Yoann Maitre
email: maitreyoann@yahoo.fr

Rachid Mahalli
email: rachid.mahalli@etu.univ-tours.fr

Pierre Micheneau

Alexis Delpierre
email: alexis.delpierre@outlook.fr

Gilles Amador
email: gilles.amador@univ-nantes.fr

Frédéric Denis
email: frederic.denis@chu-tours.fr

Evidence and Therapeutic Perspectives in the Relationship between the Oral Microbiome and Alzheimer's Disease: A Systematic Review

Keywords: Alzheimer's disease, oral microbiota, oral microbiome, mental disorders

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Alzheimer's disease (AD) is progressive and neurodegenerative in the elderly (>65 years old), in which the main symptom is a decline in cognitive ability, severe enough to interfere with daily living activities. Approximately 47 million people worldwide have AD-related dementia, and this number has doubled almost every 20 years. It is expected to reach 131.5 million by 2050 [START_REF] Prince | The global prevalence of dementia: A systematic review and metaanalysis[END_REF].

AD is characterized by protein conformation [START_REF] Adav | Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling[END_REF][START_REF] Leandro | Protein misfolding in conformational disorders: Rescue of folding defects and chemical chaperoning[END_REF], mainly caused by aberrant processing and polymerization of normally soluble proteins [START_REF] Tran | Exploring the Alzheimer amyloid-β peptide conformational ensemble: A review of molecular dynamics approaches[END_REF]. When misfolded, soluble neuronal proteins reach altered conformations, due to genetic mutations (Apolipoprotein ε4 gene (APO ε4) is the most important risk factor in sporadic AD), external factors like aging and aggregates, lead to abnormal neuronal function and neuronal loss [START_REF] Adav | Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling[END_REF][START_REF] Leandro | Protein misfolding in conformational disorders: Rescue of folding defects and chemical chaperoning[END_REF][START_REF] Tran | Exploring the Alzheimer amyloid-β peptide conformational ensemble: A review of molecular dynamics approaches[END_REF][START_REF] Ellisdon | The role of protein misfolding in the pathogenesis of human diseases[END_REF]. To date, AD causes are still poorly understood and, although many treatments have been tested in clinical trials, none can cure or stop its progression.

However, it was established that even before the first symptoms appear, neurons are affected by two types of lesions: amyloid plaques located between neurons and neurofibrillary degeneration, which is located inside neurons [START_REF] Wilkins | Amyloid precursor protein processing and bioenergetics[END_REF]. Amyloid plaques are formed by the abnormal accumulation of a protein called "β-amyloid" between nerve cells in the grey matter of the cerebral cortex, with a dysfunction of the connections between neurons [START_REF] O'brien | Amyloid precursor protein processing and Alzheimer's disease[END_REF]. Neurofibrillary degeneration corresponds to an abnormal accumulation of filaments inside the neuron; the protein responsible for this dysfunction is called "Tau protein" [START_REF] Alonso | Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer's disease[END_REF]. Both lesions are clusters of proteins that form during the normal aging process. Yet, in Alzheimer's type disease, these proteins accumulate in much larger quantities [START_REF] Alonso | Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules[END_REF].

AD is considered a multifactorial disease, with its onset thought to result from the interaction between genetic background and various risk factors [START_REF] Jiang | Epidemiology and etiology of Alzheimer's disease: From genetic to non-genetic factors[END_REF]. Age is the main proven risk factor, with a prevalence that doubles every 5 years from the age of 65 years (2% after 65, 15% after 80 years) [START_REF] Prince | The global prevalence of dementia: A systematic review and metaanalysis[END_REF]. Other risk factors are now well-established, such as low level of education, cardiovascular risk factors (untreated hypertension, stroke, hypercholesterolemia, diabetes, overweight status, obesity, and periodontal disease); women; environmental factors (tobacco, alcohol, pollution, certain drugs); and sleep disorders. Chronic inflammation of the body is linked to shrinkage of brain areas in AD; mood disorders like chronic stress or depression are also correlated. An unbalanced diet, lack of physical and stimulating mental activity may also be associated with an increased risk of AD [START_REF] Pan | Factors Affecting Rapid Cognitive Decline in Patients with Alzheimer's Disease: A Longitudinal Follow-Up Study[END_REF][START_REF] Chantanachai | Risk factors for falls in older people with cognitive impairment living in the community: Systematic review and meta-analysis[END_REF][START_REF] Profennoa | Meta-Analysis of Alzheimer's Disease Risk with Obesity, Diabetes, and Related Disorders[END_REF].

Recently, many studies show epidemiological correlations between AD and periodontitis. There are also pathophysiological arguments for a causal relationship between AD and periodontal disease (PD) [START_REF] Gil-Montoya | Association between periodontitis and amyloid β peptide in elderly people with and without cognitive impairment[END_REF][START_REF] Kamer | Periodontal disease associates with higher brain amyloid load in normal elderly[END_REF]. Periodontitis is a peripheral infectious/inflammatory condition, one of the major risk factors in tooth loss [START_REF] Gugnani | Tooth loss in Periodontitis: How valuable are the predictors?[END_REF]. Periodontitis is associated with increased serum levels of C-reactive protein (CRP) and pro-inflammatory cytokines (e.g., tumor necrosis factor-α), as well as decreased anti-inflammatory markers (e.g., interleukin-10) [START_REF] Bansal | C-Reactive Protein (CRP) and its Association with Periodontal Disease: A Brief Review[END_REF]. Many researchers hypothesised that the association between AD and periodontitis may be due to increased systemic inflammation accompanying the growth of periodontal pathogens [START_REF] Cerajewska | Periodontitis: A potential risk factor for Alzheimer's disease[END_REF][START_REF] Ide | Periodontitis and Cognitive Decline in Alzheimer's Disease[END_REF]. The latter would mediate the development of AD through their role in the development of vascular disease [START_REF] Gil-Montoya | Association between periodontitis and amyloid β peptide in elderly people with and without cognitive impairment[END_REF][START_REF] Paul | Inflammation in Periodontal Disease: Possible Link to Vascular Disease[END_REF][START_REF] Choi | Association of chronic periodontitis on Alzheimer's disease or vascular dementia[END_REF].

Although the link between gut dysbiosis and neurological disorders remains speculative, anatomical evidence is leading to a better understanding of a bidirectional link between the gut and brain, as is the case in AD [START_REF] Ojeda | Gut Microbiota Interaction with the Central Nervous System throughout Life[END_REF][START_REF] Schächtle | The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research[END_REF]. This bidirectional relationship is thought to exist between the oral microbiota and many systemic diseases, including AD.

This review aims to clarify the nature of the link between Alzheimer's disease and the oral microbiome at the epidemiological and pathophysiological levels, as well as to highlight new therapeutic perspectives to contribute to the management of this disease.

Materials and Methods

We performed a systematic review following the Preferred Reporting Items for Systematic Reviews (PRISMA) checklist [START_REF] Tricco | PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation[END_REF]. Authors defined research questions, objectives, search strategies, and inclusion/exclusion criteria through previous discussions.

Search Strategy

Understanding the interactions of microorganisms with the host and with each other, as well as their impact on health, was improved by the development of high-throughput sequencing techniques for genetic material since 2000 [START_REF] Hooks | Microbiota-gut-brain research: A critical analysis[END_REF]. The research was carried out from January 2000 to July 2021 to clarify the relationship between AD and the oral microbiome. So as not to restrict the search only to oral pathologies, terms identifying the main oral ecological niches "Dental plaque," "Saliva," and Mouth" were associated with the search term "Mouth diseases" and used in combination with the Boolean operator "AND"/"OR" as per the following equation:

(((("Mouth"[Mesh]) OR "Mouth Diseases"[Mesh]) OR "Dental Plaque"[Mesh]) OR "Saliva"[Mesh]) AND "Alzheimer Disease" [Mesh] The search was performed in the MEDLINE literature database through PubMed interface.

Inclusion and Exclusion Criteria

We included experimental or clinical studies (longitudinal, cross-sectional, or randomised) that explored the association between the oral microbiome and AD symptoms, and/or explored the association between the oral microbiome and AD from an immunoinflammatory perspective. We excluded conferences, abstracts, reviews, and editorials.

Data Extraction

Two independent operators (F.D. and Y.M.) manually checked the references of eligible studies on the subject, according to inclusion/exclusion criteria.

An analysis of titles and abstracts by F.D. and Y.M. was performed to identify potentially relevant articles based on inclusion criteria. When the information in the abstracts was deemed insufficient, a review of the complete study decided on its relevance. A discussion between the two reviewers took place to reach a consensus with discrepancies in the selection decision process.

Results

Study Selection

After retrieving the studies from the database, we identified the studies that met eligibility criteria. Of the 227 studies initially identified, 24 were selected. A complementary detection resulted in the selection of three additional articles. A total of 27 articles were included in the analysis (Figure 1).

Study Characteristics

Since the beginning of 2000, the number of publications about the relationship between the oral microbiome and AD has been steadily increasing, with 44% of publications from 2019 to 2021 (Figure 2a). These concern experimental in vitro studies (n = 1) or murine models (n = 6) and human clinical studies (n = 20). The case-control study design is most often used for human studies (n = 12) (Figure 2b). With the exception of retrospective cohort studies, sample sizes were limited in both animal (N = 30 to 140) and human (N = 20 to 354) studies. While they were conducted worldwide, they were concentrated in the United States (9 studies from 2002 to 2021) and in Europe (8 studies from 2010 to 2021) see Figure 2c.

Each study meeting the inclusion criteria was analysed in terms of authors, date of publication, study design, objectives, factors assessed, results and limitations (Table 1).

Clinical Oral Perturbations and Alzheimer's Disease

In 2020, Kantarci et al. showed that PD increases bone loss in AD model mice (5xFAD) and wild-type control mice (WT). While they found no significant difference in alveolar bone loss after induction of experimental PD between 5xFAD and WT mice, they noted that alveolar bone loss is higher in 5xFAD than in WT at baseline [START_REF] Kantarci | Microglial response to experimental periodontitis in a murine model of Alzheimer's disease[END_REF].

Periodontal damages were also identified in several case-control studies in humans. Thus, De Oliveira Araújo et al. found a significant association between periodontitis and AD, controlling for age, sex, income, and education [START_REF] Oliveira Araújo | Association between periodontitis and Alzheimer's disease and its impact on the self-perceived oral health status: A case-control study[END_REF]. In accordance with this result, periodontal infections, the presence of deep periodontal pockets, and generalised marginal alveolar bone loss are markers of periodontal deterioration, that appear to be significantly associated with AD patients [START_REF] Souza Rolim | Oral Infections and Orofacial Pain in Alzheimer's Disease: A Case-Control Study[END_REF][START_REF] Syrjälä | Dementia and Oral Health among Subjects Aged 75 Years or Older[END_REF][START_REF] Holmer | Association between periodontitis and risk of Alzheimer's disease, mild cognitive impairment, and subjective cognitive decline: A case-control study[END_REF][START_REF] Martande | Periodontal Health Condition in Patients with Alzheimer's Disease[END_REF]. Similarly, in 2015, the cross-sectional study by Kamer et al. found a significant association between a loss of clinical attachment and increased amyloid load in vulnerable brain areas of AD patients, after adjustment for confounding factors (age, ApoE, and smoking) [START_REF] Kamer | Periodontal disease associates with higher brain amyloid load in normal elderly[END_REF].

Several retrospective cohort studies, assessing the association between incident AD risk and PD, moderate these results. For example, in a cohort followed for 26 years (N = 6650), the association between risk of AD and periodontal pocket depth appeared marginal in men and older individuals [START_REF] Beydoun | Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey[END_REF]. The study by Choi et al. shows that in a cohort of 262,349 participants aged 50 or older with a follow-up of 11 years, developing AD tends to be higher in patients with chronic periodontitis (CP), vs. patients without CP (aHR = 1.05; 95% CI = 1.00-1.11, p = 0.042) [START_REF] Choi | Association of chronic periodontitis on Alzheimer's disease or vascular dementia[END_REF]. Conversely, in a cohort of 27,963 patients over 50 years, followed for 16 years, Chen et al. showed a significantly higher risk of developing AD in patients with 10 years of exposure to CP vs. those with no exposure [START_REF] Chen | Association between chronic periodontitis and the risk of Alzheimer's disease: A retrospective, population-based, matched-cohort study[END_REF].

Oral Dysbiosis and Alzheimer's Disease

Liu et al. showed that the salivary microbiome has significantly lower diversity in patients with AD than in healthy patients [START_REF] Liu | Analysis of Salivary Microbiome in Patients with Alzheimer's Disease[END_REF]. Maurer et al. also identified a higher bacterial load of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Fusobacterium nucleatum in dental plaque compared to controls [START_REF] Maurer | Dental health in advanced age and Alzheimer's Disease: A possible link with bacterial toxins entering the brain?[END_REF]. Rivière et al. demonstrated that brain colonisation by treponemes (T. amylovorum, T. denticola, T. maltophilum, T. medium, T. pectinovorum, T. socranskii, T. vincentii) was more frequent in AD patients than controls [START_REF] Riviere | Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer's disease[END_REF]. In 2018, Ilievski et al. detected the presence of P. gingivalis and gingipaïn in the hippocampus of mice [START_REF] Ilievski | Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration, and amyloid beta production in wild type mice[END_REF].

While the study by Liu et al. concluded that no oral bacteria are associated with the severity of AD [START_REF] Liu | Analysis of Salivary Microbiome in Patients with Alzheimer's Disease[END_REF], serum immunoglobulin G (IgG) concentration associated with common periodontal bacteria (P. gingivalis, Tannerella forsythia, A. actinomycetemcomitans, T. denticola, Campylobacter rectus, Actinomyces naeslundii) represents a risk factor in developing AD [START_REF] Noble | Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease[END_REF].

According to the study by Beydoun et al., the incidence and mortality of AD could be related to a combination of periodontal bacteria. The incidence of AD is related to a composite of C. rectus and P. gingivalis, such that the risk of mortality from AD was enhanced by a composite of P. gingivalis, Prevotella intermedia, Prevotella nigrescens, F. nucleatum, C. rectus, Streptococcus intermedius, Capnocytophaga ochracea and Prevotella melaninogenica [START_REF] Beydoun | Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey[END_REF].

Pathophysiological Evidence between the Microbiome and Alzheimer's Disease

According to the study of Dominy et al., on mice, the presence of P. gingivalis and gingipaïn in the brain plays a central role in the pathogenesis of AD [START_REF] Dominy | Porphyromonas Gingivalis in Alzheimer's Disease Brains: Evidence for Disease Causation and Treatment with Small-Molecule Inhibitors[END_REF]. In vitro, Yamada et al. demonstrated that exposure to phosphoglycerol dihydroceramide produced by P. gingivalis (PGDHC) increased Aβ peptide secretion in a dose-dependent manner in the Chinese hamster ovary-7WD10 cells, stably expressing wild-type human amyloid precursor protein (APP) and induced specific phosphorylation of Tau protein in a dose-dependent manner in human neuroblastoma cells [START_REF] Yamada | Potential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen Porphyromonas gingivalis in the Pathogenesis of Alzheimer's Disease[END_REF]. In rats, Zhang et al. showed a significant elevation of Aβ1-40 peptide levels in the cerebral cortex of AD rats with periodontitis compared to AD rats without it [START_REF] Zhang | Poor oral health conditions and cognitive decline: Studies in humans and rats[END_REF]. Similarly, Díaz-Zúñiga et al. observed a significant increase in Aβ1-42 levels and Tau hyperphosphorylation in the hippocampus of rats orally infected by K1 or K2 P. gingivalis, associated with PD [START_REF] Díaz-Zúñiga | Alzheimer's Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent[END_REF]. In mice, Kantarci et al. noted a significant elevation of the mean level of insoluble Aβ42 peptide in the prefrontal cortex of AD mice with periodontitis, compared to AD mice without it [START_REF] Kantarci | Microglial response to experimental periodontitis in a murine model of Alzheimer's disease[END_REF]. Phosphorylation of Tau protein was detected by [START_REF] Ilievski | Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration, and amyloid beta production in wild type mice[END_REF] in AD mice infected with P. gingivalis, but not in control mice [START_REF] Ilievski | Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration, and amyloid beta production in wild type mice[END_REF].

Studies of cognitive decline in murine models show no significant differences in learning and memory tests (Y maze, nest building, or the Morris Water Maze test) that may be associated with periodontitis or acute or continuous exposure to P. gingivalis-derived lipopolysaccharides (Pg-LPS) [START_REF] Zhang | Poor oral health conditions and cognitive decline: Studies in humans and rats[END_REF][START_REF] Hayashi | Continuous intracerebroventricular injection of Porphyromonas gingivalis lipopolysaccharide induces systemic organ dysfunction in a mouse model of Alzheimer's disease[END_REF]. According to Ide et al., there was also no significant relationship between serum levels of antibodies to P. gingivalis and rates of cognitive decline, based on the Mini Mental State Examination (MMSE) in AD patients [START_REF] Ide | Periodontitis and Cognitive Decline in Alzheimer's Disease[END_REF]. However, in 2020, Leblhuber et al. found a significant association between the salivary presence of P. gingivalis and lower MMSE in AD patients [START_REF] Leblhuber | Knock-on effect of Continuous intracerebroventricular disease?[END_REF].

Oral Microbiota and Immuno-Inflammation in Alzheimer Disease

While neuroimmune interactions are essential to brain function [START_REF] Pape | Immunoneuropsychiatry: Novel perspectives on brain disorders[END_REF], chronic inflammation appears to be a key factor in the pathophysiology and clinical progression of AD [START_REF] Cerovic | Neuroinflammation and the Gut Microbiota: Possible Alternative Therapeutic Targets to Counteract Alzheimer's Disease? Front[END_REF]. In vitro, Yamada et al. showed that exposure of human neuroblastoma cells to PGDHC or Pg-LPS increased expression of the senescence-associated secretory phenotype involving β-galactosidase, cathepsin B, cysteine, and pro-inflammatory cytokines TNF-α and IL-6 [START_REF] Yamada | Potential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen Porphyromonas gingivalis in the Pathogenesis of Alzheimer's Disease[END_REF].

In the hippocampus of rats infected with P. gingivalis encapsulated serotypes K1 and K2, Díaz-Zúñiga et al. observed a significant increase in pro-inflammatory cytokine (IL-1β, IL-6, TNF-α, IFN-γ) not found in rats infected with non-encapsulated bacterial strains [START_REF] Díaz-Zúñiga | Alzheimer's Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent[END_REF]. Similarly, oral application of P. gingivalis 3 times a week for 22 weeks showed a significant increase in the expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in the hippocampus of infected mice compared to controls [START_REF] Ilievski | Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration, and amyloid beta production in wild type mice[END_REF]. In AD model rats with induced periodontitis, compared to controls, TNF-α levels were significantly higher in the hippocampus, IL-1 levels were higher in the cerebral cortex, and IL6 levels were higher both in the hippocampus and cerebral cortex [START_REF] Zhang | Poor oral health conditions and cognitive decline: Studies in humans and rats[END_REF]. The inflammatory activation index (TNFa to IL-10 ratio) shows higher and unresolved inflammation in the brains of AD mice before and after induction of periodontitis, than in non-AD mice; this is associated with a reduction in microglial markers in the vicinity of Aβ plaques, vs. those without induced periodontitis [START_REF] Kantarci | Microglial response to experimental periodontitis in a murine model of Alzheimer's disease[END_REF].

Consistent with the study by Kamer et al., which showed a higher expression of antibodies against periodontal bacteria (A. actinomycetemcomitans, T. forsythia, and P. gingivalis) and TNF-α in the serum of AD patients than controls [START_REF] Kamer | TNF-Alpha and Antibodies to Periodontal Bacteria Discriminate between Alzheimer's Disease Patients and Normal Subjects[END_REF]; Cestari et al. noted a significant association between periodontitis and increased serum levels of TNF-α and IL-6 in AD patients [START_REF] Cestari | Oral Infections and Cytokine Levels in Patients with Alzheimer's Disease and Mild Cognitive Impairment Compared with Controls[END_REF]. Over a six-month follow-up in patients with mild to moderate AD, anti-P. gingivalis antibody levels were associated with a fall in serum IL10 levels and an increase in serum TNFα [START_REF] Ide | Periodontitis and Cognitive Decline in Alzheimer's Disease[END_REF]. In short-term post-mortem AD brain tissue (12h), [START_REF] Poole | Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue[END_REF] detected the presence of Pg-LPS and suggests their role in brain inflammation associated with AD [START_REF] Poole | Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue[END_REF]. Similarly, Laugish et al. ( 2018) showed in patients with AD or other forms of dementia that high levels of antibodies against periodontal bacteria in cerebrospinal fluid and serum (A. actinomycetemcomitans, T. denticola, T. forsythia, P. gingivalis) can play a significant role in the local immune response [START_REF] Laugisch | Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer's Disease[END_REF]. In AD patients, a significant reduction in the concentration of sensitive biomarkers of immune activation is associated with different oral bacteria; thus, the presence of T. denticola and T. forsythia in saliva reduced the serum concentrations of neopterin and kynurenine, respectively [START_REF] Leblhuber | Knock-on effect of Continuous intracerebroventricular disease?[END_REF].

Alzheimer's Disease Risk Factor and Therapeutic Perspectives in Relation to the Oral Microbiome

The influence of genetics on the onset and development of AD, as well as on susceptibility to pathogens is well-understood [START_REF] Sims | The multiplex model of the genetics of Alzheimer's disease[END_REF][START_REF] Tabrett | The influence of host genetics on the microbiome[END_REF]. In 2019, Liu et al. study found a significant decrease in Actinobacillus and Actinomyces levels and an abundance of Abiotrophia and Desulfomicrobium in patients carrying the APOE ε4 gene [START_REF] Liu | Analysis of Salivary Microbiome in Patients with Alzheimer's Disease[END_REF]. In P. gingivalis-infected mice, the expression of APP and BACE1 genes, involved in the development of AD, was significantly increased vs. the control group. Conversely, the expression of ADAM10, which plays an essential role in reducing the generation of amyloid-β (Aβ) peptides, was significantly reduced [START_REF] Ilievski | Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration, and amyloid beta production in wild type mice[END_REF]. The Mendelian randomization study of [START_REF] Sun | Mixed evidence for the relationship between periodontitis and Alzheimer's disease: A bidirectional Mendelian randomization study[END_REF] found no evidence for a bidirectional genetic relationship between AD and periodontitis from analysis of data from Genome-Wide Association Studies in the European ancestry population [START_REF] Sun | Mixed evidence for the relationship between periodontitis and Alzheimer's disease: A bidirectional Mendelian randomization study[END_REF]. According to Kamer et al., no significant difference in cytokine levels could be found as per the presence of the APOE ε4 gene in AD patients [START_REF] Kamer | TNF-Alpha and Antibodies to Periodontal Bacteria Discriminate between Alzheimer's Disease Patients and Normal Subjects[END_REF].

Several studies suggest that antimicrobial therapy is effective for AD [START_REF] Song | Antimicrobial therapy and the potential mechanisms in Alzheimer's disease[END_REF], but only one study on modulation of the oral microbiome was identified. In the study by Dominy et al., oral administration of gingipain inhibitors to mice, essential for the survival of P. gingivalis, reduced the load of P. gingivalis and cytokines (TNFα), as well as the production of Aβ peptide 1-42 in the brain. An increased number of neurons in the hippocampus of P. gingivalis-infected mice, treated with these inhibitors, reflects a reduction in the neurotoxicity of this bacterium [START_REF] Dominy | Porphyromonas Gingivalis in Alzheimer's Disease Brains: Evidence for Disease Causation and Treatment with Small-Molecule Inhibitors[END_REF].

A bidirectional Mendelian randomization study N = 4924 /7301

Examination of the potential causal relationship between AD and chronic periodontitis bidirectionally in the population of European ancestry.

Single-nucleotide polymorphisms associated with periodontitis and AD.

No evidence for a bidirectional genetic relationship between AD and periodontitis from analysis of Genome-Wide Association Studies data. * Mendelian randomisation does not assess the impact of the duration of periodontal disease on the risk of developing AD, The genetic tool used to define PD may not be suitable for detecting the causal link between PD and AD.

Discussion

Oral Microbiome and Alzheimer's Disease

The bidirectional relationship between the gut microbiome and AD is increasingly well-understood, leading to the definition of the gut-brain axis [START_REF] Kowalski | Brain-Gut-Microbiota Axis in Alzheimer's Disease[END_REF]. The detection of peptides in the gut and brain helped to lay the foundation for the concept of the gut-brain axis in the sixties and seventies [START_REF] Holzer | Neuropeptides and the microbiota-gut-brain axis[END_REF]. Similar studies argue for a relationship between the oral microbiome and AD. Thus, the particular dysbiotic signature in Alzheimer's patients involving periodontal bacteria (A. actinomycetemcomitans, P. gingivalis, T. denticola, F. nucleatum) suggests a modulation of oral bacterial flora by the central nervous system as observed for intestinal flora [START_REF] Martin | The Brain-Gut-Microbiome Axis[END_REF]. This finding must be moderated, due to additional factors affecting the oral microbiome of AD patients. Poor oral hygiene from reduced cognition and dexterity, age-related xerostomia, and medication can contribute to oral dysbiosis in these patients [START_REF] Gao | Oral Health and Care for Elderly People with Alzheimer's Disease[END_REF].

The presence of P. gingivalis in the brain, as well as an increase in Aβ peptide secretion, induced by associated compounds (gingipain, phosphoglycerol dihydroceramide), can be related to the antimicrobial activity of Aβ peptide, as demonstrated by Soscia et al. against several Gram-negative and Gram-positive bacteria (Esherichia coli, Streptococcus pneumonia, Streptococcus salivarius) as well as Candida albicans [START_REF] Soscia | The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide[END_REF]. Long-term colonization by pathogenic bacteria and failure to clear the Aβ peptides, which was produced in response, can lead to excessive accumulation followed by brain tissue destruction through the formation of amyloid plaques and hyperphosphorylation of the tau protein [START_REF] Bulgart | Microbial involvement in Alzheimer disease development and progression[END_REF]. These observations can be related to the survey results by Beydoun et al. [START_REF] Beydoun | Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey[END_REF], identifying a correlation between periodontal bacterial communities and the incidence or mortality of AD. In this context, while the evidence for the impact of the microbiome on cognitive performance seems well established [START_REF] Gareau | Cognitive Function and the Microbiome[END_REF], the results available in this review regarding the involvement of the oral microbiome on cognitive decline in AD patients seems contradictory.

Possible Mechanisms of the Relationship between the Oral Microbiome and Alzheimer's Disease

Neuroinflammation is an important process in the neurodegeneration associated with AD. It exacerbates key features of the disease, including the deposition of Aβ peptides and hyperphosphorylation of tau. It places this process in a vicious cycle of inflammation and cellular destruction [START_REF] Calsolaro | Neuroinflammation in Alzheimer's disease: Current evidence and future directions[END_REF]. Thus, the presence in the brain of lipopolysaccharides from T. denticola, T. forsythia, and P. gingivalis that can be associated with increased expression of major proinflammatory cytokines (IL-1β, IL-6, TNFα, and IFNγ) and decreased antiinflammatory cytokines (IL-10) suggests an involvement of the oral microbiota in the occurrence and progression of AD. Furthermore, these periodontal pathogens seem to modulate the immune response in AD patients. This modulation may be related to an alteration of microglial activity associated with an increased risk of AD [START_REF] Hansen | Microglia in Alzheimer's disease[END_REF]. However, localized transient inflammation is the normal immunological response of our immune system to cell/tissue damage, and is very important for tissue regeneration and repair [START_REF] Cooke | Inflammation and Its Role in Regeneration and Repair[END_REF]. Inflammation is a violent cell self-destructive way of clearing damaged cells. By destroying the infected tissues, the pathogens are cleared as well, and thus almost all microbial infections are self-limiting [START_REF] Levin | Antibiotics, and Self-Limiting Bacterial Infections[END_REF][START_REF] Levin | Why we don't get sick: The within-host population dynamics of bacterial infections[END_REF]. If at the same time the debris of the destroyed cells can be effectively cleaned away by our immune system [START_REF] Cunliffe | Intentional pathogen killing-or denial of substrate?[END_REF], for example through autophagy, tissue regeneration will be followed, and infection-induced tissue damage will be transient and not become chronic, the patient can easily recover from such transient tissue damage.

While several mechanisms involving nervous, endocrine, and immune signals were advanced in the context of the gut-brain axis [START_REF] Martin | The Brain-Gut-Microbiome Axis[END_REF], no study identified mechanisms of the interaction between oral bacteria and AD. Nevertheless, Rivière et al. proposed the hypothesis that oral bacteria may infect the brain via branches of the trigeminal nerve [START_REF] Riviere | Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer's disease[END_REF]. The possibility of oral bacteria accessing the bloodstream [START_REF] Horliana | Dissemination of periodontal pathogens in the bloodstream after periodontal procedures: A systematic review[END_REF] is a risk for sepsis [START_REF] Berg | Bacterial Translocation from the Gastrointestinal Tract[END_REF][START_REF] Rhodes | Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016[END_REF] and may be associated more rarely with meningitis when these bacteria translocate to the brain [START_REF] Maurer | Bacterial meningitis after tooth extraction[END_REF][START_REF] Kim | Microbial translocation of the blood-brain barrier[END_REF]. It can be assumed that their interactions with the blood-brain barrier may also alter its integrity, allowing metabolic products produced by the microbiome, such as short-chain fatty acids, to cross the BBB and then affect brain function, such as the proposed in the gut-brain axis [START_REF] Logsdon | Gut reactions: How the blood-brain barrier connects the microbiome and the brain[END_REF]. Although alterations in the BBB have been found both in AD patients and in animal models, their role in the disease process remains unclear [START_REF] Montagne | Alzheimer's disease: A matter of blood-brain barrier dysfunction?[END_REF].

The reciprocal modulation of the expression of some genes involved in AD and the modulation of oral microbiota has been identified [START_REF] Liu | Analysis of Salivary Microbiome in Patients with Alzheimer's Disease[END_REF][START_REF] Ilievski | Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration, and amyloid beta production in wild type mice[END_REF]. It provides the basis for the hypothesis of a plausible common genetic cause for oral dysbiosis and AD. However, according to Sun et al. [START_REF] Sun | Mixed evidence for the relationship between periodontitis and Alzheimer's disease: A bidirectional Mendelian randomization study[END_REF], this hypothesis must be balanced due to the lack of evidence for a bidirectional genetic relationship between AD and periodontitis. The oral microbiome and associated dysbiosis appear to be only one environmental risk factor for the expression of genes associated with AD, as is the case for diseases such as diabetes or cardiovascular disease, etc. [START_REF] Singhrao | Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease[END_REF].

Inflammation, Overnutrition and Lipotoxicity

Although the virulence of the microorganism determines the damages made by the microorganisms to the host cells before they are cleared by host immunity, this microbial virulence alone does not account for the virulence of disease [START_REF] Levin | Why we don't get sick: The within-host population dynamics of bacterial infections[END_REF][START_REF] Humphries | Pathways Linking Nutritional Status and Infectious Disease: Causal and Conceptual Frameworks[END_REF]. Most of the virulence of an infectious or chronic non-infectious disease is the result of the overactive inflammation response of our immune system [START_REF] Levin | Why we don't get sick: The within-host population dynamics of bacterial infections[END_REF][START_REF] Humphries | Pathways Linking Nutritional Status and Infectious Disease: Causal and Conceptual Frameworks[END_REF], which turns local transient inflammation into systemic or chronic inflammation. The driving force for such an inflammatory transition is overnutrition. This is because, when there is overnutrition, the debris of the destroyed cells cannot be effectively cleaned, then this debris will become the nutrition source for bacteria proliferation. This debris can also be turned into lipid intermediates, and induce lipotoxicity. The human immune system also has a pivotal role in nutrition acquisition from the pathogen or the commensal microbiota like bacteria and the damaged tissues [START_REF] Yu | Nutrition acquisition by human immunity, transient overnutrition and the cytokine storm in severe cases of COVID-19[END_REF], and uses them for tissue regeneration if these nutrients just meet the need of tissue regeneration without surplus.

But if there is overnutrition, lipotoxicity as a result of overnutrition will prevent the tissue healing process from happening. Moreover, in the state of over-nutrition, the nutrition generated from the degradation of microbial-infected tissues will make this overnutrition situation worse, lipotoxicity and tissue damage will form a vicious positive feedback loop (as lipotoxicity is also a strong stimulus for cell dysfunction and cell death), which are escalated by the inflammation response, shifting inflammation from local to systemic, creating collateral damage to all other organs including the central nervous system, and may cause AD. So overnutrition could be a more possible linking factor between microbiota (oral or gastrointestinal) and AD.

Oral Microbiota Modulation and Alzheimer's Disease Therapy

Treatments for AD are currently symptomatic, but research is targeting its pathological features, including Aβ peptides and tau protein [START_REF] Breijyeh | Comprehensive Review on Alzheimer's Disease: Causes and Treatment[END_REF]. In this context, the probable impact of the oral microbiome on the development of AD opens the door to a complementary therapeutic approach. Only the study by [START_REF] Dominy | Porphyromonas Gingivalis in Alzheimer's Disease Brains: Evidence for Disease Causation and Treatment with Small-Molecule Inhibitors[END_REF] is in line with this research by showing the interest in gingipain inhibitors in AD [START_REF] Dominy | Porphyromonas Gingivalis in Alzheimer's Disease Brains: Evidence for Disease Causation and Treatment with Small-Molecule Inhibitors[END_REF]. However, phototherapy, as well as prebiotic compounds and probiotic strains for a global/targeted modulation of the oral microbiome, represent areas of research for the prevention and treatment of AD. Indeed, the results of these potential new methods seem to demonstrate the effectiveness in the modification of the ecosystem of dental plaque by reducing the importance of the periodontal bacteria, which appear to be associated with AD (P. gingivalis, F. nucleatum, C. rectus, and others) [START_REF] Routier | What do we know about the mechanisms of action of probiotics on factors involved in the pathogenesis of periodontitis? A scoping review of in vitro studies[END_REF][START_REF] Soukos | Phototargeting human periodontal pathogens in vivo[END_REF]. Blue light is painless, fast, without drug toxicity or effect on taste, and is selective in effect. Its use could help to reduce oral dysbiosis linked to PD [START_REF] Soukos | Phototargeting oral black-pigmented bacteria[END_REF] and its impacts on AD patients. Probiotic strains affecting the periodontogenic flora through various galenic forms, such as milk drinks, yoghurts, and mouthwash could facilitate oral hygiene measures in AD patients [START_REF] Maitre | Pre-and Probiotics Involved in the Modulation of Oral Bacterial Species: New Therapeutic Leads in Mental Disorders?[END_REF].

Modulation of several pathological events in AD such as reduction in amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics and increased availability of neuronal energy seem to be associated with different metabolic pathways (e.g., Wnt signalling, 5'-adenosine monophosphate-activated protein kinase) [START_REF] Godoy | Signaling pathway cross talk in Alzheimer's disease[END_REF]. As Gram-negative bacteria-associated LPS and microbiome-generated amyloids potentially contribute to the regulation of these signalling pathways [START_REF] Jiang | The Gut Microbiota and Alzheimer's Disease[END_REF][START_REF] Friedland | The role of microbial amyloid in neurodegeneration[END_REF], therapeutic strategies to modulate oral dysbiosis as well as to modify bacterially produced amyloids or reduce their production also represent a future focus of research for the treatment of AD.

Limitations and Perspectives

While the relationship between the oral microbiome and mental disorders is a topic of growing interest, some limitations in the studies in this review must be noted. Thus, in the context of the evaluation of brain colonization by oral bacteria, some authors point to a risk of tissue contamination by the oral microbiota post-mortem [START_REF] Riviere | Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer's disease[END_REF]. Moreover, despite the microbiome changes over the life course [START_REF] O'toole | Gut microbiota and aging[END_REF], studies are predominantly based on case-control surveys and relatively small samples that do not allow assessment of the impact of exposure duration on the risk of developing AD. The promotion of longitudinal studies is essential to understand the role of the oral microbiome in the incidence and progression of AD.

The decline in cognitive function in AD patients is linked to behavioural changes that affect oral health. The progressive decline in patients' ability and interest in both performing brushing and complementary oral care leads to the rapid development of oral pathology and dysbiosis [START_REF] Brennan | Cognitive impairment in older adults and oral health considerations: Treatment and management[END_REF]. In addition to difficulties in dental self-care, access to professional dental care procedures is complicated by a progressive cognitive decline in AD patients [START_REF] Fereshtehnejad | Dental care utilization in patients with different types of dementia: A longitudinal nationwide study of 58,037 individuals[END_REF]. Faced with the challenge of an aging population and the increase in the weight of associated AD [START_REF] Prince | The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends[END_REF], it appears important to develop research towards solutions that promote the maintenance of the oral flora balance and to raise awareness among health professionals on the prevention of oral dysbiosis.

In addition, with genetic tools and molecular analyses available to identify individual bacteria and their metabolic products, it is possible to locate and track these bacteria in different host tissues to understand which cells they may affect and which metabolic signaling pathways they may activate and thus better understand how AD may be influenced by the oral microbiome. Due to the complexity of the etiopathology of AD and the interrelation between the factors responsible for the symptoms of the disease, a new therapeutic approach combining different targets is essential to develop new, more effective and personalized interventions and strategies for patients with this disease [START_REF] Martínez-Cué | Signalling Pathways Implicated in Alzheimer's Disease Neurodegeneration in Individuals with and without Down Syndrome[END_REF].

Conclusions

Several studies show a statistical link between AD and oral microbiota. Although the robustness of this link must be confirmed due to numerous confounding factors, evidence is accumulating towards the impact of the oral microbiome in pathophysiological and immuno-inflammatory mechanisms of this disease. The impact of the oral microbiome on the development of AD opens up complementary therapies, such as phototherapy, prebiotic compounds, and probiotic strains for a global or targeted modulation of the oral microbiome, with a favourable influence on the evolution of this pathology.

Figure 1 .

 1 Figure 1. Flow chart of the study selection.

Figure 2 .

 2 Figure 2. Study characteristics: years of publication (a), design, (b), research laboratory country (c).

Table 1 .

 1 Analysis of selected articles.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	Riviere et al., 2002	Case control study	Assessment of the oral treponema	T. denticola, Treponema amylovorum,	Detection of oral Treponema in brainstem, cortex
	[36]	N = 38/40	presence in the human brain, the	Treponema maltophilum, T. medium,	and trigeminal ganglia in human subjects with
			hippocampus and the trigeminal	Treponema pectinovorum, Treponema	Alzheimer's disease.
			ganglia in AD patients and controls.	socranskii, T. vincentii	AD patients had more different Treponema
					species in the brain than controls.
					Treponema brain colonisation significantly more
					frequent in patients with Alzheimer's disease
					than in controls.
					* Possibility of a post-mortem contamination of
					tissues or assays
	Kamer et al., 2009	Case-control study	Evaluation of the difference in	A. actinomycetemcomitans,	Higher expression of antibodies to periodontal
	[47]	N = 18/16	concentration of TNF α and	T. forsythia, P. gingivalis (IgG).	bacteria and TNF α in serum of AD patients than
			antibodies to periodontal bacteria in	TNF-α, IL-1β and IL-6 in plasma.	in controls.
			serum of AD and normal controls.	APOE 4ε gene expression.	These measures could contribute to the diagnosis
			Investigation of the use of		of AD.
			biomarkers (TNF α and antibodies		No significant difference in cytokine levels
			against periodontal bacteria) for the		between carriers of APOE 4ε and non-carriers
			diagnosis of AD)		* Small sample size, study design
	Syrjälä et al., 2010	Case control study	Analysis of the association between	Diagnosis of dementia as	Significant probability to have carious teeth, teeth
	[29]	N = 76/278	diagnosed dementia and oral health	Alzheimer's disease, vascular	with deep periodontal pockets and poor oral and
			among an elderly population aged	dementia, dementia due to other	denture hygiene in patient with Alzheimer's
			75 years or older.	general medical (DSM-IV),	disease and persons with other types of dementia
				dementia with Lewy bodies	compared with non-demented persons.
				(McKeith Criteria).	* Study design, sample size, lack of an
				Number of teeth with dental caries	assessment of inter-examiner and intra-examiner
				and with deep periodontal pockets	reliability of the oral examinations.
				(≥4mm), edentulousness, oral
				hygiene index.
	Poole et al., 2013	Case control study	Assessment of the presence of the	P. gingivalis, T. denticola, T. forsythia	Presence of P. gingivalis-LPS in AD brain with
	[49]	N = 10/10	major periodontal bacteria and/or		12 h maximum postmortem delay.
			their components in the brain tissue		No evidence of P. gingivalis LPS in brain tissue of
			of people with and without		non-AD controls with a longer post-mortem time
			dementia.		(up to 43 h).

* Study design, small sample size.

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	De Souza Rolim et al., 2014	Case control study	Assessment of mandibular function,	Temporomandibular disorders	Significant higher prevalence of orofacial pain,
	[28]	N = 29/30	orofacial pain and oral status in	McGill Pain Questionnaire, DMFT	articular abnormalities in temporomandibular
			patients with mild AD compared to	index,	joints and periodontal infections in AD patients
			age-and sex-matched healthy	plaque and gingival bleeding	than in healthy controls.
			subjects.	indexes (PI, BI), PPD,	* Study design, sample size
				cementoenamel junction (CEJ) and
				(CAL)
	Martande et al., 2014	Case control study	Comparison of periodontal health	Plaque index (PI), gingival index	Significant differences in mean GI, PI, PD, CAL,
	[31]	N = 58/60	status in people with and without	(GI), PPD, CAL), percentage	and %BOP between different groups (Non AD,
			AD from 50 to 80 years	bleeding on probing (% BOP).	Mild, moderate and severe AD).
				Degree of cognitive impairment by	Significant elevation of periodontal parameters in
				Mini-Mental State Examination	AD patients compared to non-AD patients.
				(MMSE)	Deterioration of periodontal status with AD
					progression
					* Study design, sample size, no assessment of
					socio-economic status, education, changes in oral
					hygiene regimes as dementia progresses, dietary
					changes and access to dental care.
	Noble et al., 2014	Case-cohort study	Study of the association between	P. gingivalis, T. forsythia, A.	The serum concentration of immunoglobulin G
	[38]	N = 110/109	pre-morbid levels of serum IgG	actinomycetemcomitans, T. denticola, C.	(IgG) against common periodontal bacteria
			antibodies to selected periodontal	rectus, Eubacterium nodatum,	represents a risk factor for developing AD.
			microbiota and risk for incident AD.	Actinomyces naeslundii (IgG)	High concentrations of serum IgG associated to
					Actinomyces naeslundii was associated to an
					increased risk for developing incident AD.
					* Sample size, Possibility of reverse causality due
					to the lack of exclusion of patients with mild
					cognitive impairment (levels of antibodies to the
					periodontal microbiota may have been affected
					by cognitive impairment).

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	Kamer et al., 2015	Cross sectional study	Evaluation of the association	CAL, PPD, Bleeding on probing	Significant association between CAL and an
	[15]	N = 38	between periodontal disease burden	(BOP).	increased amyloid load in vulnerable AD brain
			with the brain amyloid load in	Amyloid load in AD vulnerable	areas after adjusting for confounders (age, ApoE
			cognitively normal patients.	brain areas (prefrontal cortex,	and smoking).
				middle frontal gyrus, lateral	No significant interaction between ApoE and
				temporal lobe, inferior parietal	periodontal measures.
				lobule, and posterior cingulate	* Sample size, Limited generalisation of results
				cortex/precuneus)	due to the homogeneity of the study population,
					self-selected patient.
	Cestari et al., 2016	Case control study	Investigation of the prevalence of	Serum level of IL-1β, IL-6, and	Patients with AD had significantly higher IL-6
	[48]	N = 25/19/21	oral infections and blood levels of	TNF-α.	levels than controls.
			IL-1β, TNF-α, and IL-6 in patients		Significant association between IL-6 and TNF-α
			with AD, mild cognitive impairment		in patients with AD or MCI and periodontitis
			(MCI), and onn demented controls.		* Study design, sample size
	Ide et al., 2016	Observational cohort study	Evaluation of the effects of	P. gingivalis antibodies	No significant relationship between serum
	[19]	N = 60	periodontitis in patients with	CRP, TNFα, IL 10	baseline P. gingivalis antibody levels and rates of
			Alzheimer's disease over a	Cognitive scores (sMMSE and	cognitive decline.
			six-month follow-up.	ADAS-COG)	P. gingivalis antibody levels were associated with
					a fall in serum IL10 levels and an increase in
					serum TNFα levels over a six month follow up.
					* Small sample size and short term follow up
	Chen et al., 2017	Retrospective cohort study	Assessment of the risk of	Chronic periodontitis and AD	No significant higher risk of developing AD in
	[33]	N = 27 963	developing AD in patients with	diagnosis (ICM 9).	Patients with 1 year of CP exposure than those
			chronic periodontitis.		without CP.
					Significant higher risk of developing AD in
					Patients with 10 years of CP exposure than those
					without CP.
					Higher prevalence of hyperlipidaemia,
					depression, traumatic brain injury and
					co-morbiditiess in patients with CP had a than
					those in the unexposed cohort.
					* Possible underestimation of the incidence of CP
					or AD, No data regarding the severity of AD and
					education level.

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	Holmer et al., 2018	Case control study	Assessment of the possible increase	Periodontal status (oral hygiene,	Generalized marginal alveolar bone loss is
	[30]	N = 154/76	risk of mild cognitive impairment	PPD, bleeding on pocket probing	associated with early cognitive impairment and
			(MCI), subjective cognitive decline	(BoP), suppuration, tooth mobility	AD.
			(SCD) and Alzheimer's disease (AD)	furcation involvment, marginal	Poor oral health was more prevalent among cases
			associated with periodontal disease.	alveolar bone loss (MABL).	than among healthy controls.
			Investigation of the potential	Number of teeth, dental implants	* Study design, sample size, possible temporal
			associations between common	present, and dental caries.	bias with reverse causality (reduced cognitive
			biofilm-induced dental diseases		function leads to poor oral health), no APOE
			(dental caries and endodonticula),		genotyping
			their sequelae (tooth loss) and
			cognitive impairment.
	Ilievski et al., 2018	Experimental study	Assessment of the	P. gingivalis/Gingipain	P. gingivalis /gingipain were detected in the
	[37]	(mice)	neuropathological effects	TNFα, IL1β, and IL6	hippocampus of mice infected with Pg.
		N = 20	(production of extracellular Aβ42	Alzheimer's disease-related genes	Significantly higher expression of the
			and neurofibrillary tangles) of	expression (APP, BACE 1, PSEN1,	proinflammatory cytokine IL1β, IL6 and TNFα in
			repeated chronic exposure to a	ADAM10)	the hippocampus of experimental mice than
			periodontal pathogen.		controls.
					Significant increase in the expression of APP and
					BACE1 in the experimental group compared to
					the control group.
					Significant decrease in the expression of
					ADAM10 in the experimental group compared to
					the control group.
					Detection of Phospho-Tau protein in the
					experimental but not in the control mice
					* No direct or indirect mechanisms to explain
					these changes could be identified.
	Laugisch et al., 2018	Case control study	Verification of the presence of	Antibody levels against A.	Periodontal pathogens may enter the brain and
	[50]	N = 20/20	periodontal pathogens and the	actinomycetemcomitans, T. denticola, T.	stimulate a local immune response.
			intrathecal generation of	forsythia,	Significant association between T-tau levels in the
			pathogen-specific antibodies in	P. gingivalis in CSF and serum	AD group and serum levels of anti-P. gingivalis
			patients with AD and with other	Total tau protein (T-tau) and	antibodies and MCP-1/CCL-2.
			forms of dementia (DEM-noAD).	amyloid-β (Aβ1-42) in CSF.	* Sample size
				Monocyte chemoattractant protein-1
				(MCP-1/CCL2)

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	Maurer et al., 2018	Case control study	Evaluation of the possible link	A. actinomycetemcomitans, P.	AD-patients showed higher bacterial load in
	[35]	N = 20/20	between Alzheimer's dementia and	gingivalis, F. nucleatum	dental plaque compared to controls.
			bacterial infestation of the oral		* Study design, sample size
			cavity.
	Choi et al., 2019	Retrospective cohort study	Determination of the association	CP diagnosis (CD-10 code K05.3)	Chronic periodontitis patients had elevated risk
	[21]	N = 262 349	between chronic periodontitis (CP),	associated with at least one of the	for overall dementia (aHR = 1.06;
			AD and vascular dementia (VD)	CP-related treatments.	95% CI = 1.01-1.11, p = 0.042) and AD
			from the Korean National Health	Prescription of dementia-related	(aHR = 1.05; 95% CI = 1.00-1.11, p = 0.042) than
			Insurance Service (NHIS) database,	drugs as part of a diagnosis of AD	non-chronic periodontitis participants.
			using a several covariates (smoking,	(ICD-10 codes F00, G30) or VD	* Study design, Information on CP-related clinical
			alcohol consumption and physical	(ICD-10 code F01)	index limited, definition of dementia based on
			activity).	Age, sex, household income,	drug reimbursement, no evaluation of level of
				smoking status, alcohol	education or apolipoprotein E (APOE) e4
				consumption, physical activity,	genotype.
				body mass index, systolic blood
				pressure, fasting serum glucose,
				total cholesterol and Charlson
				Comorbidity Index
	Dominy et al., 2019	Experimental study	Assessment of the prevalence of P.	P. gingivalis and Gingipaïn load in	P. gingivalis and gingipains load in the brain play
	[39]	(mice)	gingivalis (Pg) in the brains of people	brain tissue	a significative role in the pathogenesis of AD.
		N = 140	with Alzheimer's disease and		Reduction in P. gingivalis brain bacterial load and
			possible Pg-dependent mechanisms		neuroinflammation as well as a blockage of Aβ
			of action in neurodegeneration and		1-42 peptide production were obtained by
			Alzheimer's pathology.		gingipain inhibition.
					* Study design, sample size
	Hayashi et al., 2019	Experimental study	Evaluation of the effects of brain	P. gingivalis LPS	No cognitive impairment could be associated
	[43]	(Mice)	exposure to Porphyromonas	Morris water maze tests	with acute or continuous brain exposure to
		N = 80	gingivalis-derived		Pg-LPS.
			lipopolysaccharide (Pg-LPS) on		Continuous brain exposure to Pg-LPS triggered
			cognitive impairment and organ		sarcopenia and heart damage in AD model mice.
			dysfunction in an AD mouse model.		* Study design

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	Liu et al., 2019	Case control study	Identification of differences in oral	Alpha and beta diversity of salivary	Significant decrease of richness and diversity of
	[34]	N = 39/39	bacterial community composition	microbiota	salivary microbiota in patients with Alzheimer's
			between AD patients and healthy	APOE ε4 expression	disease than in healthy controls.
			patients.		No bacteria associated with the severity of AD.
			Evaluation of the association		Significant decrease in Actinobacillus and
			between oral bacteria and AD		Actinomyces levels in patients with APOE ε4
			severity		Abundance of Abiotrophia and
			Evaluation of differences in oral		Desulfomicrobium levels in patients with APOE
			bacterial flora according to APOE ε4		ε4(+)
			expression.		* Small sample size, no collection of dental
					plaque bacteria
	Beydoun et al., 2020	Retrospective cohort study	Evaluation of the association of	Periodontal pathogens	AD incidence was linked to a composite of C.
	[32]	N = 6650	immune response (IgG) to	Immunoglobulin G (IgG):	rectus and P. gingivalis.
			periodontal pathogens with the	A. actinomycetemcomitans, P.	AD mortality risk was increased with composite
			incidence of dementia and AD	gingivalis, T. forsythia, T. denticola, C.	loading highly on IgG for P. gingivalis, P.
			mortality in middle-aged (>45 years)	rectus, Eubacterium nodatum, P.	intermedia, Prevotella nigrescens, F. nucleatum, C.
			and elderly (>65 years) US adults.	intermedia, Prevotella nigrescens,	rectus, Streptococcus intermedius, Capnocylophaga
				Prevotella melaninogenica, F.	Ochracea, and P. melaninogenica.
				nucleatum, Parvimonas micra,	Only a marginal association between incident
				Selenomonas noxia, Eikenella corrodens,	AD risk and PPD was detected among men and
				Capnocylophaga ochracea,	older individuals
				Streptococcus intermedius,	* Study design
				Streptococcus oralis, Streptococcus
				mutans, Vellonella Parvula,
				Actinomyces naeslundii.
				AD Mortality and Incidence Status.
				Clinical Attachment loss (CAL) and
				probing pocket depth (PPD)

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	De Oliveira Araújo et al.,	Case control study	Test the association between	PPD ≥ 5 mm, and CAL ≥ 5 mm	AD patients had fewer teeth, greater and a
	2021	N = 50/52	periodontitis and AD.	Geriatric Oral Health Assessment	superior percentage of sites with plaque, calculus,
	[27]		Assessment of the possible negative	Index (GOHAI) questionnaire.	and bleeding on probing than healthy controls.
			impact of periodontal status on	Socio-demographic data.	Significant association between periodontitis and
			perceived oral health-related quality		AD after adjusting for age, gender, income and
			of life (OHRQoL)		education.
					Periodontitis is associated with AD, but not with
					patients' OHRQoL
					* Study design, sample size
	Díaz-Zúñiga et al., 2020	Experimental study	Evaluation of the effects of short	P. gingivalis K1, K2, or K4 serotypes	Significant increase of pro-inflammatory
	[42]	(Rats)	exposure to encapsulated strains of	and the K1-isogenic	cytokines (IL-1b, IL-6, TNF-a, IFN-γ) in the
		N = 30	P. gingivalis on AD brain markers,	non-encapsulated mutant (GPA).	hippocampus of rats infected with P. gingivalis
			neuroinflammation and cognitive	Oasis maze task.	encapsulated serotypes K1 and K2.
			decline in young rats.	Cytokines (IL-1b, IL-4, IL-6, IL-10,	None of these effects were observed in rats
				TNF-α, IFN-γ).	infected with the non-encapsulated bacterial
				Aβ1-42 peptide and tau	strains.
				phosphorylation levels in	K1 or K2 P. gingivalis-infected rats displayed
				hippocampus.	memory deficits, increased Aβ 1-42 levels, and
					Tau hyperphosphorylation in the hippocampus
					* Sample size, study design

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	Kantarci et al., 2020	Experimental study (Mice)	Evaluation of the impact of	Alveolar bone loss	Periodontal disease increases bone loss in
	[26]	N = 30	experimentally induced periodontal	Insoluble Aβ40 and Aβ442 peptide.	AD-modelled (5xFAD) and control wild-type
			disease in a mouse model of AD on	Microglial markers in brain (Iba1).	(WT) mice. Alveolar bone loss is higher in 5xFAD
			the inflammatory process in the	Cytokine and Chemokine in CSF	than in WT at baseline.
			brain and microglia function.	(GM-CSF, IFN-γ, IL-1β, IL-6, IL-10,	No significant difference in alveolar bone loss
				TNF-α, MCP 1).	after the induction of experimental PD between
					5xFAD and WT mice
					The mean level of insoluble Aβ42, but not Aβ40,
					was significantly higher in 5xFAD mice with
					induced PD than in 5xFAD mice without induced
					PD.
					Decline in microglial markers (Iba1 )in the
					proximity of Aβ plaques in 5xFAD mice with
					periodontal disease compared to those without
					periodontal disease.
					Induced periodontal disease reduced IL-10 in
					5xFAD mice.
					Higher unresolved inflammation in the brain of
					5xFAD mice before and after induction of
					periodontal disease compared to WT controls
					based on the ratio of TNF-α to IL-10.
					* Study design, Sample size, no characterization
					of the bacterial flora
	Leblhuber et al., 2020	Cross sectional	Evaluation of the effects of chronic	A. actinomycetemcomitans, T. denticola,	Significant association between the salivary
	[44]	study	low-grade immune activation by	T. forsythia,	presence of P. gingivalis and lower MMSE and
		N = 20	salivary periodontopathogen	P. gingivalis, P. intermedia in salivary.	lower tendency to CDT.
			bacteria in AD patients	MMSE and CDT.	Significant lower neopterin concentrations
				Serum concentrations of neopterin	associated with the presence of T. denticola in AD
				and of tryptophan.	patient saliva.
					Significant lower kynurenine concentrations
					associated with the presence of T. forsythia in AD
					patient saliva.
					* Sample size, study design, no evaluation of the
					ApoE status

Table 1 .

 1 Cont.

	Reference(s)	Study Design	Objectives	Evaluated Factors	Mains Results and Limitations *
	Sun et al., 2020
	[

Table 1 .

 1 Cont.

	Yamada et al., 2020	In vitro study	Evaluation of the influence of	Concentrations of PGDHC, Aβ	Exposure to PGDHC, but not to Pg-LPS,
	[40]	(cells)	phosphoglycérol dihydrocéramide	peptide, Protein Tau and	significantly enhances secretion of Aβ peptide in
			(PGDHC) produced by P. gingivalis	senescence-associated secretory	a dose-dependent manner from CHO-7WD101
			on hallmark findings in AD.	phenotype (β-galactosidase,	cells in vitro 1 .
				cathepsin B, cysteine, TNF-α and	PGDHC also significantly Induces the
				IL-6 pro-inflammatory cytokines)	Site-Specific Phosphorylation of protein Tau in a
					dose-dependent manner in SH-SY5Y2 cells
					compared to the control cells.
					PGDHC or Pg-LPS elevated expression of
					β-galactosidase, cathepsin B, cysteine, TNF-α
					and IL-6 pro-inflammatory cytokines in SH-SY5Y
					cells.
					* In vitro study

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: No data were generated.

Conflicts of Interest:

The authors declare no conflict of interest.