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. 2025 Jan 17;18:360–365. doi: 10.1016/j.ibneur.2024.12.004

Association between periodontitis and Alzheimer's disease: A narrative review

Mohammad Amin Seyedmoalemi a,1,⁎, Zahra Saied-Moallemi b,2
PMCID: PMC11889340  PMID: 40060035

Abstract

Periodontitis is a chronic inflammatory disease that progressively damages the supporting structures of teeth, resulting in gum bleeding, inflammation, gum recession, and eventual tooth loss. Key factors, including poor oral hygiene, plaque accumulation, smoking, inadequate nutrition, and genetic predisposition, drive its development. Recent evidence underscores the potential role of periodontitis as a contributing factor to systemic diseases, including Alzheimer's disease (AD). AD is a neurodegenerative disorder marked by memory loss, cognitive decline, and brain inflammation. Emerging clinical and experimental studies indicate that these two conditions share overlapping risk factors and may be interconnected. One notable finding is the detection of specific periodontal pathogens, such as Porphyromonas gingivalis (P. gingivalis), in the brains of individuals with AD. This suggests a possible link between chronic oral infections and neurodegeneration. These pathogens are believed to exacerbate neuroinflammatory processes by activating microglia and promoting systemic inflammation, which is central to AD pathogenesis. Further research is needed to clarify the biological mechanisms underlying this association. Targeted interventions that address periodontitis, such as anti-inflammatory therapies or treatments targeting specific pathogens like P. gingivalis, could potentially mitigate its impact on the onset and progression of AD, offering a novel avenue for prevention and management strategies.

Keywords: Periodontitis, Alzheimer’s disease, Oral microbiome, Neuroinflammation, Cognitive decline

1. Introduction

AD is a prevalent neurodegenerative disorder and a leading cause of mortality worldwide, particularly in ageing populations. Neuroinflammation plays a pivotal role in this disease's initiation and progression (Selkoe, 2015). Hallmark cognitive and behavioral impairments characterize it, including memory loss, difficulties in reasoning, and language deficits.

At the pathological level, AD is identified by the presence of amyloid plaques and neurofibrillary tangles in the brain, both strongly associated with cognitive decline (Long and Holtzman, 2019). The disease becomes increasingly prevalent with advancing age, with its most prominent symptoms being short-term memory loss and a gradual reduction in cognitive abilities (Kumar et al., 2018, Patterson, 2018).

Chronic inflammation, particularly when exacerbated by immune system activation, plays a critical role in driving the progression of AD. This inflammatory cascade creates a cycle of neurodegeneration and further inflammation. Infectious agents, including periodontal pathogens such as P. gingivalis, are increasingly recognized as significant contributors to this process due to their capacity to induce systemic inflammation and neuroimmune activation (Jagust, 2018, Jindal et al., 2014, Selkoe, 2019).

Periodontitis, a chronic inflammatory disease affecting the gums and supporting structures of teeth, may substantially exacerbate these neuroimmune responses (Van Cauwenberghe et al., 2016, Self and Holtzman, 2023). Studies have shown that periodontitis not only causes a significant systemic inflammatory response but is also associated with cognitive impairments (Kinane et al., 2017). This condition is prevalent among older adults, affecting nearly half of the adult population globally. Its prevalence may increase in individuals with AD, as the progression of cognitive decline often reduces the ability to maintain proper oral hygiene (Meyle and Chapple, 2015).Periodontal infections lead to the destruction of tooth-supporting tissues, tooth loss, and diminished quality of life but may also accelerate AD progression through mechanisms such as microglial activation and synapse pruning, as demonstrated in experimental animal models (Franco et al., 2017).

The risk of developing AD is reported to double within a decade following a diagnosis of periodontitis, underscoring the importance of effective periodontal disease (PD) management in potentially reducing AD risk (Hajishengallis, 2014, Zhang et al., 2021). Given the shared risk factors, including poor oral hygiene, tobacco use, inadequate dietary practices, and advancing age, both conditions could be addressed through comprehensive preventive strategies (Parra-Torres et al., 2023, Salhi et al., 2023, Na et al., 2024).

Furthermore, exploring differences in salivary metabolism between AD patients and healthy individuals with similar periodontal conditions is critical for understanding the interplay between oral flora and systemic health. Elevated levels of pro-inflammatory cytokines such as TNF-α and IL-1β in saliva and serum have been observed in individuals with AD and periodontitis, suggesting an interplay between systemic inflammation and oral health. With the global elderly population proliferating, recognizing and addressing the role of PD in AD onset and progression is essential for reducing morbidity in ageing populations (Lundergan et al., 2024, Tang et al., 2023).

This study investigates the well-documented relationship between periodontitis and AD, with a focus on uncovering the mechanisms that link oral health to neuroinflammation and AD pathology. By addressing these conditions' shared risk factors and pathogenic processes, further research can pave the way for novel preventive and therapeutic strategies targeting systemic and neurological health.

2. Materials and methods

This narrative review explored the relationship between periodontitis and AD by analyzing mechanisms identified in peer-reviewed literature. The review focused on articles published between 2017 and 2024, addressing the biological, epidemiological, and pathophysiological connections between these conditions.

2.1. Search strategy

An extensive literature search was performed using electronic databases, including PubMed, ScienceDirect, and Google Scholar. Keywords such as "periodontitis," "Alzheimer's disease," "neuroinflammation," "oral microbiome," "cytokines," and "systemic inflammation" were utilized. Boolean operators (AND, OR) were applied to refine the search strategy and ensure comprehensive coverage of relevant studies. Only articles published in English were included in the review.

Inclusion Criteria:

  • •

    Studies investigating the association between periodontitis and AD, including direct and indirect mechanisms.

  • •

    Research providing clinical, microbiological, or epidemiological data relevant to the link between these two conditions.

  • •

    Experimental studies employing animal models or in vitro systems to explore molecular and cellular pathways involved in the association.

  • •

    Review articles synthesizing evidence related to the relationship between periodontitis and AD.

  • •

    Articles emphasizing the elderly population, given the role of aging as a significant risk factor for both diseases.

  • •

    Studies incorporating quantitative or qualitative data regarding biomarkers like TNF-α, IL-1β, or microbiome diversity to evaluate their relevance in the context of periodontitis and AD.

Exclusion Criteria: Studies were excluded if they did not meet the inclusion criteria, lacked methodological rigor, failed to outline their methods clearly, or had inadequate sample sizes or reproducibility.

These criteria, if they lacked methodological rigor, or if sample sizes and reproducibility were inadequate.

3. Investigating the relationship between AD and periodontitis

Multiple studies have examined the bidirectional relationship between periodontitis and AD, emphasizing the influence of oral health on cognitive decline. Epidemiological evidence, molecular studies, and animal models suggest that systemic inflammation induced by PD contributes to neurodegeneration. Key findings from the reviewed literature are outlined below.

Recent research has focused on mechanisms by which PD may influence AD pathology. A 2020 study used a murine model to evaluate the impact of ligature-induced periodontitis on AD. Over five weeks, periodontitis was induced in mice, and behavioral changes were assessed using the open-field test. Histological analysis of the upper jaw examined periodontal bone resorption. Findings revealed that periodontitis impaired long-term memory in mice but did not affect short-term memory. Additionally, although not directly measured, periodontal bone resorption was inferred to contribute to systemic inflammation and its impact on neurodegeneration (Wang et al., 2020).

In 2024, a cohort analysis investigated the association between periodontal pathogens and AD using data from the National Health and Nutrition Examination Survey (NHANES). This study examined how markers of PD, including clinical attachment loss and gingival bleeding, correlated with cognitive impairment and Alzheimer's outcomes. The results demonstrated that periodontal inflammation significantly increased the risk of AD, particularly in men and individuals over 65 years old, suggesting a demographic susceptibility (Beydoun et al., 2024).

A 2022 study employed amyloid precursor protein (APP) knock-in mice to evaluate the effects of P. gingivalis infection on behavioral and cognitive disorders and amyloid pathology in AD. The results showed that Pg infection accelerated Alzheimer's progression by increasing neuroinflammation, enhancing amyloid deposition, and facilitating Pg entry into the brain through microglial activation. This highlights the direct involvement of periodontal pathogens in exacerbating AD pathology (Hao et al., 2022).

A 2023 prospective cohort study assessed the effects of periodontitis and occlusal relationships on AD progression. The study divided 90 AD patients into three groups based on disease severity and assessed cognitive function using the Standardized Mini-Mental Test (SMMT). Periodontal examinations and occlusal relationships were also evaluated. Findings indicated that 65 out of 90 patients had periodontitis, with more severe infections observed in the advanced stages of AD. Age was identified as a significant variable, with periodontitis severity and occlusal dysfunction worsening as AD progressed, suggesting a bidirectional relationship (Karaduran et al., 2023).

A 2016 study focused on AD patients with Down syndrome, analyzing 75 individuals and finding that periodontitis increased susceptibility to AD. Notably, a more aggressive form of periodontitis was observed in this population, likely due to both systemic vulnerability and reduced oral hygiene practices (Kamer et al., 2016).

In 2020, a pilot study analyzed the relationship between periodontitis-associated microbes and AD using buccal plaque samples. Results indicated that AD patients exhibited higher microbial diversity in subgingival microbiota than healthy controls. Specific bacteria, including P. gingivalis and Treponema denticola, were identified in higher concentrations, suggesting a potential role of oral microbial dysbiosis in AD pathology (Na et al., 2020).

A 2023 study in Taiwan evaluated the oral microbiome and serological markers to identify connections between periodontitis and AD. Clinical parameters and biomarkers, including β42 amyloid and pro-inflammatory cytokines such as TNF-α and IL-1β, were significantly elevated in AD patients with periodontitis, reinforcing the link between oral inflammation and systemic neurodegeneration (Fu et al., 2023).

A 2021 review investigated the pathophysiological links between PD and AD, particularly in elderly populations. Based on data from PubMed and ScienceDirect, the review emphasized that inflammatory responses triggered by oral pathogens can exacerbate central nervous system inflammation, accelerating AD development. Key pathways identified included microglia activation, blood-brain barrier disruption, and systemic cytokine elevation (Desta, 2021). A 2020 review article explored molecular mechanisms linking periodontitis with AD, noting the roles of β-amyloid oligomers and periodontal pathogens in promoting AD progression. The review provided foundational insights into the molecular interactions, such as increased amyloid aggregation and neuroinflammation, relevant to developing therapeutic strategies for AD (Sadrameli et al., 2020). Further, a 2023 study examined emerging clinical evidence on the relationship between periodontitis and AD, focusing on the role of periodontal pathogens in the onset and progression of AD. The study highlighted that periodontitis can increase AD severity by promoting systemic inflammation, neuroinflammatory pathways, and direct translocation of oral bacteria to the brain, emphasizing the importance of oral health management in reducing AD risk (Wu et al., 2023).

In 2022, a semi-experimental study conducted in Germany evaluated the effect of periodontal treatment on preclinical AD. This study involved 177 periodontal patients under 60 years of age and used MRI imaging to assess markers of late-stage AD and brain aging, including hippocampal atrophy and white matter lesions. Results demonstrated a significant association between periodontitis and preclinical AD, providing evidence that periodontal treatment could influence neurological outcomes and potentially slow the progression of brain aging (Schwahn et al., 2022).

A 2021 case-control study investigated the relationship between periodontitis and AD and its impact on oral health. Data were collected from 100 participants using a detailed questionnaire assessing oral hygiene practices and dental health status. Statistical analyses (chi-square and t-test) revealed that periodontitis was significantly associated with AD. The study emphasized the importance of routine oral examinations and preventive dental care for AD patients to maintain oral health and mitigate systemic complications, such as exacerbated neuroinflammation (de Oliveira Araújo et al., 2021).

Lastly, a 2019 retrospective cohort study examined chronic periodontitis and dementia risks using National Health Insurance data. Results showed that periodontitis increased dementia risk by 95 %, even among individuals maintaining otherwise healthy lifestyle behaviors. The study highlighted early periodontal intervention's importance in reducing systemic inflammation and neurodegeneration (Choi et al., 2019).

A high-throughput sequencing study identified bacterial markers such as Treponema denticola and Veillonella in the brains of AD patients, both strongly associated with periodontitis. Findings suggested that periodontal conditions could double the risk of AD within ten years, emphasizing the role of oral microbial dysbiosis in systemic disease progression (Siddiqui et al., 2019).

In the United States, a 2020 study analyzed bacterial indicators of periodontitis and their relationship with AD using national health survey data. Results demonstrated that bacterial markers of periodontitis, particularly in individuals over 65 years of age, increased mortality rates in AD patients, suggesting a direct link between oral health and AD outcomes (Beydoun et al., 2020).

A 2021 study investigated the interplay between Helicobacter pylori (H. pylori), periodontal pathogens, and AD in individuals over 65. The analysis of 1431 participants revealed that periodontal pathogens, along with H. pylori, exacerbated AD severity by promoting systemic and neuroinflammatory responses, further supporting the link between oral infections and neurodegeneration) (Beydoun et al., 2021).

A 2017 study explored the relationship between periodontitis and AD, aiming to highlight the underlying inflammatory mechanisms connecting the two conditions. Results indicated that periodontitis initiates systemic inflammation by releasing cytokines such as IL-1β and TNF-α, which may lead to neuroinflammation in the brain. Additionally, tooth loss caused by periodontitis was found to worsen patients’ clinical conditions and quality of life through both direct effects, such as impaired food consumption, and indirect effects, such as inflammation-related brain disorders (Silvestre et al., 2017).

In 2020, a Japanese study focused on the role of P. gingivalis in AD pathology. Results demonstrated that targeting this specific bacterium through antimicrobial or anti-inflammatory therapies could mitigate the progression of AD, suggesting a potential therapeutic approach that targets oral pathogens to reduce neuroinflammation and amyloid aggregation (Matsushita et al., 2020).

A 2022 study in China examined the relationship between salivary microbiota associated with periodontitis and AD. Saliva samples from periodontitis patients and healthy controls were analyzed for microbial diversity and inflammatory markers. The microbiota was transplanted into mice for two months to simulate oral-to-systemic transmission. Findings indicated that periodontal pathogens, particularly Treponema denticola and Fusobacterium nucleatum, and their associated inflammatory responses may contribute to AD by ingesting contaminated saliva, facilitating systemic inflammation and neurodegeneration (Lu et al., 2022).

Another 2021 study in China used text mining to explore the connection between chronic periodontitis and AD. By analyzing three datasets and employing Cytoscape software to construct protein-protein interaction networks, the study demonstrated that chronic periodontitis is linked to an increased risk of AD through systemic inflammation and activating pathways involving pro-inflammatory mediators such as IL-1β and TNF-α (Jiang et al., 2021).

A more recent study in China investigated the role of cytokines in the pathogenesis of both periodontitis and AD. Pro-inflammatory cytokines, including interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), were injected into the buccal area of rats to mimic periodontal inflammation. Results showed that systemic inflammation induced by periodontitis contributed to AD progression by exacerbating neuroinflammatory responses, further confirming the role of inflammatory mediators in the link between these two conditions (Wang et al., 2023).

A 2017 retrospective cohort study in Taiwan analyzed the relationship between chronic periodontitis and AD using National Health Insurance Research Database data. Results showed that chronic periodontitis increased the prevalence of AD, with a more significant impact observed in older populations. This study emphasized the importance of preventive measures and improved healthcare services, such as routine periodontal examinations and early interventions, to mitigate the risks associated with chronic periodontitis (Chen et al., 2017).

A recent 2024 study examined the impact of serum antibodies to periodontal pathogens on AD progression. This study included 158 participants and found that elevated antibodies against P. gingivalis and other periodontal pathogens were significantly associated with both the onset and progression of AD. Findings highlighted the potential role of immune responses to oral pathogens, including dysregulated systemic immunity, in the pathogenesis of AD (Al-Hassan et al., 2024).

4. Discussion

The studies reviewed in this article collectively underscore the significant relationship between periodontitis and AD. Numerous investigations have established a direct link with PD contributing to the onset and progression of AD through systemic inflammation and the translocation of oral pathogens, such as P. gingivalis, to the central nervous system. However, while the association between these two conditions is well-documented, the precise extent and mechanisms underlying this relationship remain insufficiently explored. Many studies have highlighted the connection without addressing the varying impacts across different age groups, populations, or stages of disease progression. Additionally, although inflammatory pathways have been identified as central to this relationship, there is limited consensus on how to effectively target these pathways for the treatment of both periodontitis and AD.

A fundamental limitation of existing literature is the absence of longitudinal studies that establish causality. While several cohort and cross-sectional studies have demonstrated associations between periodontitis and AD, the causal link remains unclear. Future research should prioritize long-term studies to determine whether periodontal treatment can reduce the incidence or progression of AD. Moreover, most studies have focused on elderly populations, neglecting younger age groups. Investigating whether early periodontal interventions can prevent or delay neurodegenerative conditions warrants further exploration.

This review distinguishes itself by corroborating the association between periodontitis and AD

To summarize and better understand all the articles reviewed, they are presented in a categorized and summarized format:

In order to synthesize the current research on the relationship between periodontitis and Alzheimer's disease, we categorized all the mentioned studies earlier into five main areas: microbial involvement and inflammation, genetic and molecular mechanisms, cytokine involvement, epidemiological evidence and experimental and clinical trials. Table 1 provides a comprehensive overview of these categories, along with the key findings from each group of studies

Table1.

Categorization of Studies on the Relationship Between Periodontitis and Alzheimer's Disease.


Category
Reference numbers
Key Findings Summary
Microbial Involvement and Inflammation 33, 37, 34, 38, 42, 28, 29 Investigates the relationship between oral bacteria associated with periodontitis, such as Porphyromonas gingivalis, and the increased risk and severity of Alzheimer's disease.
Biomarker and Molecular Analysis 26, 42, 29, 38, 28, 19 Assesses serum biomarkers and oral microbiome to establish a connection between periodontitis and Alzheimer's disease through molecular analysis.
Cytokine-Mediated Inflammation 40, 35, 36, 28, 42 Examines the role of pro-inflammatory cytokines like interleukin−1 beta and tumor necrosis factor-alpha in systemic inflammation contributing to Alzheimer's disease progression
Epidemiological Evidence 27, 32, 41, 31, Higher prevalence of AD in individuals with chronic periodontitis; need for public health interventions.
Experimental Studies (Animal Models) 30, 28, 39, 24, 22, 20 Evaluates the effects of periodontitis on memory and Alzheimer's disease progression in animal models (e.g., mice).
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Explanation of the Table:

- Category: Each category represents a major area of focus in the studies.

- References: Lists the reference numbers in our study that fall under each category.

- Key Findings Summary: Provides a brief summary of the main findings from the studies in that category.

While providing an in-depth analysis of biological mechanisms and demographic factors. Unlike prior works primarily relying on cross-sectional data, this review synthesizes findings from experimental animal models and clinical cohorts. This integrated approach allows for a more comprehensive understanding of how periodontal pathogens, particularly P. gingivalis, exacerbate neurodegeneration through mechanisms such as amyloid deposition and neuroinflammation. For instance, studies involving APP knock-in mice provided direct evidence of how P. gingivalis promotes cognitive decline and accelerates AD pathology (Hao et al., 2022).

Additionally, this review highlights the nuances of PD progression in AD patients at varying stages of severity. For example, the prospective cohort study, included in this review, offered valuable insights into the evolving relationship between periodontitis, occlusal dysfunction, and Alzheimer’s severity. These findings underscore the critical need to address oral health early in AD, a perspective insufficiently emphasized in prior research (Karaduran et al., 2023).

Another unique contribution of this review is its focus on the role of the oral microbiome in AD pathogenesis, a growing area of interest that remains underexplored. Studies such as the pilot investigation by Hee Sam demonstrated increased microbial diversity in the subgingival microbiota of AD patients, highlighting the importance of microbial dysbiosis in AD progression. By incorporating this dimension, this review extends beyond the inflammatory cytokine-centric focus of earlier studies to provide a more holistic view of Alzheimer’s pathogenesis. Furthermore, while much of the (Na et al., 2020).

Existing literature has concentrated on older populations, this review emphasizes the necessity of investigating periodontal health in younger individuals. Early intervention may present a critical opportunity to prevent or delay cognitive decline. By analyzing findings across diverse age groups and Alzheimer’s severity levels, this review offers a more nuanced understanding of the bidirectional relationship between periodontitis and AD.

Finally, this review synthesizes data from both human studies and animal models, bridging a gap often observed in prior reviews. Many earlier studies have limited their scope to either clinical data or experimental models, but this work integrates insights from both approaches to offer a more comprehensive perspective on the mechanisms linking periodontal health to neurodegeneration. This integrative approach enhances understanding of the periodontitis-AD relationship and provides a robust foundation for future research.

5. Future recommendations

The evidence reviewed in this article underscores that PD is not merely an oral health issue but a condition with profound systemic implications, particularly in its association with AD. Future research and clinical practices should adopt a more integrated and multidisciplinary approach to address gaps in understanding and intervention.Longitudinal research is crucial to establish a causal relationship between PD and AD. While many studies demonstrate a significant association, they fall short of proving causality. Long-term cohort studies tracking at-risk populations over extended periods are essential to determine whether treating or preventing PD can reduce the risk or progression of AD. These studies should include diverse populations to account for variations in susceptibility and outcomes.Another critical need is clinical trials to evaluate the efficacy of periodontal treatments in mitigating AD. Trials should focus on anti-inflammatory therapies, microbial-targeted interventions (e.g., therapies aimed at P. gingivalis), and combined approaches addressing systemic and local factors. Such investigations could substantiate the role of periodontal treatments as part of comprehensive strategies for preventing or slowing neurodegenerative diseases.Healthcare systems must also embrace an integrated care approach, particularly for elderly and at-risk populations. Routine periodontal assessments should become standard in medical examinations to enable early detection and management of PD. Multidisciplinary collaboration between dentists, neurologists, and primary care physicians is essential to address PD's systemic effects on cognitive health comprehensively. Including periodontal health in public health guidelines for cognitive decline prevention would further enhance these efforts.Education and awareness initiatives play a pivotal role in combating PD and AD. Patients, caregivers, and healthcare providers need to understand the systemic impact of periodontal health on brain function. Promoting proper oral hygiene, regular dental check-ups, and community-based programs targeting vulnerable populations, particularly the elderly, can enhance prevention efforts. Early interventions can potentially mitigate systemic and neurodegenerative consequences of PD.

6. Conclusion

Addressing these priorities—advancing longitudinal research, conducting interventional trials, integrating care systems, and enhancing public awareness—can significantly reduce the burden of AD. These efforts will not only improve oral and systemic health but also contribute to enhancing the quality of life for aging populations worldwide.

Ethics

The authors of this paper (Title: Association Between Periodontitis and Alzheimer's Disease: A Narrative Review Reference: IBNEUR546) declare that there are no competing interests related to this manuscript.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank Dr Zahra Saied-Moallemi for her significant Contribution in conception, design and revising the manuscript. Dr Mohammad Amin Seyedmoalemi Contributed to data acquisition and interpretation. All authors gave their final approval and agree to be accountable for all aspects of the work.

Limitations

The relationship between periodontitis and the progression of Alzheimer's disease is a new issue that, despite the many studies presented in this field, has not been fully and comprehensively investigated. On the other hand, various techniques have been presented to investigate this relationship, which cannot be combined and evaluated in a comprehensive format. In addition, because Alzheimer's disease and in general, diseases related to neuroinflammation and cognitive disorders may be caused by many and even unknown causes, therefore, it is not possible to definitively and accurately, determined the effect of periodontitis on Alzheimer's.

Contributor Information

Mohammad Amin Seyedmoalemi, Email: doctoraminsm@yahoo.com.

Zahra Saied-Moallemi, Email: smoallemi@mui.ac.ir.

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