Oral Health and Cognitive Decline: A Systematic Review of the Periodontitis–Alzheimer’s Connection

Abstract

Background: Alzheimer’s disease (AD), a neurodegenerative disorder characterized by cognitive decline, has been linked to systemic inflammation. Periodontal disease (PD), a chronic inflammatory condition, may contribute to neurodegeneration via microbial dysbiosis and inflammatory pathways. This systematic review explores the potential association between PD and AD, emphasizing microbial and systemic mechanisms. Materials and Methods: Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science for studies published between 2015 and 2024. The boolean keywords “Alzheimer” AND “parodont*” were used. The inclusion criteria focused on human studies evaluating salivary and blood biomarkers, as well as periodontal therapies. Data extraction adhered to the PICO framework, assessing study design, outcomes, and quality using the ROBINS-I tool (original 2016 version), as provided by the Cochrane Bias Methods Group. Results: Out of the 1244 articles screened, 19 studies met the inclusion criteria. Evidence indicates that periodontal pathogens, such as Porphyromonas gingivalis, promote neuroinflammation, amyloid-β aggregation, and brain atrophy. Elevated inflammatory markers and oral dysbiosis correlated with increased AD risk. Periodontal treatment demonstrated benefits in reducing systemic inflammation and stabilizing cognitive decline. Conclusion: The findings suggest a strong link between PD and AD through systemic inflammation and microbial invasion. Maintaining oral health may serve as a preventive strategy against cognitive decline, underscoring the need for integrated medical–dental care and further longitudinal research.

1. Introduction

Alzheimer’s disease (AD), a progressive neurodegenerative disorder affecting over 55 million people worldwide, represents one of the most pressing global health challenges due to its rising prevalence (projected to reach 139 million by 2050) and socioeconomic impact (costs exceeding $1.3 trillion annually). Periodontal disease (PD), a chronic inflammatory condition affecting >47% of adults globally (with severe forms in 11%), has emerged as a modifiable risk factor for AD, compounding the disease burden through shared pathways of systemic inflammation and microbial dysbiosis [1,2,3,4,5,6]. Characterized by cognitive decline, memory impairment, and behavioral changes, Alzheimer’s disease is the most common form of dementia, accounting for 60–80% of all cases. Despite extensive research, the etiology and pathophysiology of AD remain incompletely understood, with a complex interplay of genetic, environmental, and lifestyle factors contributing to its onset and progression. Recent evidence has increasingly suggested a link between systemic inflammation and neurodegenerative diseases, with periodontal disease (PD) emerging as a potential modifiable risk factor for AD [7,8,9,10,11,12,13,14,15,16]. Periodontal disease, a chronic inflammatory condition affecting the supporting structures of the teeth, including the gingiva, periodontal ligament, and alveolar bone, is primarily caused by microbial dysbiosis within the oral cavity [17,18,19,20,21,22,23,24,25,26]. It is one of the most prevalent chronic diseases worldwide, affecting up to 50% of adults and increasing in severity with age. The clinical manifestations of PD range from gingivitis, characterized by reversible inflammation of the gingiva, to periodontitis, a destructive and irreversible condition that can lead to tooth loss. Notably, periodontitis is associated with a systemic inflammatory burden and has been linked to various systemic conditions, including cardiovascular disease, diabetes mellitus, and rheumatoid arthritis [27,28,29,30,31,32,33,34,35,36]. In recent years, the potential connection between periodontal disease and Alzheimer’s disease has garnered significant attention [37,38,39,40,41,42,43,44,45,46]. The proposed link is grounded in the hypothesis that chronic systemic inflammation, driven by periodontal pathogens and their virulence factors, may contribute to neuroinflammation and the pathological processes underlying AD [47,48,49,50]. This bidirectional relationship suggests that while periodontal disease may act as a risk factor for Alzheimer’s, the cognitive decline associated with AD may also exacerbate oral health issues, creating a vicious cycle [51,52,53,54,55,56,57,58,59]. This introduction aims to provide a comprehensive overview of the potential mechanisms linking periodontal disease to Alzheimer’s disease, explore the epidemiological evidence supporting this association, and discuss the implications for early diagnosis, prevention, and treatment. The emerging paradigm underscores the importance of interdisciplinary collaboration between dentistry, neurology, and other healthcare fields to address the shared inflammatory pathways and systemic implications of these conditions [60,61,62,63,64,65,66,67,68,69].

1.1. Epidemiological Evidence Linking Periodontal Disease and Alzheimer’s Disease

Several epidemiological studies have explored the relationship between periodontal disease and cognitive decline, with mixed but increasingly supportive findings. Observational studies indicate that individuals with chronic periodontitis are at a higher risk of developing Alzheimer’s disease and other forms of dementia [70,71,72,73,74,75,76,77,78]. For instance, longitudinal studies have demonstrated that markers of periodontal inflammation, such as elevated serum levels of C-reactive protein (CRP) and pro-inflammatory cytokines, are associated with an increased risk of cognitive impairment. Furthermore, retrospective analyses have found that tooth loss, a surrogate marker for severe periodontal disease, correlates with a heightened incidence of dementia [79,80,81,82,83,84,85,86,87,88]. The connection between oral health and systemic diseases, including Alzheimer’s, is also supported by studies investigating oral microbiota [89,90,91,92,93,94,95,96,97,98,99,100]. Advances in metagenomics and microbiome research have revealed that specific periodontal pathogens, such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum, may play a role in neurodegenerative processes. P. gingivalis, in particular, has been implicated in the pathogenesis of Alzheimer’s disease through the detection of gingipains—virulence factors produced by this pathogen—in the brains of AD patients. These findings suggest a potential causal link, although further research is needed to establish direct pathways and mechanisms [101,102,103,104,105,106,107,108,109,110,111].

1.2. Pathophysiological Mechanisms Connecting Periodontal Disease to Alzheimer’s Disease

The mechanisms underlying the relationship between periodontal disease and Alzheimer’s disease are complex and multifactorial. The primary hypotheses include systemic inflammation, direct microbial invasion, and the impact of dysregulated immune responses [112,113,114,115,116,117,118,119,120,121].

1.2.1. Systemic Inflammation and Neuroinflammation

Periodontal disease is characterized by chronic local inflammation, which can spill over into systemic circulation, contributing to a sustained inflammatory state. Pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), are elevated in individuals with PD and have been implicated in the pathogenesis of Alzheimer’s disease [122,123,124,125,126,127,128,129,130,131]. These cytokines can cross the blood–brain barrier (BBB) and activate microglia, the resident immune cells of the central nervous system. Chronic microglial activation leads to neuroinflammation, which is a hallmark of Alzheimer’s pathology [132,133,134,135,136,137,138,139,140,141].

1.2.2. Microbial Invasion and Direct Effects

The oral cavity serves as a reservoir for pathogenic bacteria, which can gain access to systemic circulation through periodontal pockets and bacteremia [142,143,144,145,146,147,148,149]. Porphyromonas gingivalis and its gingipains have been detected in the brain tissue and cerebrospinal fluid of AD patients, suggesting a direct microbial invasion. These pathogens can disrupt the integrity of the BBB, facilitate the aggregation of amyloid-β (Aβ) peptides, and induce tau hyperphosphorylation, all of which are key features of AD pathology [150,151,152,153,154,155,156,157,158,159].

1.2.3. Aβ as an Antimicrobial Peptide

An intriguing hypothesis proposes that Aβ, traditionally viewed as a pathological hallmark of Alzheimer’s disease, may function as an antimicrobial peptide in response to chronic infection [160,161,162,163,164,165,166,167,168,169,170,171,172,173]. Periodontal pathogens may trigger the overproduction of Aβ as part of the host defense mechanism, which, while initially protective, becomes detrimental through the formation of insoluble plaques and neurotoxic aggregates [174,175,176,177,178,179,180,181,182,183].

1.2.4. Dysregulated Immune Responses

Periodontal disease is associated with altered immune responses, including the dysregulation of toll-like receptor (TLR) pathways and the activation of complement systems [184,185,186,187,188,189,190,191,192]. These immune mechanisms may contribute to neuroinflammation and the propagation of Alzheimer’s pathology. Moreover, genetic predispositions, such as polymorphisms in the apolipoprotein E (APOE) gene, may modulate the susceptibility to both PD and AD, providing a genetic link between these conditions (Figure 1) [193,194,195,196,197,198,199,200,201,202].

1.3. Enviromental Factors

Mounting evidence underscores a significant mechanistic link between PD and AD, mediated through systemic inflammation, microbial dysbiosis, and direct pathogen invasion. Chronic PD elevates pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), which traverse the blood–brain barrier, activate microglia, and drive neuroinflammation—a hallmark of AD pathology. Critically, periodontal pathogens like Porphyromonas gingivalis invade the brain, where their virulence factors (gingipains) promote Aβ aggregation, tau hyperphosphorylation, and neuronal damage. This is corroborated by biomarkers: elevated plasma p-Tau and Aβ1-40 levels, distinct oral microbiome shifts (increased Firmicutes, decreased Bacteroidetes), and salivary metabolites like galactinol all correlate with cognitive decline. Clinically, periodontal treatment reduces systemic inflammation, stabilizes cognition, and mitigates brain atrophy, underscoring PD as a modifiable AD risk factor. Severe PD with tooth loss increases AD risk by 6–16%, amplified by pro-inflammatory diets and vitamin D deficiency. Beyond these pathways, environmental factors in the oral milieu during PD accelerate protein misfolding and fibrillogenesis, which are pivotal in AD pathogenesis. Saliva in PD patients exhibits elevated concentrations of divalent cations (Ca²⁺, Zn²⁺, Fe²⁺). These ions neutralize negative charges on Aβ peptides, reducing electrostatic repulsion and promoting hydrophobic collapse into neurotoxic fibrils. Concurrently, increased ionic strength in PD saliva—driven by inflammatory exudate and microbial byproducts—compresses the electric double layer around Aβ, further accelerating aggregation. This creates a permissive environment for Aβ fibrillization even before systemic dissemination, potentially initiating or exacerbating neurodegeneration [203,204].

1.4. Clinical Implications and Future Directions

Understanding the interplay between periodontal disease and Alzheimer’s disease has significant clinical implications for the early detection, risk assessment, and prevention of AD. Periodontal health may serve as a modifiable risk factor for AD, emphasizing the importance of maintaining oral hygiene and managing chronic inflammation [205]. Regular dental check-ups and targeted interventions, such as scaling and root planing, may reduce systemic inflammatory markers and potentially mitigate the risk of cognitive decline [206,207]. Furthermore, the integration of oral health assessments into routine medical care for older adults and individuals at risk of Alzheimer’s disease could facilitate the early identification of at-risk populations [208,209]. Biomarker research, focusing on inflammatory mediators and oral microbiota, holds promise for developing diagnostic tools and therapeutic strategies [210,211]. Future research should prioritize longitudinal studies to establish causal relationships and elucidate the temporal dynamics between periodontal disease and Alzheimer’s disease. Advances in imaging techniques, molecular biology, and systems biology are likely to provide deeper insights into the shared mechanisms and pathways [212,213,214,215,216]. Additionally, exploring the efficacy of anti-inflammatory and antimicrobial therapies targeting periodontal pathogens may open new avenues for AD treatment. The emerging evidence linking periodontal disease to Alzheimer’s disease underscores the interconnectedness of systemic and neurodegenerative conditions. While the precise mechanisms remain to be fully delineated, the role of chronic inflammation and microbial dysbiosis appears to be central to this relationship. Addressing periodontal health as part of a comprehensive approach to dementia prevention and management offers a promising avenue for reducing the burden of Alzheimer’s disease. Interdisciplinary collaboration, coupled with continued research and public health initiatives, will be essential in unraveling the complexities of this relationship and improving outcomes for affected individuals [217,218].

2. Materials and Methods

2.1. Protocol and Registration

This review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, and it was filed with the number CRD1005141 on PROSPERO (The International Prospective Register of Systematic Reviews) [219]. The primary research aim of this review is to evaluate the relationship between periodontitis and the beginning of Alzheimer’s disease.

2.2. Search Processing

We focused our search on English-language publications published between 1 January 2015 and 15 January 2025 on PubMed, Scopus, and Web of Science that were relevant to our topic. In the search, the boolean keywords “Alzheimer” AND “parodont*” were utilized. We picked these terms because they best characterized the purpose of our study, which was to learn more about the relationship between periodontitis and the start of Alzheimer’s disease (

Table 1. Indicators for database searches.

Article screening strategy	KEYWORDS: “A”: Alzheimer; “B”: parodont*;
	Boolean indicators: “A” AND “B”
	Timespan: 1–15 January 2025
	Electronic databases: Pubmed; Scopus; Web of Science

).

2.3. Inclusion Criteria

Three reviewers reviewed all relevant publications using the following criteria: (1) research using only human subjects, (2) full text, and (3) scientific studies evaluating the connection between periodontitis and the onset of Alzheimer’s disease. The PICO model was created using the following steps:

• Criteria: application in the present study;
• Population: human subjects;
• Intervention: evaluation of salivary biomarkers, blood biomarkers, periodontal therapy;
• Comparison: control group;
• Outcome: evaluation of the connection between periodontitis and the onset of Alzheimer’s disease;
• Study design: randomized controlled trial, observational study, cohort study, retrospective study.

2.4. Exclusion Criteria

The exclusion criteria included non-English-language articles, ineligible research designs, ineligible outcome measures, ineligible populations, case studies, reviews, and animal studies.

2.5. Data Processing

Author conflicts about the choice of articles were addressed and resolved.

2.6. Article Identification Procedure

Two reviewers, F.I. and P.A., independently assessed appropriateness. An additional manual search was conducted to increase the number of articles available for full-text analysis. English-language articles that met the inclusion criteria were evaluated, and duplicates and non-qualifying items were identified and labeled with an explanation for exclusion.

2.7. Study Evaluation

The reviewers separately evaluated the article data using a specific electronic form established according to the following categories: authors, year of study, aim of study, materials and methods, and results.

2.8. Quality Assessment

Two reviewers, P.A. and F.I., used the ROBINS-I technique to assess the quality of the included papers. ROBINS-I was designed to evaluate the risk of bias in non-randomized trials comparing the health effects of two or more drugs. Each of the seven analyzed factors was assigned a bias degree. In the event of a dispute, G.D., the third reviewer, was called in to find a solution. To strengthen the impartiality and consistency of the assessments, any discrepancies or conflicts amongst reviewers were resolved through discussion and consensus-building. When there was no consensus, a third reviewer made the ultimate decision. Recognizing the evidence base’s strengths and weaknesses contributed to a more accurate assessment of the quality and reliability of the outcomes. By accounting for the likelihood of bias, the authors of this review were able to draw more informed interpretations and conclusions based on the evidence presented.

3. Results

The databases Web of Science (364), PubMed (337), and Scopus (543) yielded a total of 1244 publications. Removing 589 duplicates produced 655 items. Following an analysis of their abstracts and titles, 488 entries were removed. The remaining 167 papers were successfully obtained by the writers, who were able to verify their validity. This method resulted in the elimination of 148 articles that were deemed off subject. This study includes the qualitative analysis of the final 19 articles (Figure 2). The results of each investigation are shown in

Table 2. Descriptive item selection summary.

Authors	Type of Study	Aim of Study	Matherials and Methods	Results
Cerajewska et al. (2024) [220]	Feasibility interventional study	Determine the feasibility of recruiting, retaining, and treating individuals with mild dementia and periodontitis; assess cognition during dental visits.	Non-randomized clinical study, cognitive and periodontal assessments over 24 months, involving professional and personalized care.	In total, 18 participants enrolled, 15 completed 12 months, 8 completed 24 months. Significant improvement in periodontal health indicators (e.g., reduced bleeding and plaque levels). Cognition declined initially but stabilized later.
Hategan et al. (2021) [221]	Cross-sectional neuropsychological study	Investigate whether young healthy subjects with periodontal disease have lower cognition compared to those without periodontal disease, and assess salivary cytokine levels in relation to cognition.	Monocenter, cross-sectional study with 40 subjects divided into three groups based on periodontal condition: aggressive periodontitis, mild/moderate periodontitis, and no periodontitis. Neuropsychological tests (RAVLT, MOCA, MMSE) and ELISA for cytokine levels.	Subjects with aggressive periodontitis had impaired cognition and learning rates. Salivary IL-1β correlated with immediate memory but not delayed recall.
Chen et al. (2017) [222]	Retrospective cohort study	Investigate whether chronic periodontitis (CP) increases the risk of developing Alzheimer’s disease (AD).	Retrospective matched-cohort study using National Health Insurance Research Database (NHIRD) of Taiwan, with cohort of 9291 CP patients and 18,672 matched non-CP controls, followed over 16 years.	10 years of CP exposure was associated with 1.707-fold increase in AD risk. Study highlighted role of chronic inflammation as potential pathway linking CP to AD.
Qiu et al. (2024) [223]	Cross-sectional metabolic study	Characterize subgingival microbiomes and gingival crevicular metabolic signatures in AD and aMCI patients.	Cross-sectional study, 16S rRNA sequencing, LC-MS/MS.	Identified 165 metabolites and 16 species associated with cognitive function.
Rubinstein et al. (2024) [224]	Cross-sectional MRI study	Examine the association of periodontitis features with MRI markers of Alzheimer’s disease and cognitive aging.	Study with 486 participants, clinical periodontal data, microbial and serum samples, brain MRIs analyzed using regression models.	Higher tooth retention linked to favorable MRI outcomes; severe periodontitis associated with adverse changes.
Beydoun et al. (2024) [225]	Longitudinal cohort study	Examine the interplay of infection burden and periodontal pathogens with incident Alzheimer’s and all-cause dementia.	NHANES III (1988–1994) survey data linked to CMS-Medicare with 2975 participants, Cox proportional hazards model.	Hepatitis C and herpes simplex virus 2 strongly associated with dementia risk. Periodontal pathogens increased risk in minority groups.
Schwahn et al. (2022) [226]	Quasi-experimental design	Investigate the relationship between periodontal treatment and preclinical Alzheimer’s disease (AD).	Quasi-experimental design: 177 periodontally treated patients (GANI_MED cohort) compared to 409 untreated subjects (SHIP-TREND cohort). Brain atrophy markers and MRI outcomes analyzed over median observation period of 7.3 years. Propensity score matching and sensitivity analyses were used to adjust for confounders.	Periodontal treatment had favorable effect on AD-related brain atrophy (mean shift −0.41; 95% CI −0.70–−0.12; p = 0.0051). Brain aging effects were uncertain. Strong evidence of link between periodontitis and preclinical AD.
Franciotti et al. (2021) [227]	Case–control study with systemic markers	Investigate the association between Porphyromonas gingivalis abundance in the oral cavity, neurodegenerative diseases, and systemic antibodies.	Pilot study: Oral samples from 49 patients (21 with ND, 28 with no-ND) and 29 healthy controls were analyzed for Pg using qPCR. Anti-Pg antibodies were measured using ELISA. Oral and systemic health parameters were assessed.	Pg abundance was significantly higher in ND patients compared to no-ND and HC (p < 0.01). Correlation between Pg abundance and anti-Pg antibody levels was observed in no-ND but not in ND, suggesting impaired immune response in ND. No link was found with systemic inflammation markers. Study supports bidirectional oral–brain connection.
Choi et al. (2019) [228]	Retrospective cohort study	Investigate the association between CP and AD or vascular dementia (VD).	Retrospective cohort study of 262,349 participants from Korean National Health Insurance Service. CP was defined based on diagnosis codes and treatment records. Participants were followed from 2005 to 2015 for dementia outcomes. Adjusted hazard ratios (aHRs) were calculated.	CP patients showed 6% higher risk of overall dementia (aHR = 1.06, 95% CI: 1.01–1.11) and similar increase for AD (aHR = 1.05, 95% CI: 1.00–1.11). Risk of VD was higher but not statistically significant. Healthy lifestyle behaviors appeared to amplify CP’s association with dementia.
Carballo et al. (2023) [229]	Interventional cohort study	Investigate the relationship between periodontitis and cognitive decline, as well as the latter’s progression, focusing on blood-based Alzheimer’s biomarkers like p-Tau and Aβ1-40.	Prospective cohort study with 101 participants aged ≥ 60 years with hypertension. Cognitive decline was assessed using ACE and MMSE. Periodontal health evaluated through clinical parameters. Blood samples analyzed for p-Tau, Aβ1-40, and other biomarkers.	Periodontitis was associated with lower cognitive scores (MMSE: β = −1.5, p < 0.05) and progression of cognitive decline (HR = 1.8, 95% CI: 1.0–3.1). Participants with periodontitis had higher plasma p-Tau (p < 0.001) and Aβ1-40 levels, with latter increasing significantly over 2 years.
Na et al. (2024) [230]	Microbiome profiling study	Compare the subgingival microbiome of patients with periodontitis and AD with that of cognitively unimpaired individuals with periodontitis.	Cross-sectional analysis of 29 participants (15 AD and 14 cognitively unimpaired). Samples were collected from buccal, supragingival, and subgingival regions. Next-generation sequencing and network analysis were used to characterize microbiome.	Subgingival microbiome in AD patients displayed higher diversity and distinct microbial composition compared to cognitively unimpaired participants. Specific periodontopathogens (e.g., Prevotella spp., Saccharibacteria, Treponema) were more prevalent in AD. Findings highlight need for targeted periodontal care in AD patients to mitigate potential pathogen-induced systemic effects.
Xiaoshu Li et al. (2024) [231]	Cross-sectional neuroimaging study	Investigate the associations between periodontitis and metrics of brain structure and function in cognitively normal middle-aged and elderly adults.	Cross-sectional study of 40 participants (aged ≥ 50 years). Periodontal condition was assessed, and multimodal MRI (T1-weighted structural data, resting-state functional MRI) analyzed cortical volume, thickness, area, and regional homogeneity. Correlation analyses were conducted.	Severe periodontitis was negatively correlated with cortical volume, area, thickness, and brain function metrics (e.g., default-mode network, limbic network). Mild periodontitis showed positive correlations in some regions, potentially indicating compensatory mechanisms. Periodontitis was linked to systemic inflammatory pathways and neurodegeneration, emphasizing its role as modifiable risk factor for dementia.
Moghadam et al. (2022) [232]	Case–control study	Assess the association between oral microbiota, inflammatory cytokines, and AD through qPCR analysis of bacterial abundance.	Case–control study of 30 participants (15 AD, 15 healthy controls). Oral samples analyzed using qPCR for five bacterial species. Inflammatory cytokines (IL-1β, IL-6, TNF-α) measured using ELISA. Statistical analysis of bacterial loads and cytokine levels.	Abundance of Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia significantly higher in AD group (p < 0.05). AD patients exhibited elevated inflammatory cytokines (IL-1β, IL-6, TNF-α). Positive correlation between bacterial load and cytokine levels supports oral microbiota’s role in systemic inflammation and AD progression.
An Li et al. (2022) [233]	Cross-sectional study	Explore whether mitochondrial dysfunction mediates the link between periodontitis and cognitive impairment in older adults.	Cross-sectional analysis using NHANES 2011–2014 data of 1883 participants aged ≥ 60 years. Periodontitis was assessed via mean probing depth (PDT) and attachment loss (AL), while cognitive function was measured using standardized tests (e.g., CERAD-IR, DSST). Mitochondrial dysfunction was evaluated via circulating methylmalonic acid (MMA) levels.	Participants with severe periodontitis (Stage III/IV) showed worse cognitive performance and higher MMA levels compared to those with mild periodontitis (Stage I/II). Mediation analysis revealed that mitochondrial dysfunction explained 9.9% to 11.7% of association between periodontitis and cognitive decline. Findings suggest shared oxidative stress mechanisms in periodontitis and neurodegeneration.
Kamer et al. (2015) [234]	Clinical trial	Assess the association between PD and brain Aβ load in cognitively normal elderly individuals using PET imaging.	Cross-sectional study of 38 cognitively normal participants (mean age 61.3 years). PDT measured using clinical attachment loss (CAL ≥ 3 mm). Brain Aβ load assessed via 11C-PIB PET imaging. Covariates included age, ApoE genotype, and smoking.	Participants with higher CAL showed significantly increased Aβ retention in brain regions prone to Aβ deposition (p = 0.002). Periodontal disease burden explained 22% of variance in brain Aβ retention. Suggests long-term periodontal inflammation contributes to brain Aβ accumulation.
Kim et al. (2020) [235]	Population-based cohort study	Evaluate severe periodontitis with tooth loss as a modifiable risk factor for AD, vascular dementia (VaD), and mixed dementia (MD) using long-term cohort data.	Retrospective cohort study using NHIS-HEALS database (2002–2015). In total, 20,230 participants (10,115 with severe periodontitis, 10,115 healthy controls) were analyzed. Severe periodontitis defined based on the need for surgical intervention. Cox proportional regression was used to adjust for sociodemographic characteristics, lifestyle, and comorbid factors.	Severe periodontitis with 1–9 remaining teeth significantly increased risk of AD (HR: 1.08, p = 0.022), VaD (HR: 1.24, p < 0.001), and MD (HR: 1.16, p < 0.001). Findings emphasize periodontitis as modifiable risk factor and advocate for improved periodontal care to mitigate dementia risk.
Botelho et al. (2021) [236]	Secondary data analysis	Investigate whether an inflammatory diet and serum vitamin D levels mediate the association between periodontitis and cognitive function.	Secondary analysis of 2062 older adults (≥60 years) from NHANES 2011–2014 datasets. Periodontitis assessed via PDT and attachment loss AL. Cognitive function measured using CERAD-WLT, CERAD-DRT, animal fluency test, and DSST. Dietary Inflammatory Index (DII) computed from dietary data. Serum vitamin D analyzed as biochemical mediator.	Periodontitis patients showed worse cognitive scores than healthy controls across all tests. DII mediated 9.2–36.4% of periodontitis–cognition link, while vitamin D mediated 8.1–73.2%. Proinflammatory diets and vitamin D deficiency were significant mediators of association between periodontitis and cognitive dysfunction. Recommendations include dietary modification and vitamin D supplementation.
Issilbayeva et al. (2024) [237]	Cross-sectional microbiome study	Investigate the diversity and composition of oral microbiomes in AD patients compared to healthy individuals.	Case–control study involving 135 participants (64 AD and 71 controls) from Kazakhstan. 16S rRNA sequencing analyzed bacterial diversity in oral samples. Data on clinical, demographic, and laboratory parameters were also collected.	AD patients displayed higher microbial diversity, with increase in Firmicutes and decrease in Bacteroidetes. Certain taxa (e.g., Haemophilus parainfluenzae, Prevotella melaninogenica) were significantly lower in AD patients. Metabolic pathway analysis revealed distinct patterns associated with AD, emphasizing potential role of oral microbiome in its pathogenesis.
Dominy et al. (2019) [238]	Preclinical and cross-sectional study	Investigate the presence of Porphyromonas gingivalis in AD brains and evaluate gingipain inhibitors as potential therapeutic agents.	Analyzed AD and control brain tissue for P. gingivalis DNA, gingipain antigens, and Aβ pathology. Developed small-molecule gingipain inhibitors and tested their effects in murine models of P. gingivalis infection and neurodegeneration.	P. gingivalis DNA and gingipains detected in AD brains. Gingipains were neurotoxic, increasing Aβ production and tau pathology. Gingipain inhibitors reduced bacterial load, blocked Aβ production, and mitigated neurodegeneration in mice. Results support gingipains as therapeutic targets for AD.

.

3.1. Characteristics of Reviewed Studies

The studies examined in this analysis span a wide range of methodologies, including both cross-sectional and longitudinal designs, with a focus on various pathways linking PD and AD. Cerajewska et al. (2024) [220] conducted a non-randomized clinical study to determine the feasibility of treating individuals with mild dementia and periodontitis over 24 months. Hategan et al. (2021) [221] explored the cognitive differences in young subjects with periodontal disease using neuropsychological tests in a cross-sectional study. In a retrospective cohort study, Chen et al. (2017) [222] investigated whether chronic periodontitis increased the risk of AD, revealing long-term inflammation as a key factor. Qiu et al. (2024) [223] identified significant metabolic and microbial differences in AD and aMCI patients through 16S rRNA sequencing and metabolomics. Rubinstein et al. (2024) [224] examined brain MRI markers, while Beydoun et al. (2024) [225] linked systemic infection burden to dementia risk through a large cohort analysis using NHANES data. Schwahn et al. (2021) [226] utilized a quasi-experimental approach to explore periodontal treatment’s impact on brain atrophy markers. Franciotti et al. (2021) [227] highlighted the abundance of Porphyromonas gingivalis in neurodegenerative conditions, whereas Choi et al. (2019) [228] documented a modest increase in dementia risk linked to chronic periodontitis in a nationwide cohort. Carballo et al. (2023) [229] correlated periodontitis with elevated Alzheimer’s biomarkers, and Na et al. (2023) [230] reported distinct microbial diversity in AD patients. Similarly, Issilbayeva et al. (2024) [237] onducted a case–control study on oral microbiome composition, finding increased microbial diversity in AD patients, characterized by a rise in Firmicutes and a reduction in Bacteroidetes. Specific taxa such as Haemophilus parainfluenzae and Prevotella melaninogenica were altered, suggesting the role of oral dysbiosis in neurodegeneration. Li et al. (2024) [231] and Moghadam et al. (2022) [232] analyzed structural brain changes and inflammatory markers, respectively, highlighting systemic inflammation as a central mechanism. An Li et al. (2022) [233] explored mitochondrial dysfunction’s role as a mediator in the link between periodontitis and cognitive impairment, highlighting the fact that oxidative stress mechanisms explained a significant portion of the cognitive decline observed in individuals with severe periodontitis. Kamer et al. (2015) [234] found elevated Aβ retention in cognitively normal individuals with periodontal disease, supporting a long-term inflammatory pathway. Kim et al. (2020) [235] identified periodontitis with tooth loss as a modifiable risk for multiple dementia types. Botelho et al. (2021) [236] revealed the mediation effect of pro-inflammatory diets and vitamin D deficiency on cognitive outcomes. Finally, Dominy et al. (2019) [238] investigated gingipain inhibitors, providing preclinical evidence for potential therapeutic interventions targeting P. gingivalis. These diverse approaches collectively underline the multifaceted relationship between PD and AD.

3.2. Quality Assessment and Risk of Bias of Included Articles

The risk of bias in the selected studies is shown in

Table 3. Bias assessment.

Authors	D1	D2	D3	D4	D5	D6	D7	Overall
Cerajewska et al. (2024) [220]
Hategan et al. (2021) [221]
Chen et al. (2017) [222]
Qiu et al. (2024) [223]
Rubinstein et al. (2024) [224]
Beydoun et al. (2024) [225]
Schwahn et al. (2022) [226]
Franciotti et al. (2021) [227]
Choi et al. (2019) [228]
Carballo et al. (2023) [229]
Na et al. (2024) [230]
Xiaoshu Li et al. (2024) [231]
Moghadam et al. (2022) [232]
An Li et al. (2022) [233]
Kamer et al. (2015) [234]
Kim et al. (2020) [235]
Botelho et al. (2021) [236]
Issilbayeva et al. (2024) [237]
Dominy et al. (2019) [238]

. Most studies are in danger of bias caused by confounding. The measurement bias is a parameter that is unlikely to be biased. The majority of studies are at high risk of bias owing to participant selection bias. The significant variability makes it impossible to determine post-exposure bias. Missing data bias causes worries about the likelihood of bias in many studies. The bias coming from the measurement of the outcome raises some concerns about bias in numerous studies. The majority of studies had negligible bias when selecting the stated outcomes. The final results suggest that ten studies have a minimal risk of bias, whereas nine cause some worries about bias.

4. Discussion

Recent studies underscore the complex relationship between PD and Alzheimer’s disease (AD), implicating both conditions in pathways of systemic inflammation, microbial dysbiosis, and neurodegeneration. In the context of diagnosis, advancements in understanding microbial and metabolic biomarkers are pivotal for the early detection of cognitive impairment. Similarly, therapeutic research highlights the potential for periodontal care to mitigate AD progression through both systemic and localized interventions [239].

4.1. Diagnosis: Microbial and Systemic Markers of Cognitive Impairment

Microbiome-based diagnostic research has provided compelling evidence regarding the role of oral pathogens in AD progression. Dominy et al. (2019) [238] demonstrated that Porphyromonas gingivalis (P. gingivalis) and its gingipain enzymes are present in AD brains, contributing to Aβ aggregation. Similarly, Issilbayeva et al. (2024) [237] identified increased microbial diversity in the oral cavities of AD patients, characterized by elevated Firmicutes and decreased Bacteroidetes, including taxa such as Haemophilus parainfluenzae and Prevotella melaninogenica. These findings suggest that microbial dysbiosis may serve as an early biomarker for neurodegeneration. Na et al. (2023) [230] reported distinct microbial signatures in AD patients, corroborating the association between oral pathogens and systemic inflammation. Qiu et al. (2024) [223] further advanced diagnostic potential by identifying metabolic profiles in gingival crevicular fluid (GCF), including elevated galactinol and D-mannitol, which correlated with cognitive impairment. Such biomarkers offer non-invasive methods for the early identification of at-risk populations [240,241,242,243,244,245,246,247,248,249]. The role of inflammatory markers in diagnosis is equally significant. Moghadam et al. (2022) [232] found elevated levels of pro-inflammatory cytokines such as IL-1β and TNF-α in individuals with both PD and cognitive impairment. Beydoun et al. (2024) [225] demonstrated that a high systemic infection burden, including periodontal pathogens, was linked to increased risks of AD and vascular dementia [250,251,252,253,254,255,256]. These findings emphasize the importance of systemic inflammation as a diagnostic criterion for cognitive disorders. Neuroimaging studies have also contributed to diagnostic advancements. Rubinstein et al. (2024) [224] and Li et al. (2024) [231] conducted cross-sectional studies using MRI, revealing that periodontitis was associated with reduced cortical volume and disrupted brain connectivity in regions related to memory and executive function. Kamer et al. (2015) [234] observed that individuals with periodontal disease exhibited elevated Aβ retention in brain regions prone to AD pathology. Such imaging techniques offer complementary diagnostic tools by linking structural brain changes to periodontal health [257]. Population-based studies further validate these diagnostic markers. Choi et al. (2019) [228] conducted a nationwide cohort analysis, showing a modest but statistically significant increase in dementia risk among patients with chronic periodontitis. Similarly, Chen et al. (2017) [222] reported that prolonged exposure to periodontal disease increased the likelihood of developing AD. These large-scale studies underscore the epidemiological relevance of periodontal health in cognitive disorders.

The Role of the Oral Microbiome as a Diagnostic Tool

The oral microbiome is emerging as a valuable diagnostic tool for the early detection of AD. Studies by Issilbayeva et al. (2024) [237] and Qiu et al. (2024) [223] highlighted the potential of microbial and metabolic biomarkers in distinguishing AD patients from healthy controls. These biomarkers, such as P. gingivalis and galactinol, demonstrate high diagnostic accuracy, offering a non-invasive approach to identifying individuals at risk of cognitive decline.

4.2. Therapy: Periodontal Interventions and Cognitive Protection

Therapeutic research highlights the potential of periodontal care to mitigate AD progression. Cerajewska et al. (2024) [220] conducted a 24-month feasibility study on individuals with mild dementia, demonstrating that personalized periodontal treatment improved oral health and stabilized cognitive decline. Carballo et al. (2023) [229] corroborated these findings, showing that reducing periodontal inflammation mitigated Alzheimer’s-related brain atrophy and slowed cognitive deterioration.

Several studies have highlighted early intervention as a key therapeutic strategy. Chen et al. (2017) [222] noted that improved management of periodontal disease could delay the onset of dementia. Kim et al. (2020) [235] demonstrated that severe periodontitis with significant tooth loss independently increased the risk of developing AD, vascular dementia, and mixed dementia. These findings suggest that maintaining periodontal health may reduce systemic inflammatory burden and protect against cognitive decline [258].

Therapeutic mechanisms are also supported by preclinical research. Dominy et al. (2019) [238] explored the use of small-molecule gingipain inhibitors, which reduced bacterial load, blocked Aβ production, and mitigated neurodegeneration in animal models. This approach highlights the potential of pharmacological interventions targeting periodontal pathogens [259,260,261,262].

Nutritional and metabolic factors play a crucial role in therapy. Botelho et al. (2021) [236] found that pro-inflammatory diets and vitamin D deficiency exacerbated the relationship between periodontitis and cognitive dysfunction. These findings emphasize the need for dietary modifications and supplementation to support periodontal and cognitive health. Qiu et al. (2024) [223] highlighted the importance of metabolic pathways, suggesting that interventions targeting dysregulated metabolites in GCF could offer additional therapeutic benefits [263].

Intervention studies also address systemic inflammation as a therapeutic target. Moghadam et al. (2022) [232] and Beydoun et al. (2024) [225] emphasized the role of inflammatory cytokines and infection burden in exacerbating cognitive decline. Reducing systemic inflammation through periodontal care, pharmacological agents, or lifestyle modifications may, therefore, provide protective effects against neurodegeneration.

The integration of dental, neurological, and nutritional care is crucial for effective therapy. Schwahn et al. (2021) [226] demonstrated that periodontal treatment had a favorable impact on brain atrophy markers in a quasi-experimental study. Similarly, Li et al. (2024) [231] emphasized the importance of addressing both localized and systemic inflammatory processes to protect brain structure and function.

4.3. Challenges and Future Directions

Despite significant progress in both diagnosis and therapy, challenges remain in the elucidation of the causal pathways linking PD and AD. An Li et al. (2022) [233] focused on the mediating role of mitochondrial dysfunction between periodontitis and cognitive decline, demonstrating that oxidative stress mechanisms explained a significant portion of the cognitive impairment observed. Studies such as those by Rubinstein et al. (2024) [224] highlight the need for longitudinal research to establish the temporal relationship between periodontal disease and cognitive decline. Furthermore, the variability in study designs, sample sizes, and methodologies underscores the need for standardized diagnostic and therapeutic protocols [264,265,266,267,268,269,270,271,272,273]. Future research should also focus on refining biomarkers for early detection. Studies like those by Issilbayeva et al. (2024) [237] and Qiu et al. (2024) [223] emphasize the diagnostic potential of microbiome and metabolomic profiles, which could be integrated into routine clinical assessments. Additionally, therapeutic strategies targeting both oral and systemic inflammation, such as those proposed by Dominy et al. (2019) [238] and Botelho et al. (2021) [236], require further clinical validation through randomized controlled trials. In conclusion, the relationship between periodontal disease and Alzheimer’s disease is a multifaceted interplay of microbial, inflammatory, and metabolic pathways. Diagnostic advancements in microbial and systemic markers, coupled with therapeutic research emphasizing early intervention and integrated care, hold promise for mitigating the burden of cognitive disorders. Continued interdisciplinary collaboration is essential to fully realize the potential of these findings for both prevention and treatment [274].

4.4. Limitations of the Study

Despite significant progress, challenges remain in the elucidation of the causal pathways linking PD and AD. The complex interactions between microbial invasion, systemic inflammation, and genetic predispositions require further investigation. Studies by Choi et al. (2019) [228] and Taati Moghadam et al. (2022) [232] emphasize the need for longitudinal research to establish causality and identify critical intervention points.

Additionally, Rubinstein et al. (2024) [224] and Cerajewska et al. (2024) [220] have underscored the importance of interdisciplinary approaches that integrate dental, neurological, and nutritional care. Such strategies could provide holistic solutions to mitigate the dual burden of PD and AD in aging populations. Future research should also focus on developing targeted therapies, such as gingipain inhibitors, and evaluating their efficacy in clinical trials.

5. Conclusions

The link between periodontal disease and Alzheimer’s disease is a compelling example of the interconnectedness of systemic and neurological health. Through pathways involving microbial invasion, systemic inflammation, and metabolic dysregulation, periodontal disease emerges as both a risk factor and a potential therapeutic target for Alzheimer’s disease. The findings across these studies highlight the critical need for preventive and therapeutic interventions that prioritize oral health as a means to protect cognitive function. Future research should focus on longitudinal and interventional studies to fully elucidate the causal mechanisms and refine strategies for integrated care.