Introduction: Neuroinflammation is a hallmark of Alzheimer’s disease (AD). Multiple infectious agents have been demonstrated in the brain and proposed to be involved in AD, but robust evidence of causation has not yet been established. It was hypothesized that periodontitis (PD) and infection with Porphyromonas gingivalis may be linked to onset and progression of AD. Although inflammation is present in both diseases, the exact mechanisms and interactions between periodontitis and AD are poorly understood.
Method: In this narrative review, we highlight recent progress in exploring potential associations of PD with AD and its surrogates (amyloid plaques) and clinical sequelae (i.e. dementia), respectively.
Discussion and Result: Recent evidence suggests that periodontitis interacts with AD to increase the severity of clinical dementia and to accelerate its manifestations. These results indicate that periodontitis may be an emerging risk factor for AD and that the risk may be mediated directly by Porphyromonas gingivalis and its secreted neurotoxic gingipains. The recent development of an oral gingipain inhibitor, which is currently tested in a randomized controlled trial, offers the unique opportunity to verify the infectious hypothesis of AD. If successful, this research can be expected to result in a significant improvement of prevention and treatment of PD and AD.
Department of Prosthetic Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg-Eppendorf, Germany: PD Dr. Ghazal Aarabi, Dr. Carolin Walther, Prof. Dr. Guido Heydecke, Prof. Dr. Udo Seedorf
Department of Neurology, Head- and Neurocenter, University Medical Center Hamburg-Eppendorf, Germany: Prof. Dr. Götz Thomalla, Carola Meyer
Department of Periodontics, Preventive and Restorative Dentistry, University Medical Center Hamburg-Eppendorf, Germany: Prof. Dr. Thomas Beikler
* Corresponding Author
Citation: Aarabi G, Thomalla G, Walther C, Mayer C, Beikler T, Heydecke G, Seedorf U: Periodontitis as potential risk factor for Alzheimer’s disease. Dtsch Zahnärztl Z Int 2021; 3: 121–128
Peer-reviewed article: submitted: 15.04.2020, revised version accepted: 22.06.2020
In Germany, approximately 1.2 million mostly elderly people suffer from dementia (GDB 2016 Dementia Collaborators, 2019). The number of people living with dementia has increased significantly in the last 3 decades due to ageing. Despite of some evidence of minor decreases in the age-specific incidence rates , further increases in the number of people affected by dementia may be expected due to the prevailing demographic trends. Limited starting points for prevention and the absence of an effective treatment suggest that the dementia-related burden on patients, caregivers, and the health-care system will likely continue to rise.
Dementia is a neurodegenerative disease in which neurons are gradually lost. The most common forms are Alzheimer‘s disease (AD) and vascular dementia, which together account for approximately 85 % of all cases . While AD is caused by protein deposits called amyloid plaques or senile plaques in the brain (Fig. 1), vascular dementia is due to a circulatory disorder resulting in a diminished cerebral oxygen supply. Well established risk factors for vascular dementia are hypertension, heart disease, diabetes, high cholesterol levels (hyperlipidemia), obesity, physical inactivity, and smoking . Age and the ε4 allele of apolipoprotein E are major established risk factors for the frequent multifactorial forms of AD . In addition, rarer familial forms exist, which are primarily due to high-penetrance mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Together, these mutations explain only 5–10 % of the occurrence of early-onset AD (reviewed by .
Previous research supports that chronic inflammatory processes play a pivotal role in AD dementia [24, 43, 49]; but the events that trigger inflammation in the first place are still unclear. One repeatedly postulated possibility is that AD associated inflammation may result from an infectious etiology . Multiple infectious agents, including Cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), Helicobacter pylori, Chlamydophila pneumoniae, Borrelia burgdorferi, and Porphyromonas gingivalis have been demonstrated in the brain and proposed to be involved in AD, but robust evidence of causation has not yet been established [28, 37]. Extracellular amyloid-β (Aβ) deposits, which accumulate in the gray matter of the brain, are a hallmark of the AD. It could be demonstrated Aβ belongs to an evolutionarily conserved family of proteins, collectively known as antimicrobial peptides (AMPs) [19, 39]. AMPs act as a first-line of defense against a large range of pathogens including bacteria, mycobacteria, viruses, fungi, and protozoans . Mice lacking the amyloid precursor protein (APP) show an attenuated survival rate after bacterial infection and it is assumed that oligomerization and fibrillization is required for Aβ‘s antimicrobial activity . The recent finding that Aβ has antimicrobial activity has motivated the scientific community to verify a possible infectious cause of AD [25, 39, 40]. It was hypothesized that periodontitis (PD) and infection with Porphyromonas gingivalis may be linked to onset and progression of AD. Although inflammation is present in both diseases, the exact mechanisms and interactions between PD and AD are poorly understood. The impact of inflammation on vascular dementia and its association with PD was discussed comprehensively in a recent review by Aarabi et al. . Thus, this narrative review aims at presenting and evaluating recent progress in exploring potential associations of infections with Porphyro- monas gingivalis with AD and its clinical sequelae, i.e. dementia and mild cognitive impairment (MCI). In AD, PD was shown to be associated with increased dementia severity and more pronounced cognitive decline, thus indicating a link to an increased systemic pro-inflammatory state . An example of a case of severe generalized PD is shown in Figure 2.
The search strategy for this review was developed in view of our aim to find and present recent evidence supporting an infectious etiology of AD and the potential contribution of Porphyromonas gingivalis to AD and its clinical sequelae, i.e. dementia and mild cognitive impairment (MCI). The literature search was restricted to PubMed, PMC (NCBI) and Web of Science SCI with the following search terms: 1) Oral medicine: oral infection, periodontitis, gingivitis, bleeding on probing, gum disease, tooth-loss, endodontic lesion OR infection, apical OR periapical abscess, Porphyromonas gingivalis, Porphyromonas endodentalis, Streptococcus mutans, GroEL, lipopolysaccharide. 2) Neurology: Alz- heimer’s disease, dementia, cognitive decline, brain, amyloid plaques or senile plaques, magnetic resonance imaging OR tomography, CT OR computer tomography. 3) Inflammation: autoimmunity, C-reactive protein OR CRP, interleukin, periodontitis, oral infection, systemic inflammation, acute phase, endothelial AND function OR dysfunction. Other: epidemiology.
Search terms of each subject area were combined logically and resulted in 230 hits, which were recorded and screened by GA and US manually and categorized a priori relevant or interesting. Excluded were non-peer-reviewed studies and studies with insufficient sample sizes to yield at least a statistical power of 80 % to detect the claimed effects. Also studies that were prone to the possibility of reverse causation (typically case-control studies comparing the frequency of periodontitis in healthy subjects and dementia patients) were excluded (18 publications). Animal studies that had no direct relationship to human AD (21 publications), and studies that concerned with dementia rather than with AD (146 publications) were also excluded. This prescreening procedure resulted in 45 proposed references (98.3 % agreement between both authors, Cohen’s kappa: 0.95), which were stored in an Endnote web database that was accessible to all authors, who decided consensually which publication should be referenced based on the article’s content (41 publications) and 8 additional references resulting from manual searches were added during peer- reviewing. This procedure resulted in the 49 references cited in this review.
Association between chronic oral infections and dementias
Chronic oral infections such as PD may be able to modulate the risk of AD dementia. In the Third National Health and Nutrition Examination Survey (NHANES-III), a large representative cross sectional observatio- nal study among 2,355 participants ≥ 60 years of age, PD was associated with cognitive decline, which is considered to be a precursor of dementia . However, the type of dementia was not assessed and brain MRI was not available for the study. A reduced number of teeth – a frequent cause of a past PD – increased the risk of higher prevalence and incidence of dementia of all causes in the Nun Study [27, 41]. The Nun Study is a longitudinal survey on aging and AD of nearly 700 nuns from across the United States. Its strength relates to the fact that AD diagnosis was performed post mortem to ensure a high sensitivity and specificity of the AD diagnosis. In addition, the dental records were complemented with results from cognitive tests longitudinally over a long period of time.
Data from the U.S. Department of Veterans Affairs Dental Longitudinal Study (VA-DLS) of almost 600 men aged 28 to 70 at entry who had been followed for up to 32 years showed that the risk of cognitive decline increased with the number of lost teeth and that also PD and caries lesions were associated with cognitive decline . Gatz et al. evaluated data from the Swedish Twin Registry to identify potentially mod-ifiable risk factors for AD. The most consistent risk factor for AD was tooth loss before the age of 35. Low educational status also associated with the risk for dementia and lack of physical exercise associated with the risk for non-Alzheimer’s dementia . However, tooth loss is a poor outcome measure because tooth loss may have an adverse influence on diet. Thus, a poor diet and not the periodontal inflammation per se may have been the causal factor underlying the observed association in these studies.
The hypothesis that PD may be associated with Aβ deposits in the brain was also investigated by positron emission tomography imaging, which enabled non-invasive imaging of these deposits . The study included 38 healthy elderly men and women. After adjusting for confounders, clinical attachment loss of ≥ 3 mm was associated with elevated Aβ in affected brain regions (p = 0.002) . There are a number of additional studies that supported an association between dementia and periodontal disease or tooth loss (reviewed by ). Although these studies had limitations, such as small sample sizes, lack of rigorous criteria to diagnose PD and differentiate between different types of dementia, and the possibility of reverse causation, the evidence for an association between PD and dementia or AD nevertheless appears to be rather solid, thus raising questions about possible mechanisms underlying these findings.
How periodontal pathogenic bacteria cross blood-brain barriers
Key pathogens involved in the pathogenesis of PD are, amongst others, Porphyromonas gingivalis and Treponema denticola , which colonize deep periodontal pockets. Serum IgG antibody levels to Porphyromonas gingivalis were shown to be associated with an increased incidence of AD and AD progression [30, 41], suggesting an involvement of Porphyromonas gingivalis in AD.
In general, the blood-brain barrier protects the brain against exposure to bacteria and other toxic agents. However, there are 2 main routes via which bacteria may cross an impaired blood-brain barrier and enter the brain: first, by bacteremia and second, by migrating along the trigeminal nerve (mouth brain axis) [34, 43]. Pro-inflammatory cytokines that are triggered by Porphyromonas gingivalis and other periodontal pathogens are secreted from the infected sites at the periodontium, enter the blood stream and reach the brain via the circulation and weaken the blood-brain barrier by inducing a proinflammatory state favoring cerebral small vessel disease (CSVD). Moreover, Porphyromonas gingivalis can infect endothelial cells and stimulate the expression of endothelial adhesion molecules, which may promote monocyte/macrophage adhesion and infiltration into the endothelial layer of the blood-brain barrier . Thus, infections with Porphyromonas gingivalis may contribute to the destruction of the blood-brain barrier via inflammation during CSVD. Imaging markers of CSVD were found to be associated with cognitive decline in elderly people affected by AD [7, 8]. The subgingival biofilm is composed mostly of lipopolysaccharide (LPS)-producing Gram-negative bacteria , some of which can trigger inflammatory responses in the brain , damage the blood-brain barrier in animal models of AD , and stimulate the production of Aβ peptides by neurons . Porphyromonas gingivalis has the ability to impair the blood-brain barrier by gingipain-mediated degradation of the junctional adhesion molecule (JAM1), a tight junction–associated protein that regulates the epithelial barrier function . Gingipains cleave JAM1 specifically at residues K134 and R234, resulting in permeability of the epithelium to LPS, and proteoglycan (PGN). Knockdown of JAM1 in cultured cells increased the permeability to LPS, PGN, and gingipains . Thus, bacterial toxins may be able to penetrate the brain via the damaged blood-brain barrier. Moreover, oral bacteria may access the brain via infection of monocytes followed by brain recruitment [5, 11] or direct infection of endothelial cells, which protect the blood-brain barrier .
Passage through the trigeminal nerve is supported by the observation that higher levels of periodontal pathogen Treponema could be detected in the brain and the trigeminal nerve of AD patients than in unaffected controls . The trigeminal nerve innervates the oral cavity and connects it with the central nervous system. Compared to periodontally healthy subjects, patients with PD have a higher risk for trigeminal neuralgia, which is characterized by recurrent paroxysmal pain within the distribution of the trigeminal nerve .
The most likely mechanism employed by Porphyromonas gingivalis and the gingipains for passage through the nerve is axonal transport using the axonal transport machinery. It could be demonstrated, for instance, that the rabies virus enters the central nervous system by retrograde axoplasmic flow , the tetanus neurotoxin is retrogradely transported towards the soma in signaling endosomes after uptake at the neuromuscular junction  and the HSVs are transported inside the nerve in transport vesicles along with APP [4, 35]. However, whether Porphyromonas gingivalis and the gingipains reach the CNS via axonal transport and whether they are also co-transported with APP is currently unclear.
Detection of Porphyromonas gingivalis and gingipains in the brain
Experimental disruption of the trigeminal nerve led to age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in a mouse model of AD (SAMP8 mice) , suggesting that the integrity of the trigeminal nerve, which may be impaired by oral infections, is crucial for these brain functions. Oral infection of ApoE knockout mice with Porphyromonas gingivalis led to sustained brain infections and activation of the complement pathway . In transgenic mice over-expressing a mutated form of the human APP, oral infection with Porphyromonas gingivalis impaired the cognitive function and increased the buildup of AD-like deposits together with alveolar bone loss compared to non-infected mice . Porphyromonas gingivalis, the key stone bacterium of PD, was recently detected in the brains of AD patients for the first time post mortem  and Porphyromonas gingivalis gingipains and LPS have also been detected in human AD brains [6, 33]. One of the first brain regions to be damaged in AD is the hippocampus. The study by Dominy et al. could demonstrate gingipain RgpB in neurons of the dentate gyrus and CA3, CA2, and CA1 of the hippocampus . In addition, RgpB co-localized primarily with neurons and astrocytes as well as with tau tangles, and intra-neuronal Aβ, but not with microglia, which was consistent with the proposed roles of Porphyromonas gingivalis in the pathogenesis of AD.
Implications for treatment of Alzheimer’s disease
To date, several classes of gingipain inhibitors have been described. These include inhibitors from natural sources, synthetic compounds, antibiotics, antiseptics, antibodies, and bacteria. Most known synthetic compounds are potent gingipain inhibitors but have undesirable side effects because they also inhibit a wide range of host proteases. Natural inhibitors include cranberry and rice extracts, which inhibit gingipain activity and prevent the growth and biofilm formation of periodontal pathogens. Meanwhile a small molecule gingipain inhibitor, COR388, has been developed, which was safe and well-tolerated in 2 Phase 1 trials. COR388 is currently tested in a larger phase 2/3 clinical trial (the GingipAIN Inhibitor for Treatment of Alzheimer’s Dis-ease trial, GAIN, ClinicalTrials.gov ID: NCT03823404) to evaluate whether this oral drug is safe and can slow or halt the progression of AD by blocking the neurotoxic activity of gingipains. The GAIN trial follows a randomized controlled design and is looking to enroll more than 500 participants with mild to moderate AD at more than 90 clinical trial centers in the United States and Europe.
The results reviewed here clearly support the notion that inflammation plays an important role in PD and AD. Figure 3 shows some of the basic mechanisms and the sequence of events that may be involved in the neurodegeneration induced by PD. The hypothesis that PD and Porphyromonas gingivalis are causally related to AD and its progression is highly attractive. On the other hand, gingipains were found also in healthy people and some people with AD did not have increased levels compared to these controls. People with AD reduce their oral hygiene and they tend to get leaky blood-brain barriers, which may increase their susceptibility to infections in their brains. Thus, it cannot be excluded that the brain infection is merely a by-product instead of a cause of the disease. The data from the mouse models may not be of much relevance for the situation in humans because Porphyro- monas gingivalis is a pathogen that infects humans and has evolved alongside the human immune system. Nevertheless, animal models are essential to generate new hypotheses, which can be tested, preferentially in randomized clinical trials, to see whether a new intervention benefits people suffering from AD. Since it is highly unlikely that a single type of bacteria is the only cause of a disease as complex as AD, we need a better understanding of the potential role of the whole oral microbiota as a cause of the disease, i.e. microbiome studies of human brains post mortem. Also important are state-of-the-art brain magnetic resonance imaging studies to demonstrate a potential impact of the oral microbiota on preclinical surrogate markers of AD, such as global brain volume, atrophy of subcortical structures, like the hippocampus, cerebral white matter disintegration, and graph-theoretical measures of topology of large-scale structural brain networks.
Since PD is preventable and treatable, subjects with PD should be informed and treated in order to lower the microbial challenge and to prevent the systemic inflammatory burden, thereby promoting a higher quality of life. The recent development of an oral gingipain inhibitor, which is currently tested in a randomized controlled trial, for the first time offers the opportunity to verify the infectious hypothesis of AD. If successful, this research can be expected to result in a significant improvement of prevention and treatment of PD and PD-related AD.
Ghazal Aarabi, Götz Thomalla, Guido Heydecke and Thomas Beikler are employed at and receive salaries from the University Medical Center Hamburg-Eppendorf, Carolin Walter and Carola Mayer and Udo Seedorf are employed at the University Medical Center Hamburg-Eppendorf and their salary is funded by third party funds.
Conflicts of interest
GA, CW, CM, TB, GH, and US declare no potential conflicts of interest, GT declares that he has received consulting fees from Acandis and Stryker, grants from Bayer, and lecture fees from Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb/Pfizer, Daiichi Sankyo, Portola, and Stryker.
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