNA expression of proinfammatory cytokines (nterleukin-1β, nterleukin-6, and TNF-α) in the brain that were elevated by periodontal infection and markedly reduced the Aβ42, total Tau, and phosphorylated Tau deposition in the brain of the infection group [ 51 ] . This provides a new direction for PD-related AD treatment and can be further explored in future studies. Abbreviations PD: Periodontal disease AD: Alzheimer Disease MCI: Mild cognitive impairment Aβ: Amyloid-β NFTs: Neurofibrillary tangles APP: Amyloid precursor protein Pg: P.gingivalis LPS: Lipopolysaccharide IL-6: Interleukin-6 Declarations Ethics approval and consent to participate : Not applicable. Consent to publish: Not applicable. Availability of data and materials: All data generated or analyzed during this study are included in this published article. Competing Interests: The authors declare that they have no competing interests. Funding: Not applicable. Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xiaocui Zhang, Diemeng Chang and Yali Wu . The first draft of the manuscript w ere written by Xiaocui Zhang, Diemeng Chang , and all authors commented on previous versions of the manuscript. Acknowledgements: Not applicable. References 2016 Alzheimer's disease facts and figures . Alzheimers Dement 2016, 12 (4):459-509. Hu X, Zhang J, Qiu Y, Liu Z: Periodontal disease and the risk of Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis . Psychogeriatrics 2021, 21 (5):813-825. Association As: 2019 Alzheimer's disease facts and figures . 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Tables Table 1 Evidence on Periodontal disease and Alzheimer's disease Study Objectives and study design Study type Number of participants Location of study Outcomes and conclusions Ma KS [11] Identify the relationship between the longitudinal risk of developing Periodontal disease (PD) in a cohort of patients with dementia and Alzheimer's disease (AD) who did not show any signs of PD at baseline. Retrospective cohort study 1212 China Outcomes: The incidence of PD in the AD group was significantly higher than that in the non-AD group [RR=1.531, adjusted hazard ratio (aHR) =1.667)]. Conclusions: AD were associated with a higher risk of PD dependent of age and independent of systemic confounding factors. Schwahn C [12] Investigate the relationship between periodontal treatment and pre-clinical AD. Quasi-experimental 586 Pomerania Outcomes: Periodontal treatment had a favorable effect on AD-related brain atrophy (OR=-0.41). Conclusions: Periodontitis is related to pre-clinical AD. Choi S [9] Investigate the association of Chronic Periodontitis on AD. Retrospective cohort study 262349 Korean Outcomes: Compared with nonchronic periodontitis participants, chronic periodontitis patients had elevated risk for AD (aHR = 1.05). Conclusions: Chronic periodontitis may be associated with a higher risk of developing AD. Carballo Á[13] Assess whether periodontitis is associated with cognitive decline and its progression with certain blood-based markers of AD. Prospective cohort study 101 Spain Outcomes: Periodontitis was associated with poor cognitive performance and progression of cognitive impairment (hazard ratio [HR] =1.8). The baseline levels of p-Tau ( p<.001 ) and Aβ1-40 ( p =.036 ) in periodontitis patients were significantly higher than those in non-periodontitis patients. The concentration of Aβ1-40 protein increased with time in the periodontitis group ( p =.005 ). Conclusions: Periodontitis is associated with cognitive decline. And overexpression of p-Tau and Aβ1-40 may play a role in this association. Fu KL[14] Investigate the association between AD and periodontitis in the aspects of periodontal status, serological markers, and oral microbiome. Case-control study 40 China Outcomes: AD patients with Clinical Dementia Rating (CDR) ≥1 exhibited significantly more clinical attachment loss (CAL) than those with lower CDR. Conclusions: Periodontal infection is associated with AD. Ide M[15] To investigate whether periodontitis is associated with increased severity of dementia, decreased cognitive function and increased systemic pro-inflammatory state in patients with AD. Cohort study 60 United Kingdom Outcomes: The presence of periodontitis was associated with a six fold increase in the rate of cognitive decline as assessed by the AD over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six monthes follow up period. Conclusions: Periodontitis is associated with an increase in cognitive decline in AD, which may be mediated through effects on systemic inflammation. Panzarella V[16] Evaluate the oral health status and its relationship with cognitive impairment of participants. Case-control study 60 Italy Outcomes: AD (p = 0.001) were positively correlated with the decayed, missing, and filled teeth. And the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p = 0.02). Conclusions: AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum. Noble JM,[17] Evaluate serum IgG to periodontal microbiota as possible predictors of incident AD. Case-cohort study 219 USA Outcomes: High anti-A. naeslundii titer was associated with increased risk of AD (HR=2.0). High anti-E. nodatum IgG was associated with lower risk of AD (HR=0.5). Conclusions: Serum IgG levels to common periodontal microbiota are associated with risk for developing incident AD. Syrjälä AM[18] Study the association between diagnosed dementia and oral health. Cross-sectional study 354 Finland Outcomes:Patients with AD had an increased likelihood of having teeth with deep periodontal pockets compared with non-demented persons. Conclusions: Patients with AD are at increased risk of periodontal diseases. Yoo JE[19] Investigate the associations of dental diseases and oral hygiene care with the risk of dementia. Retrospective cohort study 2555618 Korean Outcomes: Periodontal diseases was associated with an increased risk of all-cause dementia(aHR=1.07). The increased risks by dental diseases was reduced by oral hygiene care (aHR= 0.94). Conclusions: Periodontal disease was independently associated with a higher risk of dementia. Conversely, improved oral hygiene care may modify the risk of dementia associated with dental diseases. Laugisch O[20] Compare the periodontal and dental status in patients with either AD or other forms of dementia. Cross-sectional study 20 Germany Outcomes: Both patients with AD and other forms of dementia had periodontal disease. Conclusions: Patients with all forms of dementia (AD/other) need special dental care to improve periodontal and oral health. Saito M[21] This study examined the relationship between the use of dental care among older people and the incidence of dementia based on health insurance claims data. Cross-sectional study 31,775 Japan Outcomes: Regarding the days of periodontal treatment, participants with ≥5 days had significantly lower aHRs for AD than those with 0 days(aHR=0.88) . Conclusions: Individuals who received periodontal treatment on many days had a low risk of AD. Kamer AR[22] Compare the differences of TNF-alpha and elevated antibodies to periodontal bacteria in AD and normal controls. Case-control study 34 USA Outcomes: Plasma TNF-alpha and antibodies against periodontal bacteria were elevated in AD patients compared with normal controls. and independently associated with AD. Conclusions: TNF-alpha and elevated numbers of antibodies against periodontal bacteria associate with AD and contribute to the AD diagnosis. Na HS[23] Evaluate the association between oral microbes and AD in periodontitis. Case-control study 29 Korea Outcomes: Differential analysis showed subgingival samples of the AD group had higher prevalence of Atopobium rimae, Dialister pneumosintes, Olsenella sp. HMT 807, Saccharibacteria (TM7) sp. HMT 348 and several species of Prevotella than the control group. Subgingival microbiome network analysis revealed a distinct, closely connected network in the AD group comprised of various Prevotella spp. and several anaerobic bacteria. Conclusions: A unique microbial composition was discovered in the subgingival region in the AD group. Potential periodontal pathogens were found to be more prevalent in the subgingival plaque samples of the AD group. These bacteria may possess a potential to worsen periodontitis and other systemic diseases. Merchant AT[24] Examine associations between empirically derived groups of 19 IgG antibodies against periodontal microorganisms and AD mortality. Cross-sectional study 160 USA Outcomes: With up to 21 years of follow-up, 160 AD-related deaths were documented. In the multivariable-adjusted model, AD mortality overall was not associated with IgG antibodies against periodontal microorganisms. Conclusions: Clusters of IgG antibodies against periodontal microorganisms did not predict AD mortality. Karaduran K[25] Investigate the effect of periodontitis and current occlusal relationship on the progression rate of AD. Prospective cohort study 90 Turkey Outcomes: Stage II and Stage III toothed AD patients had higher percentage of bleeding on probing (BOP%) and clinical attachment level values than Stage I patients (p<0.05). Stage III AD patients had significantly higher probing pocket depth (PPD) values than Stage I individuals (p<0.05). Standardized Mini-Mental Test values showed positive correlation with BOP% (r=0.308, p=0.013) and PPD (r=0.275, p=0.027). Among the evaluated parameters, being in the AD Stage II-Stage III, having periodontitis and age variable had significant effects on Standardized Mini-Mental Testlevels (p<0.05). Conclusions: Periodontitis may increase the severity and also accelerate the progression rate of AD. Sparks Stein P[26] Compare serum antibody levels to bacteria of periodontal disease in AD and control subjects.Compare serum antibody levels to bacteria of periodontal disease in AD and control subjects. Case-control study 158 USA Outcomes: Antibody levels to F nucleatum and P intermedia were significantly increased (α = 0.05) at baseline serum draw in the patients with AD compared with controls. Conclusions: In the years before the cognitive impairment, subjects had elevated antibodies to periodontal bacteria. Periodontal disease could potentially contribute to the risk of AD onset/progression. Sun YQ[27] Apply a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD. Bidirectional Mendelian randomization study 117386 European Outcomes: There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00). Conclusions: Did not find convincing evidence to support periodontitis being a causal factor for the development of AD. Martande SS[28] Compare periodontal health status in individuals with and without AD. Case-control study 118 India Outcomes: All the evaluated periodontal parameters were higher in individuals with AD than that in cognitively normal individuals, and the periodontal status deteriorated with the progression of AD. There were significant differences in mean Gingival index, plaque index, probing depth, clinical attachment level, and percentage of bleeding sites between all the groups. Conclusions: The periodontal health status of individuals with AD deteriorates with disease progression and was closely related to their cognitive function. Chen CK[29] To determine whether patients with CP are at increased risk of developing AD Matched-cohort study 27963 China Outcomes: Patients with 10 years of CP exposure exhibited a higher risk of developing AD than unexposed groups (aHR =1.707). Conclusions: 10-year CP exposure was associated with a 1.707-fold increase in the risk of developing AD. Holmer J[30] To test whether PD contributes to increased risk of mild cognitive impairment (MCI), subjective cognitive decline and AD. Case-control study 154 Sweden Outcomes: Poor oral health and marginal alveolar bone loss were more prevalent among MCI and AD patients than nomal controls. The MCI and AD group was associated with generalized marginal alveolar bone loss (OR=5.81), increased number of deep periodontal pockets (OR = 8.43;) and dental caries (OR = 3.36). Conclusions: Marginal periodontitis is associated with early cognitive impairment and AD. Beydoun MA[31] Examine associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality. Cross-sectional study 33199 USA Outcomes: Among those ≥65 years, AD incidence and mortality were consistently associated with probing pocket depth, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P.gingivalis), Prevotella melaninogenica (P. melaninogenica) and Campylobacter rectus (C. rectus) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (aHR=1.22), while AD mortality risk was increased with another composite (aHR=1.46) loading highly on IgG for P.gingivalis, Prevotella intermedia, Prevotella nigrescens, Fusobacterium nucleatum, C. rectus, Streptococcus intermedius, Capnocylophaga Ochracea, and P. melaninogenica. Conclusions: Periodontal pathogens are associated with AD, which was stronger for older adults. Table 2 Potential mechanisms on Periodontal disease and Alzheimer's disease study Objectives and study design Study type Number of participants Location of study Outcomes and conclusions Leblhuber F[32] Investigate the correlation between oral pathogens and AD. Cross-sectional study 20 Austria Outcomes: The presence of Porphyromonas gingivalis, the key pathogen and one of the species involved in chronic periodontitis, was found to be associated with lower mini mental state examination scores (p < 0.05) and with a tendency to lower scores in the clock drawing test (p=0.056). And association between lower serum concentrations of the immune biomarker neopterin and the presence of Treponema denticola (p<0.01) as well as of kynurenine were found in AD patients positive vs. negative for Tannerella forsytia (p < 0.05). Conclusions: Periodontal pathogens may be associated with cognitive impairment, Treponema denticola and Tannerella forsytia may alter the host immune response in AD. An altered salivary microbiome may be a causal link between chronic periodontitis and cognitive impairment in AD. Poole S[33] Establish a link between PD and AD. Case-control study 20 UK Outcomes: Lipopolysaccharide (LPS) from P. gingivalis were positive when screened by immunofluorescence in 4 AD brain specimens. But all controls remained negative (p = 0.029). Conclusions: LPS from periodontal bacteria can access the AD brain during life. Qiu C[34] Aim to characterize both the microbial community of subgingival plaque and the metabolomic profiles of gingival crevicular fluid in patients with AD and mild cognitive impairment (MCI). Cross-sectional study 96 China Outcomes: The severity of periodontitis was significantly increased in AD patients compared with MCI patients and cognitively normal people. 19 differentially abundant metabolites were significantly correlated with Veillonella parvula, Dialister pneumosintes, Leptotrichia buccalis, Pseudoleptotrichia goodfellowii, and Actinomyces massiliensis, in which galactinol, sn-glycerol 3-phosphoethanolamine, D-mannitol, 1h-indole-1-pentanoicacid, 3-(1-naphthalenylcarboy)- and L-iditol yielded satisfactory accuracy for the predictive diagnosis of AD progression. Conclusions: Periodontal microbial dysbiosis and metabolic disorders may be involved in the etiology and progression of AD. Kubota T,[35] Compare differences of AD pathway molecules in healthy tissues and periodontitis tissues, including amyloid beta (A4) precursor protein (APP), a key gene in AD, interleukin-1 beta (IL-1β), and complement component 1 (q subcomponent, A chain) (C1QA). Case-control study 28 Japan Outcomes: APP, IL-1β, and C1QA mRNA levels were significantly upregulated in periodontitis-affected gingival tissues. Conclusions: Elevated APP, IL-1β, and C1QA transcripts and APP-expressing macrophages in periodontitis-affected gingival tissues were observed, suggesting a relationship between periodontitis and AD pathogenesis. Kamer AR[36] Investigate whether peripheral inflammatory and/or infectious conditions in humans can promote Aβ brain accumulation. Cross-sectional study 38 USA Outcomes: Clinical attachment loss (≥3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased C-Pittsburgh compound B uptake in Aβ vulnerable brain regions (p= 0.002). Conclusions: There is a correlation between periodontal disease and brain Aβ load. Sato N[37] Cells research describes the effect of Porphyromonas gingivalis (P gingivalis) LPS on the expression of interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2) in cultured hCMEC/D3 human brain microvascular endothelial cells. Outcomes: P gingivalis LPS-induced mRNA and protein expression of IL-6 and CCL2 in hCMEC/D3 cells in a concentration-dependent manner at the concentration of 0.5-50 µg/mL. Induction of IL-6 and CCL2 by P gingivalis LPS was almost completely inhibited by pretreatment of cells with TLR4 inhibitor but not by TLR2 inhibitor. Treatment of cells with P gingivalis LPS induced phosphorylation of nuclear factor-κB (NF-κB) p65, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). IL-6 induction was decreased by pretreatment of cells with NF-κB inhibitor SN50 or p38 MAPK inhibitor SB203580, while CCL2 induction was reduced by SN50 or JNK inhibitor SP600125. Conclusions: IL-6 and CCL2 produced upon P gingivalis LPS stimulation may contribute to the inflammatory reactions in brain endothelial cells and subsequent neurological disorders such as cerebrovascular and AD. Díaz-Zúñiga J[38] Cell research determine the effects of different serotypes of (a, b or c) aggregatibacter actinomycetemcomitans (Aa) LPS on primary cultures of microglia or mixed hippocampal cells. Outcomes: Both culture types exhibited higher levels of inflammatory cytokines (IL-1β, IL-6 and TNFα) when treated with serotype b-LPS, compared with controls. Also, cultures treated with serotype a-LPS displayed increased mRNA levels of the modulatory cytokines IL-4 and IL-10. Mixed hippocampal cultures treated with serotype b-LPS exhibited severe neuronal morphological changes and displayed increased levels of secreted Aβ1-42 peptide. These results indicate that LPS from different Aa serotypes triggers discriminatory immune responses, which differentially affect primary hippocampal cells. Conclusions: Treatment with serotype b-LPS triggers the secretion of proinflammatory cytokines by microglia, induces neurite shrinking, and increases the extracellular Aβ1-42 levels, all features strongly associated with the etiology of AD. Xue L[39] Animal study to investigate the causal relationship between chronic periodontitis (CP) and cognitive decline and the underlying mechanism in mice. Outcomes: During the 12-month follow-up period of induce CP in mice. Severe alveolar bone loss and inflammatory changes were observed in gingival tissues, accompanied by progressive cognitive deficits. And observed cerebral neuronal and synaptic injury and glial activation in this mouse model of CP. Furthermore, CP mice exhibited significant dysbiosis of the oral and gut microbiota, disruption of the intestinal barrier and blood-brain barrier, increases in the serum contents of proinflammatory cytokines and LPS, and increases in brain LPS levels, Toll-like receptor 4 (TLR4) expression, nuclear factor-κB (NF-κB) nuclear translocation and proinflammatory cytokine mRNA levels. Conclusions: CP may directly induce progressive cognitive decline and its mechanism is probably related to microbiota-gut-brain axis disorders, LPS/TLR4/NF-κB signaling activation and neuroinflammatory responses in mice. Therefore, the microbiota-gut-brain axis may provide the potential strategy for the prevention and treatment of CP-associated cognitive impairment. Kantarci A[40] Tested the impact of ligature-induced PD on 5xFAD mice and WT littermates. Outcomes: PD increased the level of Iba1-immunostained microglia in WT mice. In 5xFAD mice, PD increased the level of insoluble Aβ42. The increased level in Iba1 immunostaining that parallels the accumulation of Aβ in 5xFAD mice was not affected by PD except for a decrease in the dentate gyrus. A decline in Iba1 in the proximity of Aβ plaques in 5xFAD mice with PD compared to those without PD suggesting a PD-induced decrease in plaque-associated microglia (PAM). PD reduced IL-6, MCP-1, GM-CSF, and IFN-γ in brains of WT mice and reduced IL-10 in 5xFAD mice. Conclusions: PD increases neuroinflammation in WT mice and disrupts the neuroinflammatory response in 5xFAD mice and suggest that microglia is central to the association between PD and AD. Gu Y[41] Animal study to test whether periodontitis is involved in the exacerbation, contributing to AD pathologies. Outcomes: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to Porphyromonas gingivalis (P gLPS) ( p=0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (p=0.0052; p=0.0019), while that in the cortex was negatively correlated with the memory test latency (p=0.0017; p=0.0351). Furthermore, the IL-17 expression in microglia was positively correlated with Aβ42 accumulation in neurons (p < 0.0001). In cultured MG6 microglia, the P gLPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from P gLPS-stimulated microglia (MCM) but not P gLPS increased the productions of AβPP, CatB, and Aβ42, which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease). Conclusion: Chronic systemic exposure to PgLPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression. Ilievski V[42] Animal study to test whether repeated exposure of wild type C57BL/6 mice to orally administered Pg results in neuroinflammation, neurodegeneration, microgliosis, astrogliosis and formation of intra- and extracellular amyloid plaque and neurofibrillary tangles (NFTs) which are pathognomonic signs of AD. Outcomes: Significantly greater levels of expression of IL6, TNFα and IL1β were evident in experimental as compared to control group (p<0.01, p<0.00001, p<0.00001 respectively). In addition, microgliosis and astrogliosis were evident in the experimental but not in control group (p <0.01, p<0.0001 respectively). amyloid precursor protein (APP) and beta-site APP cleaving enzyme 1 gene expression were increased in experimental group compared with control group (p<0.05, p<0.001 respectively). a disintegrin and metalloproteinase domain-containing protein10 gene expression was significantly decreased in experimental group compared with control group (p<0.01). Extracellular amyloid beta1-42(Aβ42) was detected in the parenchyma in the experimental but not in the control group (p< 0.00001). Finally, phospho-Tau (Ser396) protein was detected and NFTs were evident in experimental but not in the control group (p<0.00001). Conclusions: Neurodegeneration and the formation of extracellular Aβ42 in young adult WT mice after repeated oral application of Pg, which suggest that low grade chronic periodontal pathogen infection can result in the development of neuropathology that is consistent with that of AD. Qian X[43] Animal study to investigate the effect of periodontitis on learning capacity and memory of amyloid-β protein precursor (AβPP)/presenilin (PS1) transgenic mice along with the mechanisms underlying these effects. Outcomes: Mice in the P.g-LPS Injection + Ligation group exhibited cognitive impairment and a significant reduction in the number of neurons. Glial cell activation in the experimental groups with significantly increased Aβ levels was more pronounced relative to the control group. Induction of periodontitis was concurrent with an increase in cyclooxygenase-2, inducible nitric oxide synthase, AβPP, and beta-secretase 1 expression and a decrease in A disintegrin and metalloproteinase domain-containing protein 10 expression. Conclusions: Periodontitis exacerbated learning and memory impairment in AβPP/PS1 mice and augmented Aβ and neuroinflammatory responses. Lu J[44] Animal study to explore the influence of periodontitis-related salivary microbiota on AD based on the gut-brain crosstalk in APPswe/PS1 ΔE9 (PAP) transgenic mice. Outcomes: Continuous gavage of periodontitis-related salivary microbiota in PAP mice impaired cognitive function and increased β-amyloid accumulation and neuroinflammation. Moreover, these AD-related pathologies were consistent with gut microbial dysbiosis, intestinal proinflammatory responses, intestinal barrier impairment, and subsequent exacerbation of systemic inflammation, suggesting that the periodontitis-related salivary microbiota may aggravate AD pathogenesis through crosstalk of the gut-brain axis. Conclusions: Periodontitis might participate in the pathogenesis of AD by swallowing salivary microbiota, verifying the role of periodontitis in AD progression. Yamada C[45] Cells research to evaluate the influence of phosphoglycerol dihydroceramide（PGDHC） on hallmark findings in AD. Outcomes: P. gingivalis (Pg)-derived PGDHC, but not Pg-LPS, upregulated secretion of soluble Aβ42 peptide and expression of APP in CHO-7WD10 cells. Furthermore, hyperphosphorylation of tau protein was observed in SH-SY-5Y cells in response to PGDHC lipid. In contrast, Pg-LPS had little, or no significant effect on the tau phosphorylation induced in SH-SY-5Y cells. However, both PGDHC and Pg-LPS contributed to the senescence of SH-SY5Y cells as indicated by the production of senescence-associated secretory phenotype (SASP) markers, including beta-galactosidase, cathepsin B (CtsB), and pro-inflammatory cytokines Tumor Necrosis Factor α(TNF-α), and IL-6. Additionally, PGDHC diminished expression of the senescence-protection marker sirtuin-1 in SH-SY-5Y cells. Conclusions: P. gingivalis-derived PGDHC ceramide promotes amyloidogenesis and hyperphosphorylation, as well as the production of SASP factors. Thus, PGDHC may represent a novel class of bacterial-derived virulence factors for AD associated with periodontitis. Bahar B[46] Animal study to investigate the effect of Porphyromonas gingivalis (W83) oral infection on the development of AD pathophysiology in a wild-type obese, diabetic (db/db) mouse model. Outcomes: Immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group. Conclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease. Table 3 Treatment on Periodontal disease and Alzheimer's disease study Objectives and study design Study type Number of participants Location of study Outcomes and conclusions Animal study on treatment of periodontal disease and Alzheimer's disease Zhao Co[47] Animal study to investigate the effect of a probiotic/lantibiotic, nisin, in modulating brain pathology triggered by periodontitis. Outcomes: Nisin treatment mitigated the changes in the brain microbiome composition, diversity, and community structure, and reduced the levels of periodontal pathogen DNA in the brain induced by periodontal disease. Nisin treatment signifcantly decreased the mRNA expression of proinfammatory cytokines (IL-1β, IL-6, and TNF-α) in the brain that were elevated by periodontal infection. In addition, the concentrations of Aβ42 total Tau, and Tau were signifcantly higher in the infection group compared to the control group, respectively. Nisin treatment markedly reduced the Aβ42, total Tau, and phosphorylated Tau deposition in the brain of the infection group. Conclusions: Nisin abrogation of brain microbiome dysbiosis induces benefcial efects on AD-like pathogenic changes and neuroinfammation, and thereby may serve as a potential therapeutic for periodontal–dysbiosis-related AD. Dominy SS[48] Animal study to investigate the effect of small-molecule inhibitors targeting gingipains on block Pg neurotoxicity. Outcomes: Gingipain inhibition reduced the bacterial load of an established Pg brain infection, blocked Aβ1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. Conclusions: Gingipain inhibitors could be valuable for treating Pg brain colonization and neurodegeneration in AD. Additional Declarations No competing interests reported. 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Background","content":"\u003cp\u003eAlzheimer 's disease (AD) is the most common type of dementia, accounting for 60\u0026ndash;80% of all dementia cases\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. It is estimated that the number of dementia patients in the world will reach 74.7\u0026nbsp;million by 2030, and the number of deaths caused by AD will increase by more than 40%\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. In addition, the economic burden of disease caused by AD is also serious. In 2019, the total cost of AD and other types of dementia patients was as high as USD 2900 billion\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Mild cognitive impairment (MCI) is a concept proposed by Petersen et al.in 1995, which is defined as a condition in which cognitive function is lower than expected due to physiological aging. It is an intermediate state between normal cognition and pre-dementia. It has also been identified as the first clinical stage of AD\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. The ability to carry out daily activities in the MCI state is still normal. Systematic review found that 32% of MCI cases will be converted to AD within 5 years\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. However, this process is reversible\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Interventions that eliminate related risk factors or enhance preventive factors in patients with MCI can effectively prevent AD\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Therefore, controlling the development of MCI is important for AD prevention.\u003c/p\u003e \u003cp\u003ePeriodontal disease (PD) is an inflammatory injury of periodontal protection and supporting tissues caused by pathogenic bacteria or plaque biofilm, mainly including gingival disease and periodontitis. The survey results of Eke et al. showed that about 64% of adults over 65 years old had chronic moderate to severe periodontitis\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. PD is not only a common chronic inflammatory oral disease, but also can lead to stroke, major depression, diabetes, chronic kidney disease, dyslipidemia and other systemic diseases\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Nowadays, people are paying more and more attention to the relationship between periodontal disease and AD or MCI. Periodontal disease seems to be related to AD and MCI. At present, there is an urgent need to determine the modifiable factors of AD risk in the absence of cure methods.\u003c/p\u003e \u003cp\u003eThis scoping review compiled and evaluated recent evidence from clinical human studies that assessed associations between PD and AD and potential mechanisms for such associations. Specifcally, a scoping review was undertaken to establish areas in which evidence on associations between PD and AD is available.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Data sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo independent investigators (Xiaocui Zhang \u0026amp; Diemeng Chang) independently searched PubMed, Cochrane library, and EMBASE databases in february 2024 in PubMed, Embase and Cochrane Central Register for Controlled Trials. Results were limited to articles published from 2004 to 2024 in the English language.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Search strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following search strategy in PubMed utilized both keyword terms in the title and abstract felds as well as Medical Subject Headings (MeSH) to identify possible qualifying articles: (((((\u0026quot;Periodontal Diseases\u0026quot;[Mesh]) OR (Disease, Periodontal[Title/Abstract]) OR (Diseases, Periodontal[Title/Abstract])) OR (Periodontal Disease[Title/Abstract])) OR (Parodontosis[Title/Abstract])) OR (Parodontoses[Title/Abstract])) OR (Pyorrhea Alveolaris[Title/Abstract]) AND ((((((((((((((((((((((((((((((((((\u0026quot;Alzheimer Disease\u0026quot;[Mesh]) OR (Alzheimer Dementia[Title/Abstract]) OR (Alzheimer Dementias[Title/Abstract])) OR (Dementia, Alzheimer[Title/Abstract])) OR (Alzheimer\u0026apos;s disease[Title/Abstract])) OR (Dementia, Senile[Title/Abstract])) OR (Senile Dementia[Title/Abstract])) OR (Dementia, Alzheimer Type[Title/Abstract])) OR (Alzheimer Type Dementia[Title/Abstract])) OR (Alzheimer-Type Dementia (ATD[Title/Abstract]))) OR (Alzheimer Type Dementia (ATD[Title/Abstract]))) OR (Dementia, Alzheimer-Type (ATD[Title/Abstract]))) OR (Alzheimer Type Senile Dementia[Title/Abstract])) OR (Primary Senile Degenerative Dementia[Title/Abstract])) OR (Dementia, Primary Senile Degenerative[Title/Abstract])) OR (Alzheimer Sclerosis[Title/Abstract])) OR (Sclerosis, Alzheimer[Title/Abstract])) OR (Alzheimer Syndrome[Title/Abstract])) OR (Alzheimer\u0026apos;s diseases[Title/Abstract])) OR (Alzheimer Diseases[Title/Abstract])) OR (Alzheimers Diseases[Title/Abstract])) OR (Senile Dementia, Alzheimer Type[Title/Abstract])) OR (Acute Confusional Senile Dementia[Title/Abstract])) OR (Senile Dementia, Acute Confusional[Title/Abstract])) OR (Dementia, Presenile[Title/Abstract])) OR (Presenile Dementia[Title/Abstract])) OR (Alzheimer Disease, Late Onset[Title/Abstract])) OR (Late Onset Alzheimer Disease[Title/Abstract])) OR (Alzheimer\u0026apos;s disease, Focal Onset[Title/Abstract])) OR (Focal Onset Alzheimer\u0026apos;s disease[Title/Abstract])) OR (Familial Alzheimer Disease (FAD[Title/Abstract]))) OR (Alzheimer Disease, Familial (FAD[Title/Abstract]))) OR (Familial Alzheimer Diseases (FAD[Title/Abstract]))) OR (Alzheimer Disease, Early Onset[Title/Abstract])) OR (Early Onset Alzheimer Disease[Title/Abstract])) OR (Presenile Alzheimer Dementia[Title/Abstract]).\u003c/p\u003e\n\u003cp\u003eThis search was translated and updated for Embase and Cochrane Central Register of Controlled Trials accordingly\u003csup\u003e[11]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Data fltering\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSearch results were then saved and exported into EndNote, a bibliographic software\u0026nbsp;program, to store, organize, and manage all results\u003csup\u003e[12]\u003c/sup\u003e. After removal of duplicates, titles were examined by one author (Xiaocui Zhang) and articles unrelated to PD and AD were removed. For retained articles, clinical human and animal studies were included where associations between PD and AD were explored or a potential mechanism was elucidated. And systematic and retrospective reviews were excluded. After title-based fltering, their eligibility was assessed by abstract-based fltering by two authors (Xiaocui Zhang and Diemeng Chang). After the evaluation, we resolved the differences between the two reviewers (Xiaocui Zhang and Diemeng Chang) through discussion with the third reviewer (Yanli Wu). When articles were on the topic of associations between PD and AD. The reference lists of included studies were hand searched and citations of all included studies were checked to ensure search completeness\u003csup\u003e[12]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIndividual studies were tabulated and brief description of the following parameters were provided: name of frst author, year of publication, number of participants, country of study participants, study design, study population (human or animal), objective of the study, outcomes including statistical parameters and conclusions (Tables 1-3).\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe initial search yielded 761 results. After deduplication, 603 articles were further evaluated, of which 246 studies were excluded for systematic and retrospective reviews. The remaining 357 full-text articles were assessed, and after excluding studies where PD and/or AD was not the primary variable of interest, 39 studies were included in the summary tables. 21 studies explored the correlation between PD and AD through clinical research (Table 1). 16 studies explored the potential mechanism of the correlation between PD and AD, within 6 clinical studies, 7 animal studies and 3 cell researches (Table 2). 2 animal studies reported the treatment progress based on the potential mechanism of the correlation between PD and AD (Table 3).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e4.1 The correlation between PD and AD\u003c/h2\u003e \u003cp\u003eMost studies have shown that PD is associated with AD\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. A 10-year cohort study found that the risk of AD in PD patients was 1.707 times higher than that without PD patients\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. The results of a 13-year retrospective cohort study showed that the risk of AD in PD patients was 1.667 times higher than that without PD patients\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Another 10-year retrospective cohort study showed that the risk of AD in PD patients was 1.05 times higher than that without PD patients\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. In addition, studies have shown that PD is also associated with MCI in the preclinical stage of AD\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Kamer AR and Na HS found that plasma TNF-alpha, antibodies against periodontal bacteria and potential periodontal pathogens were elevated in AD patients compared with normal controls \u003csup\u003e[\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Besides, Sparks Stein P found that in the years before the cognitive impairment, subjects had elevated antibodies to periodontal bacteria\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. At the same time, studies have shown that the risk of PD in AD patients increased\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. But a bidirectional mendelian randomization study invovled 117386 European patients showed that PD is not the cause of AD development\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. And a cross-sectional study showed that clusters of IgG antibodies against periodontal microorganisms did not predict AD mortality\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. In general, the general trend of most studies investigating the cross-sectional or longitudinal association between PD and AD suggests that there is a positive correlation between these two disease processes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Potential mechanisms on PD and AD\u003c/h2\u003e \u003cp\u003eAD is a progressive neurodegenerative disease, neuropathologically characterised by intracerebral, extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles (NFTs). The cause of sporadic AD, and the pathophysiological mechanisms involved, remain major unanswered questions in medical science. At present, the three major hypotheses for the initiation and progression of AD mainly include: the β-amyloid hypothesis\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, the microbiome-infection hypothesis\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, and the inflammation-host response hypothesis\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e4.2.1 PD is associated with brain Aβ and tau protein aggregation\u003c/h2\u003e \u003cp\u003eAccording to the amyloid hypothesis, abnormal accumulation of Aβ in certain brain regions can lead to neuronal dysfunction and subsequent neuronal death. Aβ deposition comes from amyloid precursor protein (APP), which is selectively cleaved into amyloid proteins of different lengths by a series of enzymes (mainly secretory enzymes). The Aβ plaques formed by these proteins in the brain can induce a local inflammatory response mainly driven by microglia, leading to the proliferation of microglia and the release of inflammatory mediators, which in turn damages neuronal cells, interneuronal cells and blood-brain barrier\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. In addition, this inflammatory response, together with the microbiota that can penetrate the blood-brain barrier, induces tau protein phosphorylation and cleavage\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. The lysed tau protein fragment can form neurofibrillary tangles (NFTs) and cause toxicity to neuronal cells, leading to neuronal cell death and brain region atrophy\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor example, existing studies have shown that PD is related to the aggregation of Aβ and tau protein in the brain. Kubota T et al.\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003especulated that periodontitis is involved in the synthesis and accumulation of Aβ in the brain, leading to the occurrence of AD. The results of Kamer AR et al. \u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003econfirmed the relevant speculation, and the results showed that the disappearance of periodontal attachment\u0026thinsp;\u0026ge;\u0026thinsp;3 mm was related to the increase of Aβ load. The results of cell research carried out by D\u0026iacute;az-Z\u0026uacute;\u0026ntilde;iga J et al. showed that stimulating microglia with aggregatibacter actinomycetemcomitans, the most aggressive form of PD, will increase extracellular Aβ levels\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e. Animal studies carried out by Ilievski V and Qian X et al.showed that Aβ protein accumulation was higher in PD mice\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e. Besides, Ilievski V et al. found that APP and beta-site APP cleaving enzyme 1 gene expression were increased in PD mice, and phospho-Tau protein was detected and NFTs were evident in PD mice but not in the nomal mice\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e4.2.2 The inflammatory response caused by PD is closely related to AD\u003c/h2\u003e \u003cp\u003eCurrent proposals on how PD may promote the progression of AD. PD have been proposed to promote AD pathology by two mechanisms. Firstly, PD may impact the central nervous system indirectly by provoking microbiota-gut-brain axis disorders in the alimentary tract. This induces chronic systemic inflammation which subsequently extends to the brain adding to the load of neuroinflammation. The animal experimental study carried out by Li X et al. found that PD mice exhibited significant dysbiosis of the oral and gut microbiota, disruption of the intestinal barrier and blood-brain barrier \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. The animal experimental study carried out by Lu J et al. found that AD-related pathologies in PD mice were consistent with gut microbial dysbiosis, intestinal proinflammatory responses, intestinal barrier impairment, and subsequent exacerbation of systemic inflammation\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e. Secondly, discontinuous sites within inflamed periodontal pocket epithelia allow periodontal bacteria to invade adjacent primary afferent nerves and blood vessels, along which they escape the oral cavity and directly access the brain, leading to brain infection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e4.2.3 P.gingivalis is closely related to the development of AD\u003c/h2\u003e \u003cp\u003eAlthough a number of oral bacteria have been associated with the neuropathology of AD we here focus on P. gingivalis (Pg) as this bacterium is by far the best studied and a major bacterial pathobiont that emerges as part of a subgingival pathogenic polymicrobial community during periodontitis. Poole S et al. found that lipopolysaccharide (LPS) from Pg could be detected in brain tissue samples of AD patients after death, while the samples of patients without cognitive impairment were negative\u003csup\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e.Natsu Sato d et al. 's cell research found that interleukin-6 (IL-6) and C-C motif chemokine ligand 2 produced upon Pg LPS stimulation may contribute to the inflammatory reactions in brain endothelial cells and subsequent neurological disorders such as AD\u003csup\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e. Yamada C et al. 's cell research found that Pg phosphoglycerol dihydroceramide ceramide promotes amyloidogenesis and hyperphosphorylation\u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e. Dominy SS et al. proposed that increased Pg DNA levels in saliva and cerebrospinal fluid are associated with AD\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4.3 The correlation between PD treatment management and AD\u003c/h2\u003e \u003cp\u003eFor AD treatment, there are currently no approved drug treatments or other interventions with disease modification or regeneration characteristics, and the available drugs have mild and transient effects\u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e. Effective treatment of AD needs to start earlier in the event chain, that is from the actual loss of cognitive function to the 'upstream'. These will include effective intervention and prevention of the occurrence and development of AD before advanced cognitive decline. Low levels of systemic inflammation and peripheral infectious diseases, including PD, have been proposed as potentially modifiable etiological factors of AD, which in turn opens up new therapeutic strategies for the prevention or management of AD\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e. With the potential link between PD and AD and other forms of dementia, reducing the load of oral microbiome and the inflammatory response to this microbiome is not only essential for the treatment of PD in patients with cognitive impairment, but also may be beneficial to reduce the incidence, severity and rate of cognitive decline. Many studies have directly or indirectly demonstrated the benefits of periodontal treatment in preventing the occurrence and development of AD. Schwahn C et al. \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e proposed that periodontal treatment had a favorable effect on AD-related brain atrophy. Saito M et al. \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e proposed that receiving periodontal treatment on many days had a low risk of AD. Recent animal experiment suggested that gingipain inhibitors could be valuable for treating Pg brain colonization and neurodegeneration in AD\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e. And Zhao C et al. proposed that nisin abrogation of brain microbiome dysbiosis induces beneficial effects on AD-like pathogenic changes and neuroinfammation, and thereby may serve as a potential therapeutic for periodontal\u0026ndash;dysbiosis-related AD\u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn summary, PD and AD are closely related and may be risk factors for each other. On the one hand, AD patients do not pay attention to oral hygiene, and with the progress of cognitive impairment, daily oral care is not sufficient, resulting in poor periodontal status than non-AD patients, and the probability of PD is higher. On the other hand, PD spreads to the brain through periodontal pathogens and inflammatory mediators to activate microglia and induce neuroinflammation, thereby promoting the formation and development of AD. The risk of AD in patients with PS is higher than that in patients without PD. In addition, studies have shown that PD is also associated with MCI in the preclinical stage of AD\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Unlike AD, MCI is reversible, and studies have shown that about 20% of MCI patients' cognitive function improves over time\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Therefore, PD has been proposed as a potentially modifiable etiological factor for AD, which opens up new therapeutic strategies for the prevention or management of AD. Many studies have demonstrated the benefits of periodontal treatment in preventing the occurrence and development of AD\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Animal studies showed gingipain inhibition reduced the bacterial load of an established Pg brain infection, blocked Aβ1\u0026ndash;42 production, reduced neuroinflammation, and rescued neurons in the hippocampus\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e. And Nisin treatment signifcantly decreased the mRNA expression of proinfammatory cytokines (nterleukin-1β, nterleukin-6, and TNF-α) in the brain that were elevated by periodontal infection and markedly reduced the Aβ42, total Tau, and phosphorylated Tau deposition in the brain of the infection group\u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e. This provides a new direction for PD-related AD treatment and can be further explored in future studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePD: Periodontal disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAD: Alzheimer Disease\u003c/p\u003e\n\u003cp\u003eMCI: Mild cognitive impairment\u003c/p\u003e\n\u003cp\u003eA\u0026beta;: Amyloid-\u0026beta;\u003c/p\u003e\n\u003cp\u003eNFTs: Neurofibrillary tangles\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAPP: Amyloid precursor protein\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePg: P.gingivalis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLPS: Lipopolysaccharide\u003c/p\u003e\n\u003cp\u003eIL-6: Interleukin-6\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed during this study are included in this published article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003e\u003cem\u003eThe authors declare that they have no competing interests.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003cem\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by\u0026nbsp;\u003c/em\u003eXiaocui Zhang,\u0026nbsp;Diemeng Chang\u003cem\u003e\u0026nbsp;and Yali Wu\u003c/em\u003e\u003cem\u003e. The first draft of the manuscript w\u003c/em\u003e\u003cem\u003eere\u003c/em\u003e\u003cem\u003e\u0026nbsp;written by\u0026nbsp;\u003c/em\u003eXiaocui Zhang,\u0026nbsp;Diemeng Chang\u003cem\u003e,\u0026nbsp;\u003c/em\u003e\u003cem\u003eand all authors commented on previous versions of the\u0026nbsp;\u003c/em\u003emanuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e\u003cstrong\u003e2016 Alzheimer\u0026apos;s disease facts and figures\u003c/strong\u003e. \u003cem\u003eAlzheimers Dement \u003c/em\u003e2016, \u003cstrong\u003e12\u003c/strong\u003e(4):459-509.\u003c/li\u003e\n\u003cli\u003eHu X, Zhang J, Qiu Y, Liu Z: \u003cstrong\u003ePeriodontal disease and the risk of Alzheimer\u0026apos;s disease and mild cognitive impairment: a systematic review and meta-analysis\u003c/strong\u003e. 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production in wild type mice\u003c/strong\u003e. \u003cem\u003ePLoS One \u003c/em\u003e2018, \u003cstrong\u003e13\u003c/strong\u003e(10):e0204941.\u003c/li\u003e\n\u003cli\u003eQian X, Zhang S, Duan L, Yang F, Zhang K, Yan F, Ge S: \u003cstrong\u003ePeriodontitis Deteriorates Cognitive Function and Impairs Neurons and Glia in a Mouse Model of Alzheimer\u0026apos;s Disease\u003c/strong\u003e. \u003cem\u003eJ Alzheimers Dis \u003c/em\u003e2021, \u003cstrong\u003e79\u003c/strong\u003e(4):1785-1800.\u003c/li\u003e\n\u003cli\u003eLu J, Zhang S, Huang Y, Qian J, Tan B, Qian X, Zhuang J, Zou X, Li Y, Yan F: \u003cstrong\u003ePeriodontitis-related salivary microbiota aggravates Alzheimer\u0026apos;s disease via gut-brain axis crosstalk\u003c/strong\u003e. \u003cem\u003eGut Microbes \u003c/em\u003e2022, \u003cstrong\u003e14\u003c/strong\u003e(1):2126272.\u003c/li\u003e\n\u003cli\u003ePoole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S: \u003cstrong\u003eDetermining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer\u0026apos;s disease brain tissue\u003c/strong\u003e. \u003cem\u003eJ Alzheimers Dis \u003c/em\u003e2013, \u003cstrong\u003e36\u003c/strong\u003e(4):665-677.\u003c/li\u003e\n\u003cli\u003eSato N, Matsumoto T, Kawaguchi S, Seya K, Matsumiya T, Ding J, Aizawa T, Imaizumi T: \u003cstrong\u003ePorphyromonas gingivalis lipopolysaccharide induces interleukin-6 and c-c motif chemokine ligand 2 expression in cultured hCMEC/D3 human brain microvascular endothelial cells\u003c/strong\u003e. \u003cem\u003eGerodontology \u003c/em\u003e2022, \u003cstrong\u003e39\u003c/strong\u003e(2):139-147.\u003c/li\u003e\n\u003cli\u003eYamada C, Akkaoui J, Ho A, Duarte C, Deth R, Kawai T, Nichols F, Lakshmana MK, Movila A: \u003cstrong\u003ePotential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen Porphyromonas gingivalis in the Pathogenesis of Alzheimer\u0026apos;s Disease\u003c/strong\u003e. \u003cem\u003eFront Immunol \u003c/em\u003e2020, \u003cstrong\u003e11\u003c/strong\u003e:591571.\u003c/li\u003e\n\u003cli\u003eDominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePorphyromonas gingivalis in Alzheimer\u0026apos;s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors\u003c/strong\u003e. \u003cem\u003eSci Adv \u003c/em\u003e2019, \u003cstrong\u003e5\u003c/strong\u003e(1):eaau3333.\u003c/li\u003e\n\u003cli\u003eDi Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M: \u003cstrong\u003eA meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer\u0026apos;s disease\u003c/strong\u003e. \u003cem\u003eJ Alzheimers Dis \u003c/em\u003e2013, \u003cstrong\u003e35\u003c/strong\u003e(2):349-361.\u003c/li\u003e\n\u003cli\u003eZhao C, Kuraji R, Ye C, Gao L, Radaic A, Kamarajan P, Taketani Y, Kapila YL: \u003cstrong\u003eNisin a probiotic bacteriocin mitigates brain microbiome dysbiosis and Alzheimer\u0026apos;s disease-like neuroinflammation triggered by periodontal disease\u003c/strong\u003e. \u003cem\u003eJ Neuroinflammation \u003c/em\u003e2023, \u003cstrong\u003e20\u003c/strong\u003e(1):228.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 Evidence on\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePeriodontal disease\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAlzheimer\u0026apos;s disease\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"903\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eObjectives and study design\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy type\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of participants\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation of study\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes and conclusions\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eMa KS\u0026nbsp;[11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eIdentify the relationship between the longitudinal risk of developing Periodontal disease (PD) in a cohort of patients with dementia and Alzheimer\u0026apos;s disease (AD) who did not show any signs of PD at baseline.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eRetrospective cohort\u0026nbsp;\u003c/p\u003e\n \u003cp\u003estudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e1212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: The incidence of PD in the AD group was significantly higher than that in the non-AD group [RR=1.531, adjusted hazard ratio (aHR) =1.667)].\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: AD were associated with a higher risk of PD dependent of age and independent of systemic confounding factors.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eSchwahn C \u0026nbsp;[12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eInvestigate the relationship between periodontal treatment and pre-clinical AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eQuasi-experimental\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e586\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003ePomerania\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Periodontal treatment had a favorable effect on AD-related brain atrophy (OR=-0.41).\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontitis is related to pre-clinical AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eChoi S\u0026nbsp;[9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eInvestigate the association of Chronic Periodontitis on AD.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eRetrospective cohort\u0026nbsp;\u003c/p\u003e\n \u003cp\u003estudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e262349\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eKorean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Compared with nonchronic periodontitis participants, chronic periodontitis patients had elevated risk for AD (aHR = 1.05).\u003c/p\u003e\n \u003cp\u003eConclusions: Chronic periodontitis may be associated with a higher risk of developing AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eCarballo \u0026Aacute;[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eAssess whether periodontitis is associated with cognitive decline and its progression with certain blood-based markers of AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eProspective cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Periodontitis was associated with poor cognitive performance and progression of cognitive impairment (hazard ratio [HR] =1.8). The baseline levels of p-Tau ( p\u0026lt;.001 ) and A\u0026beta;1-40 ( p =.036 ) in periodontitis patients were significantly higher than those in non-periodontitis patients. The concentration of A\u0026beta;1-40 protein increased with time in the periodontitis group ( p =.005 ).\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontitis is associated with cognitive decline. And overexpression of p-Tau and A\u0026beta;1-40 may play a role in this association.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eFu KL[14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eInvestigate the association between AD and periodontitis in the aspects of periodontal status, serological markers, and oral microbiome.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: AD patients with Clinical Dementia Rating (CDR) \u0026ge;1 exhibited significantly more clinical attachment loss (CAL) than those with lower CDR.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontal infection is associated with AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eIde M[15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eTo investigate whether periodontitis is associated with increased severity of dementia, decreased cognitive function and increased systemic pro-inflammatory state in patients with AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eUnited Kingdom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes:\u0026nbsp;The presence of periodontitis was associated with a six fold increase in the rate of cognitive decline as assessed by the AD over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six monthes follow up period.\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontitis is associated with an increase in cognitive decline in AD, which may be mediated through effects on systemic inflammation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003ePanzarella V[16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eEvaluate the oral health status and its relationship with cognitive impairment of participants.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eItaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: AD (p = 0.001) were positively correlated with the decayed, missing, and filled teeth. And the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p = 0.02).\u003c/p\u003e\n \u003cp\u003eConclusions: AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eNoble JM,[17]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eEvaluate serum IgG to periodontal microbiota as possible predictors of incident AD.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes:\u0026nbsp;High anti-A. naeslundii titer was associated with increased risk of AD (HR=2.0). High anti-E. nodatum IgG was associated with lower risk of AD (HR=0.5).\u003c/p\u003e\n \u003cp\u003eConclusions: Serum IgG levels to common periodontal microbiota are associated with risk for developing incident AD.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eSyrj\u0026auml;l\u0026auml; AM[18]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eStudy the association between diagnosed dementia and oral health.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e354\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eFinland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes:Patients with AD had an increased likelihood of having teeth with deep periodontal pockets compared with non-demented persons.\u003c/p\u003e\n \u003cp\u003eConclusions: Patients with AD are at increased risk of periodontal diseases.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eYoo JE[19]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eInvestigate the associations of dental diseases and oral hygiene care with the risk of dementia.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eRetrospective cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e2555618\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eKorean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Periodontal diseases was associated with an increased risk of all-cause dementia(aHR=1.07). The increased risks by dental diseases was reduced by oral hygiene care (aHR= 0.94).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontal disease was independently associated with a higher risk of dementia. Conversely, improved oral hygiene care may modify the risk of dementia associated with dental diseases.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eLaugisch O[20]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eCompare the periodontal and dental status in patients with either AD or other forms of dementia.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Both patients with AD and other forms of dementia had periodontal disease.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: Patients with all forms of dementia (AD/other) need special dental care to improve periodontal and oral health.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eSaito M[21]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eThis study examined the relationship between the use of dental care among older people and the incidence of dementia based on health insurance claims data.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e31,775\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Regarding the days of periodontal treatment, participants with\u0026nbsp;\u0026ge;5 days had significantly lower aHRs for AD than those with 0 days(aHR=0.88) .\u003c/p\u003e\n \u003cp\u003eConclusions: Individuals who received periodontal treatment on many days had a low risk of AD.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eKamer AR[22]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eCompare the differences of \u0026nbsp;TNF-alpha and elevated antibodies to periodontal bacteria in AD and normal controls.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Plasma TNF-alpha and antibodies against periodontal bacteria were elevated in AD patients compared with normal controls. and independently associated with AD.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: TNF-alpha and elevated numbers of antibodies against periodontal bacteria associate with AD and contribute to the AD diagnosis.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eNa HS[23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eEvaluate the association between oral microbes and AD in periodontitis.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eKorea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Differential analysis showed subgingival samples of the AD group had higher prevalence of Atopobium rimae, Dialister pneumosintes, Olsenella sp. HMT 807, Saccharibacteria (TM7) sp. HMT 348 and several species of Prevotella than the control group. Subgingival microbiome network analysis revealed a distinct, closely connected network in the AD group comprised of various Prevotella spp. and several anaerobic bacteria. Conclusions: A unique microbial composition was discovered in the subgingival region in the AD group. Potential periodontal pathogens were found to be more prevalent in the subgingival plaque samples of the AD group. These bacteria may possess a potential to worsen periodontitis and other systemic diseases.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eMerchant AT[24]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eExamine associations between empirically derived groups of 19 IgG antibodies against periodontal microorganisms and AD mortality.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: With up to 21 years of follow-up, 160 AD-related deaths were documented. In the multivariable-adjusted model, AD mortality overall was not associated with IgG antibodies against periodontal microorganisms.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: Clusters of IgG antibodies against periodontal microorganisms did not predict AD mortality.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eKaraduran K[25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eInvestigate the effect of periodontitis and current occlusal relationship on the progression rate of AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eProspective cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eTurkey\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Stage II and Stage III toothed AD patients had higher percentage of bleeding on probing (BOP%) and clinical attachment level values than Stage I patients (p\u0026lt;0.05). Stage III AD patients had significantly higher probing pocket depth (PPD) values than Stage I individuals (p\u0026lt;0.05). Standardized Mini-Mental Test values showed positive correlation with BOP% (r=0.308, p=0.013) and PPD (r=0.275, p=0.027). Among the evaluated parameters, being in the AD Stage II-Stage III, having periodontitis and age variable had significant effects on Standardized Mini-Mental Testlevels (p\u0026lt;0.05).\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontitis may increase the severity and also accelerate the progression rate of AD.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eSparks Stein P[26]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eCompare serum antibody levels to bacteria of periodontal disease in AD and control subjects.Compare serum antibody levels to bacteria of periodontal disease in AD and control subjects.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Antibody levels to F nucleatum and P intermedia were significantly increased (\u0026alpha; = 0.05) at baseline serum draw in the patients with AD compared with controls.\u003c/p\u003e\n \u003cp\u003eConclusions: In the years before the cognitive impairment, subjects had elevated antibodies to periodontal bacteria. Periodontal disease could potentially contribute to the risk of AD onset/progression.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eSun YQ[27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eApply a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eBidirectional Mendelian randomization study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e117386\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00).\u003c/p\u003e\n \u003cp\u003eConclusions: Did not find convincing evidence to support periodontitis being a causal factor for the development of AD.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eMartande SS[28]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eCompare periodontal health status in individuals with and without AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: All the evaluated periodontal parameters were higher in individuals with AD than that in cognitively normal individuals, and the periodontal status deteriorated with the progression of AD. There were significant differences in mean Gingival index, plaque index, probing depth, clinical attachment level, and percentage of bleeding sites between all the groups.\u003c/p\u003e\n \u003cp\u003eConclusions: The periodontal health status of individuals with AD deteriorates with disease progression and was closely related to their cognitive function.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eChen CK[29]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eTo determine whether patients with CP are at increased risk of developing AD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eMatched-cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e27963\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Patients with 10 years of CP exposure exhibited a higher risk of developing AD than unexposed groups (aHR =1.707).\u003c/p\u003e\n \u003cp\u003eConclusions: 10-year CP exposure was associated with a 1.707-fold increase in the risk of developing AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eHolmer J[30]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eTo test whether PD contributes to increased risk of mild cognitive impairment (MCI), subjective cognitive decline and AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eSweden\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Poor oral health and marginal alveolar bone loss were more prevalent among MCI and AD patients than nomal controls. The MCI and AD group was associated with generalized marginal alveolar bone loss (OR=5.81), increased number of deep periodontal pockets (OR = 8.43;) and dental caries (OR = 3.36).\u003c/p\u003e\n \u003cp\u003eConclusions: Marginal periodontitis is associated with early cognitive impairment and AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003eBeydoun MA[31]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.783185840707965%\" valign=\"top\"\u003e\n \u003cp\u003eExamine associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.84070796460177%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.185840707964601%\" valign=\"top\"\u003e\n \u003cp\u003e33199\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1902654867256635%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.8141592920354%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Among those\u0026nbsp;\u0026ge;65 years, AD incidence and mortality were consistently associated with probing pocket depth, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P.gingivalis), Prevotella melaninogenica (P. melaninogenica) and Campylobacter rectus (C. rectus) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (aHR=1.22), while AD mortality risk was increased with another composite (aHR=1.46) loading highly on IgG for P.gingivalis, Prevotella intermedia, Prevotella nigrescens, Fusobacterium nucleatum, C. rectus, Streptococcus intermedius, Capnocylophaga Ochracea, and P. melaninogenica.\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontal pathogens are associated with AD, which was stronger for older adults.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Potential mechanisms on Periodontal disease and Alzheimer\u0026apos;s disease\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"919\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.926167209554832%\" valign=\"top\"\u003e\n \u003cp\u003estudy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.909880564603693%\" valign=\"top\"\u003e\n \u003cp\u003eObjectives and study design\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.251900108577633%\" valign=\"top\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.77198697068404%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of participants\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.166123778501628%\" valign=\"top\"\u003e\n \u003cp\u003eLocation of study\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.97394136807818%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes and conclusions\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.926167209554832%\" valign=\"top\"\u003e\n \u003cp\u003eLeblhuber F[32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.909880564603693%\" valign=\"top\"\u003e\n \u003cp\u003eInvestigate the correlation between oral pathogens and AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.251900108577633%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.77198697068404%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.166123778501628%\" valign=\"top\"\u003e\n \u003cp\u003eAustria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.97394136807818%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: The presence of Porphyromonas gingivalis, the key pathogen and one of the species involved in chronic periodontitis, was found to be associated with lower mini mental state examination scores (p \u0026lt; 0.05) and with a tendency to lower scores in the clock drawing test (p=0.056). And association between lower serum concentrations of the immune biomarker neopterin and the presence of Treponema denticola (p\u0026lt;0.01) as well as of kynurenine were found in AD patients positive vs. negative for Tannerella forsytia (p \u0026lt; 0.05).\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontal pathogens may be associated with cognitive impairment, Treponema denticola and Tannerella forsytia may alter the host immune response in AD. An altered salivary microbiome may be a causal link between chronic periodontitis and cognitive impairment in AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.926167209554832%\" valign=\"top\"\u003e\n \u003cp\u003ePoole S[33]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.909880564603693%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Establish a link between PD and AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.251900108577633%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.77198697068404%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.166123778501628%\" valign=\"top\"\u003e\n \u003cp\u003eUK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.97394136807818%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: \u0026nbsp;Lipopolysaccharide (LPS) from P. gingivalis were positive when screened by immunofluorescence in 4 AD brain specimens. But all controls remained negative (p = 0.029).\u003c/p\u003e\n \u003cp\u003eConclusions: LPS from periodontal bacteria can access the AD brain during life.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.926167209554832%\" valign=\"top\"\u003e\n \u003cp\u003eQiu C[34]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.909880564603693%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Aim to characterize both the microbial community of subgingival plaque and the metabolomic profiles of gingival crevicular fluid in patients with AD and mild cognitive impairment (MCI).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.251900108577633%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.77198697068404%\" valign=\"top\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.166123778501628%\" valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.97394136807818%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: The severity of periodontitis was significantly increased in AD patients compared with MCI patients and cognitively normal people. 19 differentially abundant metabolites were significantly correlated with Veillonella parvula, Dialister pneumosintes, Leptotrichia buccalis, Pseudoleptotrichia goodfellowii, and Actinomyces massiliensis, in which galactinol, sn-glycerol 3-phosphoethanolamine, D-mannitol, 1h-indole-1-pentanoicacid, 3-(1-naphthalenylcarboy)- and L-iditol yielded satisfactory accuracy for the predictive diagnosis of AD progression.\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontal microbial dysbiosis and metabolic disorders may be involved in the etiology and progression of AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.926167209554832%\" valign=\"top\"\u003e\n \u003cp\u003eKubota T,[35]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.909880564603693%\" valign=\"top\"\u003e\n \u003cp\u003eCompare differences of AD pathway molecules in healthy tissues and periodontitis tissues, including amyloid beta (A4) precursor protein (APP), a key gene in AD, interleukin-1 beta (IL-1\u0026beta;), and complement component 1 (q subcomponent, A chain) (C1QA).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.251900108577633%\" valign=\"top\"\u003e\n \u003cp\u003eCase-control study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.77198697068404%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.166123778501628%\" valign=\"top\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.97394136807818%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: APP, IL-1\u0026beta;, and C1QA mRNA levels were significantly upregulated in periodontitis-affected gingival tissues.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: Elevated APP, IL-1\u0026beta;, and C1QA transcripts and APP-expressing macrophages in periodontitis-affected gingival tissues were observed, suggesting a relationship between periodontitis and AD pathogenesis.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.926167209554832%\" valign=\"top\"\u003e\n \u003cp\u003eKamer AR[36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.909880564603693%\" valign=\"top\"\u003e\n \u003cp\u003eInvestigate whether\u0026nbsp;peripheral inflammatory and/or infectious conditions in humans can promote A\u0026beta; brain accumulation.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.251900108577633%\" valign=\"top\"\u003e\n \u003cp\u003eCross-sectional study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.77198697068404%\" valign=\"top\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.166123778501628%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.97394136807818%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Clinical attachment loss (\u0026ge;3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased C-Pittsburgh compound B uptake in A\u0026beta; vulnerable brain regions (p= 0.002).\u003c/p\u003e\n \u003cp\u003eConclusions: There is a correlation between periodontal disease and brain A\u0026beta; load.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eSato N[37]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eCells research describes the effect of Porphyromonas gingivalis (P gingivalis) LPS on the expression of interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2) in cultured hCMEC/D3 human brain microvascular endothelial cells.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: P gingivalis LPS-induced mRNA and protein expression of IL-6 and CCL2 in hCMEC/D3 cells in a concentration-dependent manner at the concentration of 0.5-50 \u0026micro;g/mL. Induction of IL-6 and CCL2 by P gingivalis LPS was almost completely inhibited by pretreatment of cells with TLR4 inhibitor but not by TLR2 inhibitor. Treatment of cells with P gingivalis LPS induced phosphorylation of nuclear factor-\u0026kappa;B (NF-\u0026kappa;B) p65, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). IL-6 induction was decreased by pretreatment of cells with NF-\u0026kappa;B inhibitor SN50 or p38 MAPK inhibitor SB203580, while CCL2 induction was reduced by SN50 or JNK inhibitor SP600125.\u003c/p\u003e\n \u003cp\u003eConclusions: IL-6 and CCL2 produced upon P gingivalis LPS stimulation may contribute to the inflammatory reactions in brain endothelial cells and subsequent neurological disorders such as cerebrovascular and AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eD\u0026iacute;az-Z\u0026uacute;\u0026ntilde;iga J[38]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eCell research determine the effects of different serotypes of (a, b or c) aggregatibacter actinomycetemcomitans (Aa) LPS on primary cultures of microglia or mixed hippocampal cells.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Both culture types exhibited higher levels of inflammatory cytokines (IL-1\u0026beta;, IL-6 and TNF\u0026alpha;) when treated with serotype b-LPS, compared with controls. Also, cultures treated with serotype a-LPS displayed increased mRNA levels of the modulatory cytokines IL-4 and IL-10. Mixed hippocampal cultures treated with serotype b-LPS exhibited severe neuronal morphological changes and displayed increased levels of secreted A\u0026beta;1-42 peptide. These results indicate that LPS from different Aa serotypes triggers discriminatory immune responses, which differentially affect primary hippocampal cells.\u003c/p\u003e\n \u003cp\u003eConclusions: Treatment with serotype b-LPS triggers the secretion of proinflammatory cytokines by microglia, induces neurite shrinking, and increases the extracellular A\u0026beta;1-42 levels, all features strongly associated with the etiology of AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eXue L[39]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to investigate the causal relationship between chronic periodontitis (CP) and cognitive decline and the underlying mechanism in mice.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: During the 12-month follow-up period of induce CP in mice. Severe alveolar bone loss and inflammatory changes were observed in gingival tissues, accompanied by progressive cognitive deficits. And observed cerebral neuronal and synaptic injury and glial activation in this mouse model of CP. Furthermore, CP mice exhibited significant dysbiosis of the oral and gut microbiota, disruption of the intestinal barrier and blood-brain barrier, increases in the serum contents of proinflammatory cytokines and LPS, and increases in brain LPS levels, Toll-like receptor 4 (TLR4) expression, nuclear factor-\u0026kappa;B (NF-\u0026kappa;B) nuclear translocation and proinflammatory cytokine mRNA levels.\u003c/p\u003e\n \u003cp\u003eConclusions: CP may directly induce progressive cognitive decline and its mechanism is probably related to microbiota-gut-brain axis disorders, LPS/TLR4/NF-\u0026kappa;B signaling activation and neuroinflammatory responses in mice. Therefore, the microbiota-gut-brain axis may provide the potential strategy for the prevention and treatment of CP-associated cognitive impairment.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eKantarci A[40]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eTested the impact of ligature-induced PD on 5xFAD mice and WT littermates.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: PD increased the level of Iba1-immunostained microglia in WT mice. In 5xFAD mice, PD increased the level of insoluble A\u0026beta;42. The increased level in Iba1 immunostaining that parallels the accumulation of A\u0026beta;\u0026nbsp;in 5xFAD mice was not affected by PD except for a decrease in the dentate gyrus. A decline in Iba1 in the proximity of A\u0026beta;\u0026nbsp;plaques in 5xFAD mice with PD compared to those without PD suggesting a PD-induced decrease in plaque-associated microglia (PAM). PD reduced IL-6, MCP-1, GM-CSF, and IFN-\u0026gamma;\u0026nbsp;in brains of WT mice and reduced IL-10 in 5xFAD mice.\u003c/p\u003e\n \u003cp\u003eConclusions: PD increases neuroinflammation in WT mice and disrupts the neuroinflammatory response in 5xFAD mice and suggest that microglia is central to the association between PD and AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eGu Y[41]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to test whether periodontitis is involved in the exacerbation, contributing to AD pathologies.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to Porphyromonas gingivalis (P gLPS) ( p=0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (p=0.0052; p=0.0019), while that in the cortex was negatively correlated with the memory test latency (p=0.0017; p=0.0351). Furthermore, the IL-17 expression in microglia was positively correlated with A\u0026beta;42 accumulation in neurons (p \u0026lt; 0.0001). In cultured MG6 microglia, the P gLPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from P gLPS-stimulated microglia (MCM) but not P gLPS increased the productions of A\u0026beta;PP, CatB, and A\u0026beta;42, which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease).\u003c/p\u003e\n \u003cp\u003eConclusion: Chronic systemic exposure to PgLPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eIlievski V[42]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to test whether repeated exposure of wild type C57BL/6 mice to orally administered Pg results in neuroinflammation, neurodegeneration, microgliosis, astrogliosis and formation of intra- and extracellular amyloid plaque and neurofibrillary tangles (NFTs) which are pathognomonic signs of AD.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Significantly greater levels of expression of IL6, TNF\u0026alpha; and IL1\u0026beta; were evident in experimental as compared to control group (p\u0026lt;0.01, p\u0026lt;0.00001, p\u0026lt;0.00001 respectively). In addition, microgliosis and astrogliosis were evident in the experimental but not in control group (p \u0026lt;0.01, p\u0026lt;0.0001 respectively). amyloid precursor protein (APP) and beta-site APP cleaving enzyme 1 gene expression were increased in experimental group compared with control group (p\u0026lt;0.05, p\u0026lt;0.001 respectively). a disintegrin and metalloproteinase domain-containing protein10 gene expression was significantly decreased in experimental group compared with control group (p\u0026lt;0.01). Extracellular amyloid beta1-42(A\u0026beta;42) was detected in the parenchyma in the experimental but not in the control group (p\u0026lt; 0.00001). Finally, phospho-Tau (Ser396) protein was detected and NFTs were evident in experimental but not in the control group (p\u0026lt;0.00001).\u003c/p\u003e\n \u003cp\u003eConclusions: Neurodegeneration and the formation of extracellular A\u0026beta;42 in young adult WT mice after repeated oral application of Pg, which suggest that low grade chronic periodontal pathogen infection can result in the development of neuropathology that is consistent with that of AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eQian X[43]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to investigate the effect of periodontitis on learning capacity and memory of amyloid-\u0026beta; protein precursor (A\u0026beta;PP)/presenilin (PS1) transgenic mice along with the mechanisms underlying these effects.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Mice in the P.g-LPS Injection + Ligation group exhibited cognitive impairment and a significant reduction in the number of neurons. Glial cell activation in the experimental groups with significantly increased A\u0026beta; levels was more pronounced relative to the control group. Induction of periodontitis was concurrent with an increase in cyclooxygenase-2, inducible nitric oxide synthase, A\u0026beta;PP, and beta-secretase 1 expression and a decrease in A disintegrin and metalloproteinase domain-containing protein 10 expression.\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontitis exacerbated learning and memory impairment in A\u0026beta;PP/PS1 mice and augmented A\u0026beta; and neuroinflammatory responses.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eLu J[44]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to explore the influence of periodontitis-related salivary microbiota on AD based on the gut-brain crosstalk in APPswe/PS1\u003csup\u003e\u0026Delta;E9\u003c/sup\u003e (PAP) transgenic mice.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Continuous gavage of periodontitis-related salivary microbiota in PAP mice impaired cognitive function and increased \u0026beta;-amyloid accumulation and neuroinflammation. Moreover, these AD-related pathologies were consistent with gut microbial dysbiosis, intestinal proinflammatory responses, intestinal barrier impairment, and subsequent exacerbation of systemic inflammation, suggesting that the periodontitis-related salivary microbiota may aggravate AD pathogenesis through crosstalk of the gut-brain axis.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: Periodontitis might participate in the pathogenesis of AD by swallowing salivary microbiota, verifying the role of periodontitis in AD progression.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eYamada C[45]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eCells research to evaluate the influence of phosphoglycerol dihydroceramide（PGDHC）\u0026nbsp;on hallmark findings in AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: P. gingivalis (Pg)-derived PGDHC, but not Pg-LPS, upregulated secretion of soluble A\u0026beta;42 peptide and expression of APP in CHO-7WD10 cells. Furthermore, hyperphosphorylation of tau protein was observed in SH-SY-5Y cells in response to PGDHC lipid. In contrast, Pg-LPS had little, or no significant effect on the tau phosphorylation induced in SH-SY-5Y cells. However, both PGDHC and Pg-LPS contributed to the senescence of SH-SY5Y cells as indicated by the production of senescence-associated secretory phenotype (SASP) markers, including beta-galactosidase, cathepsin B (CtsB), and pro-inflammatory cytokines Tumor Necrosis Factor \u0026alpha;(TNF-\u0026alpha;), and IL-6. Additionally, PGDHC diminished expression of the senescence-protection marker sirtuin-1 in SH-SY-5Y cells.\u003c/p\u003e\n \u003cp\u003eConclusions: P. gingivalis-derived PGDHC ceramide promotes amyloidogenesis and hyperphosphorylation, as well as the production of SASP factors. Thus, PGDHC may represent a novel class of bacterial-derived virulence factors for AD associated with periodontitis.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.934782608695652%\" valign=\"top\"\u003e\n \u003cp\u003eBahar B[46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.04347826086956%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to investigate the effect of Porphyromonas gingivalis (W83) oral infection on the development of AD pathophysiology in a wild-type obese, diabetic (db/db) mouse model.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.02173913043478%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and A\u0026beta; release in the same infection group.\u003c/p\u003e\n \u003cp\u003eConclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Treatment on\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePeriodontal disease\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAlzheimer\u0026apos;s disease\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"907\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.039647577092511%\" valign=\"top\"\u003e\n \u003cp\u003estudy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.237885462555067%\" valign=\"top\"\u003e\n \u003cp\u003eObjectives and study design\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.370044052863436%\" valign=\"top\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.911894273127754%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of participants\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.73568281938326%\" valign=\"top\"\u003e\n \u003cp\u003eLocation of study\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.70484581497797%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes and conclusions\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study on treatment of \u0026nbsp;periodontal disease and Alzheimer\u0026apos;s disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.04851157662624%\" valign=\"top\"\u003e\n \u003cp\u003eZhao Co[47]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"46.19625137816979%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to investigate the effect of a probiotic/lantibiotic, nisin, in modulating brain pathology triggered by periodontitis.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.75523704520397%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Nisin treatment mitigated the changes in the brain microbiome composition, diversity, and community structure, and reduced the levels of periodontal pathogen DNA in the brain induced by periodontal disease. Nisin treatment signifcantly decreased the mRNA expression of proinfammatory cytokines (IL-1\u0026beta;, IL-6, and TNF-\u0026alpha;) in the brain that were elevated by periodontal infection. In addition, the concentrations of A\u0026beta;42 total Tau, and Tau were signifcantly higher in the infection group compared to the control group, respectively. Nisin treatment markedly reduced the A\u0026beta;42, total Tau, and phosphorylated Tau deposition in the brain of the infection group.\u003c/p\u003e\n \u003cp\u003eConclusions: Nisin abrogation of brain microbiome dysbiosis induces benefcial efects on AD-like pathogenic changes and neuroinfammation, and thereby may serve as a potential therapeutic for periodontal\u0026ndash;dysbiosis-related AD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.04851157662624%\" valign=\"top\"\u003e\n \u003cp\u003eDominy SS[48]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"46.19625137816979%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAnimal study to investigate the effect of small-molecule inhibitors targeting gingipains on block Pg neurotoxicity.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.75523704520397%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes: Gingipain inhibition reduced the bacterial load of an established Pg brain infection, blocked A\u0026beta;1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConclusions: Gingipain inhibitors could be valuable for treating Pg brain colonization and neurodegeneration in AD.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"periodontal disease, Alzheimer's disease, scoping review","lastPublishedDoi":"10.21203/rs.3.rs-4199610/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4199610/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe objective of this study was to evaluate and present evidence from animal and human clinical studies on associations between periodontal disease (PD) and Alzheimer's disease (AD), and to suggest potential mechanisms that might explain such associations.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAn electronic search was conducted of PubMed, Embase and Cochrane Central Register of Controlled Trials for articles published from 2004to 2024 in the English language. From the initial search, 357 full-text studies were assessed for eligibility. After excluding studies for technical and study limitations, a total of 39 studies were included in the summary tables and additional studies were included in the review to support evidence.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 39 studies on the correlation between periodontal disease (PD) and Alzheimer 's disease (AD) were included in this study. Among them, 22 articles were related studies, and 20 studies showed that there was a correlation between PD and AD. 15 articles were related to mechanism research, and the research showed that PD is associated with brain Aβ and tau protein aggregation, the inflammatory response caused by PD is closely related to AD and P. gingivalis is closely related to the development of AD. Two latest treatment studies, studies have shown that gingipain inhibitors could be valuable for treating Pg brain colonization and neurodegeneration in AD and nisin abrogation of brain microbiome dysbiosis induces beneficial effects on AD-like pathogenic changes and neuroinfammation.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis scoping review shows that periodontal disease (PD) is associated with the progression of Alzheimer 's disease (AD). PD has been proposed as a potentially modifiable etiological factor for AD, which opens up new therapeutic strategies for the prevention or management of AD.\u003c/p\u003e","manuscriptTitle":"Investigating the association between periodontal disease and Alzheimer's disease: a scoping review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-16 17:01:38","doi":"10.21203/rs.3.rs-4199610/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9e18b11a-d893-486d-a43e-ec8e8ef8aa7b","owner":[],"postedDate":"April 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-09T09:26:22+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-16 17:01:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4199610","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4199610","identity":"rs-4199610","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}