Introduction

According to the Global Burden of Disease Study (2016), periodontitis had been ranked as the 11th most prevalent condition worldwide. Its prevalence varies between 20% and 50% globally. This disease significantly contributes to tooth loss, thereby impacting essential functions such as chewing, aesthetics, confidence, and overall quality of life. In 2016, periodontitis accounted for 3.5 million years lived with disability on a global scale.1 In the United States, periodontitis affects over 40–46% of adults aged 30 and above.2,3 Zini et al mentions that over 10% contend with severe manifestations of the condition. Moreover, prevalence escalates notably, affecting between 70% and 85% of individuals in the 60 to 65 ages.4,5

Table 1 Results of the Relationship Between Porphyromonas gingivalis and Alzheimer’s Disease

Periodontitis is a chronic multifactorial inflammatory disease associated with dysbiotic plaque biofilms and characterized by progressive destruction of the tooth-supporting structures. It involves the formation of periodontal pockets, clinical attachment loss, and alveolar bone resorption, which can ultimately lead to tooth loss. According to the World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions, periodontitis results from a complex interplay between microbial dysbiosis and a dysregulated host immune-inflammatory response. While gingivitis, an inflammation confined to the gingival tissues, is a common precursor, it does not always progress to periodontitis, as additional genetic, environmental, and systemic factors influence disease susceptibility and progression.6–8 Periodontitis is associated with a shift in the subgingival microbial community, with an increased presence of keystone pathogens such as Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola collectively known as the red complex contributing to a dysbiotic pathobiome.9–12 This chronic condition, which has a high global prevalence, has also been linked to various systemic diseases, including cardiovascular diseases, diabetes mellitus, certain types of cancer, and neurodegenerative disorders such as Alzheimer’s disease.13–15

Alzheimer’s disease is a form of dementia characterized by a progressive deterioration of memory, thinking, language, and learning ability.16–19 It is the most common type of dementia and affects more than 37 million people worldwide, especially people over 65 years of age.20–22 It is estimated that one in 85 people will have this disease by 2050 due to increased life expectancy and lifestyle changes.23–25

Pathogenesis starts in the neuron; interneuronal connections depend on the correct functioning of the neurons. Two structural proteins highly influence interneuronal functioning, the β-amyloid protein and the Tau protein.26–28 The β-amyloid precursor protein (β-APP) is a membrane glycoprotein and a usual component of neuron membranes, its function is mainly related to cell adhesion processes, neuronal cell repair, and growth; at this point, intraneuronal β- and γ-secretase enzymes play an important role in the processing of β-APP. The β-secretase cleaves or cleaves β-APP, creating a fragment called C99. Then, γ-secretase processes C99 and produces amyloid beta (Aβ) peptides; these fragments are insoluble and bind to each other forming a glycopeptide in the extracellular space; which start to assemble and constitute amyloid plaques, which accumulate and block the reception of neurotransmitters interfering with synapses of neurons and triggers the inflammatory response, which also influences AD symptoms.26,28,29

This first process is followed by the intervention of another intracellular structural protein, the Tau protein, which is part of the microtubules, which in turn form the cytoskeleton of the cell. The function of microtubules is not only to stabilize the cell but also to serve as rails or bridges for the transport of molecules or proteins through them. Understanding this, the formation of amyloid plaques activates protein kinases, enzymes that will phosphorylate the Tau protein, ie to place a phosphate group in its structure, which results in the separation of the microtubules, triggering their structural decomposition; without these, the passage of molecules from one end of the cell to the other cannot occur. Furthermore, all phosphorylated Tau proteins begin to form a network of agglomerations known as Tau tangles, fibrillar and insoluble in the cytoplasm of the cell.26,28 When these two processes occur, in which neurotransmitters cannot be transported through the cell employing the microtubules and neuronal synapsis cannot take place due to the formation of amyloid plaques, the neuron stops functioning properly, which leads to apoptosis (Figure 1).26

Figure 1 Representation of the pathophysiology of Alzheimer’s disease.

Note: Author’s own work. Created in BioRender. Brito, D. (2025) https://BioRender.com/k75f257.

Hypotheses of the Origin of Alzheimer’s Disease

Symptoms of Alzheimer’s disease may begin decades before the clinical onset of symptoms and are thought to be caused by the formation of beta-amyloid plaques, neuroinflammation, and Tau protein tangles.14,23–26,30–33 Therefore, two main hypotheses have emerged in the current literature regarding the development of Alzheimer’s disease:

Amyloid cascade hypothesis: suggests that AD is caused by excessive production of a protein called amyloid beta (Aβ) through a process known as primary amyloidosis. This theory also suggests that toxic Aβ fibrils accumulate in the brain and promote neurodegeneration.24,25,30,34 Mitochondrial cascade hypothesis: proposes that AD is related to brain aging and mitochondrial dysfunction, leading to excessive production of reactive oxygen species (ROS) resulting in a vicious cycle of mitochondrial dysfunction. This hypothesis also suggests that this mitochondrial dysfunction may promote programmed cell death and excessive Aβ formation, which in turn triggers an inflammatory response in the brain that can damage nerve cells and reduce levels of certain neurotransmitters important for memory and other brain functions.30,35–37

In both cases, the accumulation of beta-amyloid plaques in the brain can have direct and indirect toxic effects on neurons and the connections between them, as well as the blood-brain barrier. In addition, phosphorylation and cleavage of tau proteins can lead to the formation of toxic neurofibrillary tangles that contribute to neuronal damage and loss of memory and other cognitive functions.14,23,26,30–33,35,38–40

Microbiological Characteristics of P. gingivalis

Periodontitis is described as chronic inflammation caused by the presence of gram-negative bacteria in the host, which cause connective tissue breakdown, formation of periodontal pockets, decreased alveolar bone structure, bleeding on probing, and a swollen and discolored appearance of the gingiva.41,42 This situation becomes more chaotic as the patient ages if we add many years of bad oral habits, such as smoking, alcohol consumption, and poor oral hygiene.26,43–46 Periodontitis has long been linked to various inflammatory, chronic, and immunological diseases, such as heart disease or diabetes; however, scientific interest in the bidirectional relationship between periodontitis and the presence and progression of Alzheimer’s disease (AD) has recently increased because several studies show that aspects, such as gingival inflammation, periodontal pockets, loss of clinical attachment level, were much more prevalent in patients with dementia.13,16,20,26,31,46 It is also hypothesized that the infiltration of oral microorganisms (mainly P. gingivalis) into the bloodstream, which subsequently reaches the central nervous system (CNS), causes inflammatory processes related to AD.42

P. gingivalis is the most characteristic pathogen in periodontitis as it modulates the size and composition of the local microbial community to promote periodontitis and an inflammatory milieu with the help of secretion of gingipains, theses are proteolytic enzymes with the ability to break down proteins in the body, including those found in the brain as it can escape into the bloodstream and colonize extraoral tissues (Figure 2). Inhibition of gingipains may prevent P. gingivalis from thriving and/or proliferating. The inhibition of gingipains cannot be done naturally but can be achieved through chemical inhibitors that block their enzymatic activity, natural compounds derived from plants or microorganisms, vaccines that stimulate a specific immune response against these enzymes, and nanotechnology that delivers inhibitors directly to the bacterial environment. These strategies aim to prevent gingipains from degrading host proteins, thereby stopping P. gingivalis from thriving and causing periodontal diseases.47–49

Figure 2 Representation of the way in which P. gingivalis and its toxins can migrate extra orally.

Note: Author’s own work. Created in BioRender. Brito, D. (2025) https://BioRender.com/f60d407.

In recent years, there has been increasing interest in the role that this bacterium may play in the onset and development of Alzheimer’s disease.30,50–53 Several studies have found evidence suggesting the validity of this hypothesis; for example, one study found that patients with Alzheimer’s disease had higher levels of antibodies to P. gingivalis in their cerebrospinal fluid than the control group.54–56 Another study found that people with periodontitis were more likely to develop dementia and Alzheimer’s disease.47–49 It is believed that P. gingivalis can enter the CNS through the blood-brain barrier (BBB). Under certain conditions, such as chronic inflammation, the BBB can become more permeable and allow the passage of substances that should not normally pass through it.55,57–59 Two pathways have been considered by which P. gingivalis can cross the BBB; it can be by transcytosis known as the “transcellular pathway” or by loss of the intercellular junction of the microvascular endothelial cells of the brain (BMECs) known as the “extracellular pathway”, which are part of the blood-brain barrier structure.60

Gingipains, LPS and outer membrane vesicles produced by P. gingivalis can degrade proteins in the extracellular matrix and BMECs including tau protein (found in the neurofibrillary tangles characteristic of Alzheimer’s disease), which can weaken its integrity, allowing the bacteria to pass into the brain (extracellular pathway). Once P. gingivalis enters the brain, it can cause neuronal damage and contribute to neuroinflammation and amyloid plaque formation, which has been linked to the pathogenesis of Alzheimer’s disease.47–49,60,61 Following the transcellular pathway there is an increase in transcytosis due to the ability of P. gingivalis to bind specifically to caveolin-1 which is a protein of caveolae, structures that are part of the invagination of the cell membrane that are directly related to the process of transcytosis.60

Although further studies are still needed to confirm the exact role of P. gingivalis and its gingipains in the pathogenesis of Alzheimer’s disease, current findings suggest that these bacteria and their enzymes may play an important role in its development. Therefore, maintaining good oral hygiene and preventing or treating periodontitis may be important in reducing the risk of developing neurodegenerative diseases.43,48,49

Gingipains

Gingipains are specialized enzymes that play a crucial role in the pathogenesis of periodontitis and can have detrimental effects on the host, being directly involved in periodontal tissue damage. They are known for their ability to degrade proteins such as collagen, which is key in connective tissues. The resorption of the crest of bone, rather than just collagen degradation, is necessary for the formation of periodontal pockets. This resorption facilitates the colonization and proliferation of periodontopathogenic bacteria in these areas. In turn, these enzymes can interfere with the function of immune cells, such as leukocytes, and modulate the inflammatory response in periodontal tissue, contributing to the chronicity of periodontitis and promoting ongoing destruction.62,63

Gingipains are classified into three main types: arginine-specific gingipain A (RgpA), arginine-specific gingipain B (RgpB) and lysine-specific gingipain (Kgp).

RgpA and RgpB are proteases that contribute to the deterioration of periodontal tissue by degrading essential proteins such as collagen. These enzymes can break down the structural components of connective tissue, which weakens tooth support and promotes bone loss. In addition, it has been observed that gingipains RgpA and RgpB also play a role in evading the host immune response. These enzymes may alter the activity of immune cells, inhibiting their ability to fight bacterial infection and thus favoring the persistence of P. gingivalis in the oral cavity.63,64 Kgp, a lysine-specific protease, also plays an important role in the virulence of P. gingivalis. Kgp acts as a factor that facilitates the co-aggregation of P. gingivalis with other oral bacteria, leading to the formation and stability of dental biofilm and making it difficult to remove by conventional oral hygiene techniques, such as brushing and flossing.65,66 These biofilms are highly organized microbial communities attached to the tooth surface, which play a key role in the progression of periodontitis.64,66,67

These enzymes can spread through the bloodstream and affect other organs, such as the heart and brain. Gingipains may contribute to this association by inducing chronic and systemic inflammation, activating blood clotting, and promoting the formation of atherosclerotic plaques.66,68

Relationship Between Periodontitis and Alzheimer’s Disease

Periodontitis is associated with Alzheimer’s disease (AD) through three main mechanisms: direct invasion of periodontopathogens, increased inflammatory markers, and atherosclerotic plaque formation. First, periodontopathogens may enter the systemic circulation and cross the blood-brain barrier to invade the brain, which may stimulate cytokine production and increase the inflammatory state.69–71 Second, periodontitis may contribute to the development of dementia by inducing a systemic inflammatory state and releasing proinflammatory cytokines.69,70,72,73 Finally, periodontitis may cause damage to endothelial cells due to toxins released by the bacteria involved, leading to an increase in atherosclerotic plaques and an increased risk of dementia due to loss of blood flow, which reduces the supply of oxygen and nutrients to the brain.6,20,24,25

In the last decade, an increasing number of clinical reports have linked periodontitis to the development of dementia, and the putative mechanisms include pathogen entry through the trigeminal nerve, pathogen invasion into the bloodstream through neovascularization at the blood-brain barrier, and microorganism-induced amyloidogenesis. A more recent study using an animal model of periodontitis and human postmortem brain tissue from subjects with Alzheimer’s disease indicates that P. gingivalis and/or its product, gingipain, translocate to the brain.50,74,75 Furthermore, in another study provides evidence that P. gingivalis and its bacterial by-products may result in repeated exposure of distant organs such as the brain, liver, and pancreas to bacteria and their by-products.76–78 Periodontal pathogens and the host immunoinflammatory response in periodontitis can affect brain function, especially in more vulnerable elderly subjects, and may contribute to the onset and progression of neurodegenerative disorders.51,58

Some putative mechanisms that could explain how periodontitis may affect CNS homeostasis have been described by experimental studies and include (i) translocation of bacteria into the bloodstream (bacteremia) or invasion into the brain via the trigeminal nerve (eg, Porphyromonas gingivalis) and (ii) production of proinflammatory cytokines that enter the bloodstream and act systemically or reach the brain via the peripheral nerve pathway (Figure 3). 59,79–82

Figure 3 Process by which P. gingivalis and gingipains can induce the appearance and development of Alzheimer’s disease.

Note: Author’s own work. Created in BioRender. Brito, D. (2025) https://BioRender.com/t16q296.

The current evidence linking P. gingivalis to Alzheimer’s disease, while compelling, is subject to significant limitations that warrant cautious interpretation. A major constraint is the reliance on animal models and in vitro studies, which, while valuable, may not fully replicate the complexity of human physiology and pathology.83 Furthermore, many studies fail to account for potential confounding factors, such as genetic predispositions, lifestyle influences, or comorbidities, which could also contribute to neuroinflammation and cognitive decline. Additionally, the exact mechanisms by which P. gingivalis might induce neuroinflammation, whether through systemic circulation, direct neural pathways, or other routes, remain inadequately explored. Another notable limitation is the narrow focus on select pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, without encompassing the broader spectrum of inflammatory mediators that may be involved in the disease process. These gaps highlight the need for more comprehensive, longitudinal human studies to validate these findings and better elucidate the intricate relationship between periodontal infections and Alzheimer’s disease.54,83–86

Bidirectionality

A bidirectional relationship between periodontitis and Alzheimer’s disease (AD) has been suggested, with evidence pointing to overlapping biological and behavioral factors. On the one hand, AD can contribute to poor oral hygiene due to cognitive decline, reduced manual dexterity, or difficulty accessing dental care, all of which increase the risk of periodontal infection and tooth loss. Studies indicate that individuals with dementia are more likely to require assistance with toothbrushing, and their inability to perform effective plaque control may exacerbate oral health issues. However, poor hygiene alone is insufficient to cause periodontitis; factors such as immune dysfunction, genetic predisposition, and the presence of pathogenic bacteria are also critical in its development.43,54,87

On the other hand, periodontitis itself may play a role in exacerbating AD. For example, elevated levels of pro-inflammatory cytokines, originating from periodontal tissue, have been associated with cognitive decline and amyloid plaque deposition, hallmark features of AD. Additionally, some studies suggest that periodontal pathogens like P. gingivalis may invade the brain through hematogenous routes or cranial nerves, potentially contributing to neuroinflammation and neuronal damage.

This complex interplay highlights the possibility that AD and periodontitis not only share risk factors but also influence each other through behavioral, inflammatory, and microbiological pathways, emphasizing the importance of managing both conditions holistically.15,30

Experiments in vivo

Dominy et al developed an experiment in mice to investigate the relationship between oral infection with P. gingivalis and the development of AD. To carry out the experiment, mice were infected with this bacterium for 6 weeks. Then, the mice were sacrificed to collect their brains and analyze them.88 To analyze the effects on the brains of the mice, several techniques were used. Histological tests were performed to examine amyloid plaques and neurofibrillary fibrils in the brain. Biochemical tests were also performed to measure the levels of A-beta-42 and Tau in the brain, which are widely used indicators to determine whether dementia is related to AD. Finally, molecular techniques to analyze the presence of P. gingivalis and its toxic products in the brain. The results of the study showed that oral infection with P. gingivalis in mice resulted in colonization of the brain and increased production of A-beta-42, a component of amyloid plaques found in the brains of patients with Alzheimer’s disease.11,88,89 In addition, gingipains produced by the bacteria were shown to be neurotoxic both in vivo and in vitro and exerted detrimental effects on Tau protein, a protein necessary for normal neuronal function.12,31,88,89 The researchers also tested a specific inhibitor (compound or drug that can stop or reduce activity) in mice and found that it significantly reduced the bacterial load in the brain and improved cognitive function. This suggests that small-molecule inhibitors may be effective in treating Alzheimer’s disease by inhibiting gingipain production.26,56,88

In another study, Lu et al analyzed the effect of continuous administration of salivary microbiota in APPswe/PS1ΔE9 (PAP) transgenic mice (genetically modified mice infected with amyloid-reducing protein to develop features related to Alzheimer’s disease) for two months. The mice were divided into two groups: one received salivary microbiota from patients with periodontitis (group P) and the other received salivary microbiota from healthy individuals (group H). Then, an object was presented to the PAP transgenic mice after they had been familiarized with two identical objects previously. The time the mice spent exploring the novel object was used as a measure of their long-term cognitive ability. The results showed that the P group presented a significant decrease in novel object exploration, indicating a decrease in long-term cognitive ability. Furthermore, impairments in learning and short-term memory were observed in the P group compared to the H group. Mice in the P group were also found to have increased levels of beta-amyloid and neuroinflammation. The results suggest that periodontitis-related salivary microbiota may aggravate cognitive impairments and increase beta-amyloid accumulation and neuroinflammation in PAP transgenic mice.90

Ilievski et al conducted a study to investigate the impact of chronic oral application of a periodontal pathogen on brain health in wild type mice. The researchers induced periodontitis in 8-week-old C57BL/6 wild type mice by repeatedly applying P. gingivalis over a 22-week period. The mice were divided into experimental and control groups, with the experimental group receiving P. gingivalis and the control group receiving a vehicle alone. Bone loss around teeth was assessed to confirm periodontitis development, and body weight and food consumption were monitored throughout the study. After 22 weeks, the mice were sacrificed, and their brains were collected for analysis. Immunofluorescence, confocal microscopy, and immunohistochemistry techniques were used to detect markers such as Aβ42, intact neurons, microglia, astrocytes, and proinflammatory cytokines in the brain tissue. Gene expression levels of key genes associated with Alzheimer’s disease pathology, including APP, BACE1, ADAM10, PSEN1, and Tau, were also analyzed.91 The results showed significant neuroinflammation in the hippocampus of mice in the experimental group, with elevated levels of proinflammatory cytokines IL6, IL1β, and TNFα. Increased astrocyte numbers indicated astrocyte activation, while a decrease in intact neuronal cells and an increase in degenerating neurons suggested neurodegeneration. Extracellular Aβ42 plaques were detected in the brains of experimental mice, indicating increased amyloid beta production. Pg/gingipain was found in various locations within the hippocampus of mice following oral application of P. gingivalis. Additionally, altered gene expression levels of APP, BACE1, ADAM10, PSEN1, and Tau were observed in the experimental group, reflecting changes associated with Alzheimer’s disease pathology.91

Eri Ishida and collaborators from various departments at Hiroshima University utilized a gestational mouse model to investigate the impact of maternal odontogenic infection with P. gingivalis on offspring behavior and brain tissue. The experimental protocol involved infecting five-week-old female mice with P. gingivalis, initiating mating 6 weeks post-infection, conducting the passive avoidance test on the offspring at 45 days after birth and collecting brain tissue post-test. The results revealed that offspring from P. gingivalis-infected mothers exhibited reduced cognitive function, as evidenced by a shorter latency in the step-through passive avoidance test. P. gingivalis was observed to be widely distributed in the brain, particularly in the hippocampus, leading to decreased numbers of neuron cells and cyclic adenosine monophosphate response element-binding protein-positive cells in the hippocampus and amygdala. Moreover, there was an increase in ionized calcium-binding adapter protein 1-positive microglia and glial fibrillary acidic protein-positive astrocytes in the hippocampus.92

A study carried out by Tetsuro Morikawa et al employed several methods to analyze neprilysin expression in the hippocampus of mice. RNA was extracted from the tissues and quantitative reverse transcription was performed to measure neprilysin expression at the mRNA level. Furthermore, Western blotting assays were carried out to analyze the expression of neprilysin at the protein level in hippocampal tissues. This process included the use of a polyacrylamide gel electrophoresis and lysis kit followed by protein transfer to polyvinylidene membranes for the detection of neprilysin. Throughout the study, it was evident that systemic administration of P. gingivalis lipopolysaccharide (PG-LPS) caused a significant decrease in neprilysin expression in SAMP8 mice, a model of accelerated aging. It was found that both the expression of neprilysin at the mRNA level and at the protein level was significantly lower in the SAMP8 (senescence-accelerated mouse prone 8) mice treated with PG-LPS compared to the SAMP8 control group. Furthermore, it was observed that the fluorescence intensity of neprilysin in the CA3 region of the hippocampus was significantly lower in PG-LPS-treated mice compared to control mice.93

Chi et al carried out a study where the Morris water maze (MWM) was used to evaluate spatial learning and memory in mice. Additionally, TUNEL testing and immunofluorescence staining were performed to evaluate apoptosis and inflammation in the brain of mice.94 In the study, P. gingivalis was orally administered to mice three times a week for a month to investigate its effects on the brain and intestine. The Morris water maze (MWM) was used to assess learning and spatial memory, revealing that treated mice had significantly longer escape latency and were further from the platform compared to the control group. In the platform crossing test, a significant decrease in crossing of the target area was recorded, along with a reduction in movement time and exploration in treated mice. Moreover, in the rotarod test, treated mice showed a shorter fall time, indicating impaired motor function. The results indicate that P. gingivalis administration induced cognitive impairment in mice, as evidenced by poor performance in tests of learning and spatial memory. Significant changes in motor activity, exploration, and brain function were also observed in treated mice. Dysbiosis of the intestinal microbiota and neuroinflammation were identified as potential underlying mechanisms of cognitive impairment induced by P. gingivalis. Dysfunction of the glycmatic system may also be implicated in the observed cognitive impairment. Taken together, these findings support the hypothesis that P. gingivalis may play a crucial role in intestinal dysbiosis, neuroinflammation, and glycmatic system dysfunction, leading to cognitive impairment.94

The study conducted by Zhao et al and published in the Journal of Neuroinflammation aimed to investigate the effects of nisin, a probiotic bacteriocin, in mitigating brain microbiome dysbiosis and Alzheimer’s disease-like neuroinflammation triggered by periodontitis. The methods involved using a polymicrobial mouse model of periodontitis to evaluate the impact of this disease on brain microbiome dysbiosis, neuroinflammation, Alzheimer’s-related changes, and the therapeutic potential of nisin. Through 16S sequencing and real-time PCR analysis, the researchers found that nisin treatment effectively mitigated changes in the brain microbiome composition, diversity, and community structure induced by periodontitis. Nisin treatment significantly reduced the levels of periodontal pathogen DNA in the brain. The study showed that nisin treatment led to a significant decrease in the mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in the brain that were elevated by periodontal infection. Additionally, nisin treatment resulted in a marked reduction in the deposition of Aβ42, total Tau, and phosphorylated Tau in the brains of infected mice, indicating a potential protective effect against Alzheimer’s disease-related pathology.84

Experiment in vitro

Haditsch et al conducted a study based on the infection of neurons derived from inducible human pluripotent stem cells (iPSCs) with P. gingivalis for 24, 48, and 72 hours. The infection was characterized using transmission electron microscopy, confocal microscopy, and bacterial colony formation assays. The expression of gingipains was monitored using immunofluorescence and real-time quantitative polymerase chain reaction (RT-qPCR), and proteolytic activity was controlled using activity-based probes. Neurodegenerative endpoints were evaluated using immunofluorescence, Western blot, and Enzyme-Linked Immunosorbent Assay (ELISA). In the course of the study, it was observed that neurons survived the initial infection and exhibited time-dependent infection-induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons showed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was heavily degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons decreased. It was found that P. gingivalis can invade and persist in mature neurons. Infected neurons exhibited signs of neuropathology like Alzheimer’s disease, including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeletal alterations, an increase in the phospho-tau/tau ratio, and loss of synapses. Infection of mature neurons derived from iPSCs by P. gingivalis provides a novel model system to study the cellular mechanisms leading to Alzheimer’s disease and to investigate the potential of new therapeutic approaches.95

Materials and Methods

A literature review was carried out using different databases (PubMed, Web of Science, among others), using keywords indexed in the MESH vocabulary such as “Periodontitis”, “Alzheimer Disease”, “Porphyromonas gingivalis”, “Older adults” and the boolean operators AND, OR and NOT were used for a more specific and precise search. In this way, 307 scientific articles were found for subsequent analysis; 206 duplicate articles were eliminated. The following inclusion criteria were applied to the remaining 101 articles: articles in English, Spanish, and Portuguese; articles that are relevant and related to the topic of study, and articles that contribute to achieving the objectives of the study. Consequently, 40 articles were excluded. Finally, 15 articles were discarded after analyzing the abstract, resulting in 25 articles that met the inclusion criteria.

Results

As can be seen, there is growing and substantiated evidence suggesting an association between periodontitis and Alzheimer’s disease, specifically through the presence of P. gingivalis. Several experimental studies in mice84,85,91–94 have shown that proteolytic enzymes produced by this bacterium, such as gingipains Rgp and Kgp, can trigger neuroinflammation and contribute to the neuronal damage observed in Alzheimer’s disease. Similarly, deoxyribonucleic acid (DNA) from P. gingivalis has been found in the brains of patients with Alzheimer’s disease, and at the same time, an increased accumulation of amyloid plaques and neurofibrillary tangles was observed, further supporting the idea that P. gingivalis may have important implications in the development and progression of neurodegenerative diseases, such as Alzheimer’s disease.

Thus, proper oral health care and treatment of periodontitis may play a crucial role in preventing or delaying the onset and progression of Alzheimer’s disease. Elimination of P. gingivalis and control of periodontal infection could help reduce the gingipain load and inflammatory response in the brain, potentially slowing disease progression. However, it is important to note that further studies are needed to fully understand the underlying mechanisms of this association and to determine whether treatment of periodontitis can effectively prevent or delay the onset of Alzheimer’s disease.

Tables 1 and 2 describe the studies that show the relationship between P. gingivalis and Alzheimer’s disease.

Table 2 Systematic Reviews and Meta-Analyses on the Association Between P. gingivalis and Alzheimer’s Disease

Discussion

Several mechanisms have been proposed to associate P. gingivalis with neurogenerative processes. Ryder et al26 speak of a mouth-brain translocation when gingipains promote the formation of amyloid plaques by crossing the blood-brain barrier. Lu et al90 suggest more extensive processes, where P. gingivalis can move to the intestine when swallowed or aspirated, which at this point can cause changes in the intestinal microbiota generating an interaction of the gut-brain axis that can affect the blood-brain barrier, allowing the entry of bacteria and toxic products into the brain and triggering an inflammatory response and endotoxemia.90 Additionally, Bregaint et al104 highlight the importance of multiple experiments in mice, in which, after oral administration of P. gingivalis, changes in the composition of the intestinal microbiota associated with epithelial alterations and cellular barrier function have been found. Thus, despite the differences in the proposed mechanisms, it is agreed that chronic inflammation causes damage to brain cells and contributes to the accumulation of amyloid plaques and neurofibrillary tangles.26,90,104

According to Li et al,105 neuroinflammation can be caused by systemic and localized inflammation at the site of periodontal infection, generated by oral dysbiosis bacteria such as P. gingivalis. Takeuchi et al106 mention that the toxic products of these bacteria can induce an inflammatory response that releases proinflammatory cytokines into the bloodstream, which can reach the brain and activate resident immune cells there, such as microglia and astrocytes. These immune cells may adopt a proinflammatory phenotype and secrete their proinflammatory mediators, thus perpetuating neuroinflammation and possibly contributing to neurodegeneration.107 Within the same premise, Bregaint et al104 report that P. gingivalis can induce osteoclastogenesis and a proinflammatory response mediated by type 17 helper T cells (Th17) that is geared towards generating an inflammatory response in the organism, leading to bone damage and systemic inflammation.

Olsen I29 mentions that gingipains are enzymes known for their ability to degrade host proteins and evade the host immune response. In the context of Alzheimer’s disease, arginine-specific Gingipain A (RgpA), arginine-specific Gingipain B (RgpB), and lysine-specific Gingipain (Kgp) have been shown to have important effects on microglia residing in the brain as they can induce microglial cell migration in addition to the expression of proinflammatory cytokines. According to Xu et al,108 Kgp. can degrade host heme proteins. Heme is an essential component of many proteins, and its degradation can interfere with normal biological processes. This can have negative effects on the host, as it alters the function of heme-dependent proteins and can affect various cellular and systemic processes. Moreover, Rgp can degrade the C5 component (protein of the complement system, which is an important part of the body’s immune system) and increase inflammation. When activated in a deregulated manner, it can cause tissue damage and contribute to the pathogenesis of diseases such as periodontitis, which in turn promotes neuroinflammation by activating immune cells in the brain and increasing the production of inflammatory mediators and amyloid-beta proteins. Based on this problem, Kariu T63 conducted research on prenylated flavonoids, which are bioactive compounds found in green tea and Epimedium species, a genus of the Berberidaceae family, where they are reported to have the ability to inhibit both gingipain-dependent virulence and bacterial growth in periodontitis sites where proteins are the only source of nutrition. It also reports that prenylation (the addition of a prenyl group to the basic structure of flavonoids) enhances the hydrophobicity of the molecule and thus its biological properties. This facilitates the interaction of flavonoids with the biofilm and their uptake by bacteria across the membrane, which enhances the inhibitory effects of flavonoids on the growth and biofilm formation of P. gingivalis. Therefore, given the research reviewed, it is advisable that there be more research that can help and identify the specific targets of prenyl flavonoids in gingipains and the signaling pathways involved.

Fernandes et al109 and Dioguardi et al47 highlight the role of P. gingivalis in AD pathogenesis, showing its presence in brain tissues and its ability to induce chronic inflammation via cytokines like IL-1β, IL-6, and TNF-α. Liu et al98 reinforces this connection, reporting a sixfold increase in AD risk in patients with P. gingivalis detected in the brain (OR = 6.84, 95% CI: 2.70–17.31), while Rafiei M’s99 analysis of 49 studies identifies a strong association between P. gingivalis and PD (OR = 9.24, 95% CI: 5.78–14.77; p < 0.0001). Furthermore, Cunha et al101 and Borsa et al32 emphasize systemic inflammation as a key mediator, with cytokines such as IL-6 and TNF-α linking periodontitis to cognitive decline. Borsa32 also reports a significant increase in Fusobacterium nucleatum in AD patients, supported by Liu’s98 findings of reduced oral microbiome diversity (p < 0.00001). While, Alshehri102 finds no significant benefit in hyaluronic acid use for reducing P. gingivalis prevalence (OR = 0.95 at three months, 95% CI: 0.63–1.45; p = 0.51), the need for well-designed clinical trials remains crucial. Together, these studies underscore the complex interplay between oral pathogens, systemic inflammation, and neurodegeneration, calling for further research into preventive strategies targeting periodontal health to mitigate AD risk.

The increased presence of antibodies to P. gingivalis is associated with significantly impaired cognitive test scores in both animals and humans, based mainly on the fact that its cytotoxins, called gingipains, have the capacity to damage brain cells and contribute to neuroinflammation. These findings support the idea that P. gingivalis may play a central role in the onset and progression of Alzheimer’s disease.

To better understand the relationship between periodontitis and Alzheimer’s disease, longitudinal human studies are needed to track disease progression while accounting for confounding factors such as genetics and lifestyle. Randomized controlled trials should assess whether periodontal treatment can prevent or slow Alzheimer’s progression. Additionally, advanced imaging and molecular techniques could clarify mechanisms like bacterial translocation, neuroinflammation, and amyloid plaque formation. Research on the gut-brain axis and salivary microbiota would also provide valuable insights into cognitive decline.

Current studies face limitations, including an over reliance on animal and in vitro models, which do not fully reflect human complexity. Many fail to address confounding factors like comorbidities and genetic predispositions. The mechanisms by which P. gingivalis induces neuroinflammation remain poorly explored, and there is an overfocus on select inflammatory markers. Lastly, the lack of long-term human research hinders establishing a definitive causal link between periodontitis and Alzheimer’s disease.

Conclusion

Periodontitis not only affects oral health but also has important systemic consequences, and there is evidence of a potential link between periodontitis and neurodegenerative diseases, cardiovascular disease, diabetes and other conditions. For this reason, it is crucial to recognize the importance of maintaining good periodontal health as part of overall health, thus driving the adoption of appropriate prevention and treatment strategies to mitigate the risk of systemic complications. Finally, it is important to note that despite ongoing research on the possible relationship between P. gingivalis and Alzheimer’s disease, a definitive conclusion on its involvement in the pathogenesis of the disease has not yet been reached. However, the robust body of evidence presented in this review, which includes clinical, in vivo and in vitro studies, consistently points to a clear association between P. gingivalis and Alzheimer’s disease. All the studies reviewed indicate a consistent relationship, highlighting the potential role of periodontal health in mitigating the risk of neurodegeneration. Further research should focus on establishing causality and elucidating the precise mechanisms involved to develop effective preventive and therapeutic strategies.

Acknowledgments

The authors thank the Universidad Católica de Cuenca, Cuenca, Ecuador, for its constant and timely support. Edisson-Mauricio Pacheco-Quito, Jéssica María Sarmiento-Ordóñez, are part of the Research Group: Innovación y Desarrollo Farmacéutico en Odontología, Facultad de Odontología, Jefatura de Investigación e Innovación, Universidad Católica de Cuenca, Cuenca, Ecuador.

Funding

The work was funded by the Universidad Católica de Cuenca, Cuenca, Ecuador, and is anchored to the research project called: “Eficacia antimicrobiana in vitro de sustancias no tradicionales frente a cepas microbianas de interés periodontopatógeno”, approved under code: PIC5P23-61.

Disclosure

The authors report no conflicts of interest in this work.

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