Oral Microbiota in Patients with Alzheimer’s Disease: A Systematic Review
by
, , and
Sanne M. Pruntel
1,2,†
,
Lauren A. Leusenkamp
2,†,
Egija Zaura
3
,
Arjan Vissink
1
and
Anita Visser
2,4,*
1
Department of Oral and Maxillofacial Surgery, University Medical Center Groningen and University of Groningen, 9700 RB Groningen, The Netherlands
2
Department of Gerodontology, Center for Dentistry and Oral Hygiene, University Medical Center Groningen and University of Groningen, 9713 AV Groningen, The Netherlands
3
Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit Amsterdam, 1008 AA Amsterdam, The Netherlands
4
Department of Gerodontology, College of Dental Sciences, Radboud University Nijmegen Medical Center, 6525 EX Nijmegen, The Netherlands
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Appl. Sci. 2024, 14(19), 8869; https://doi.org/10.3390/app14198869
Submission received: 20 August 2024
/
Revised: 13 September 2024
/
Accepted: 24 September 2024
/
Published: 2 October 2024
(This article belongs to the Special Issue The Oral Microbiome in Periodontal Health and Disease)
Abstract
:Oral microorganisms have been found in the cerebral milieu, suggesting the involvement of oral microbiota in the onset and course of Alzheimer’s Disease (AD) through mechanisms such as amyloid-beta accumulation, tau phosphorylation and neuroinflammation. It is still uncertain whether and which oral bacteria are associated with AD. Therefore, the aim of this systematic review was to assess the current evidence for associations between oral microbiota and AD. A database search in Pubmed and Embase resulted in 623 hits. After removing duplicates, 437 papers remained. Of these, 13 papers passed the inclusion criteria and were included for quality/risk of bias assessment and data extraction. Analysis of these 13 studies revealed high heterogeneity in terms of sample size, age, study design and microbiological methods. Quality assessment using the MINORS criteria indicated reasonable to good quality across studies. As a result of the omission of two of the criteria, the quality results may have been biased. There is no conclusive evidence as to if and which oral microbiota are associated with AD since many conflicting results were reported. Although the overall quality of the studies was acceptable, the studies differed in study design and protocol. Further research is needed to clarify this association.
1. Introduction
Alzheimer’s disease (AD), an acquired progressive cognitive neuropathy, is the most common type of dementia [1]. AD affects memory, cognition and behavioral patterns in the daily life of patients, ultimately leading to dependency, comorbidities and mortality [1]. This neurodegenerative condition mostly affects individuals aged 65 years and older, with increasing incidence as people age [1].
AD usually starts with mild symptoms of cognitive impairment [2]. These symptoms become more and more pronounced when the disease progresses, ultimately ending in death [1]. In the early stages of AD, patients may recognize impairments in daily activities [3]. In the late stages, the primary concern shifts towards survival [4]. Currently, more than 55 million people have dementia worldwide [5,6]. AD is the most common cause of dementia, accounting for 50–75% of all cases [5]. Due to an aging society, this figure is projected to triple by 2050 [4,7].
AD is a complex disease, and its onset and course have not yet been untangled [8]. In the last decades, still no cure or definitive treatment has been developed, which means that AD, as it makes patients dependent on healthcare workers, adds to the increasing healthcare burden [7]. The increasing prevalence of AD, coupled with the absence of targeted therapeutic strategies, underscores the critical need to unravel the underlying causes of the disease [4,7,9]. Among the myriad factors under investigation as potential causes or contributors to AD, oral health has emerged as a compelling area of interest [4,7,9]. Conditions such as gingivitis, periodontitis, caries and fungal infections are not merely confined to the mouth but may also have systemic implications [7]. For instance, bacteria from the mouth can enter the bloodstream and gastrointestinal tract and spread throughout the body [10]. It has been shown that periodontitis is linked to several systemic conditions such as cardiovascular diseases, diabetes and, recently, neurodegenerative diseases [11,12].
There is indeed some evidence of intricate relationships between oral health and the pathogenesis of AD, with a focus on the potential role of the oral microbiota [12]. Oral microbiota has been found in the cerebral milieu, suggesting their involvement in the onset and course of AD through mechanisms such as amyloid-beta accumulation, tau phosphorylation and neuroinflammation [13]. Suggested pathways for oral microbiota to enter the brain are via the bloodstream and blood–brain barrier (periodontitis), the nervus olfactorius (nasopharynx) and the nervus vagus (brain–gut axis) [14,15]. The Understanding the gut–brain connection is crucial in the context of neurodegenerative diseases, as a similar mechanism may underlie the mouth–brain axis [14]. However, it remains unclear whether oral bacteria are indeed associated with the onset of AD.
This systematic review aimed to provide an overview of the associations between oral microbiota (oral microbiome) and AD.
2. Materials and Methods
This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews (PRISMA) guideline. The study protocol was registered in PROSPERO before the systematic literature search was conducted (registration number CRD42023447078) [16].
2.1. Information Sources and Search Strategy
A systematic literature search of two electronic databases (PubMed and EMBASE) was conducted (all: inception to 31 May 2024). The search strategy consisted of medical subject heading terms and free-text words (Figure 1). Overarching mesh terms were used not to restrict the search in any way. The initial search was performed on 31 January 2023, with the help of a biomedical literature specialist, and was updated on 31 May 2024. In addition, the reference lists of the included studies were screened for relevant studies. No language or period restrictions were applied.
2.2. Selection Process and Data Collection
Included studies were experimental and clinical studies that investigated the constituents of the oral microbiota in patients with AD. Excluded were review articles, case reports, letters to the editors and articles that only mentioned animal studies. References from PubMed and Embase were manually checked and imported into Mendeley Reference Manager, followed by merging the duplicates. Two independent reviewers (S.P. and L.L.) screened the titles and abstracts, selecting eligible studies on the subject according to inclusion and exclusion criteria. The inclusion criteria required studies on oral microbiota and AD. If the title and abstract provided limited information or there was any doubt, the study was also moved to the next round (full-text assessment). A discussion between the two reviewers (S.P. and L.L.) took place to reach a consensus in case of discrepancies in the selected articles. If needed, a third reviewer was involved (An.V). The full texts of articles retained after the title and abstract screening were assessed independently according to the eligibility criteria by the same reviewers. Studies without results (trial design, review articles and a letter to the editor), case reports and studies that did not focus on AD or oral microbiota and animal studies were excluded.
2.3. Quality Assessment
This systematic review used the Methodological Index for Non-Randomized Studies (MINORS) criteria as an assessment tool to evaluate the quality of the studies (Supplementary Table S1) [17]. The application of MINORS ensured a rigorous appraisal of study quality and helped identify potential sources of bias. By employing these criteria, the review enhanced the validity of its conclusions and provided valuable insights based on reliable evidence. Each item was scored as follows: 0 (not reported), 1 (reported but inadequate) or 2 (reported and adequate). The articles were divided into two groups: non-comparative studies (e.g., longitudinal and prospective studies) and comparative studies (e.g., case-control studies). Each group had an adapted ‘ideal score’ due to some subjects that could not be scored (Table 1: items 6 to 12 for non-comparative studies and items 6 and 7 for comparative studies). The ideal scores were 10 for non-comparative studies and 20 for comparative studies. The quality of the included articles was indicated in the following colors: poor—red, medium—orange and good—green. For comparative studies, with a maximum of 10 points, poor quality studies were those which received 0–3 points, medium quality—4–7 points and good quality—8–10 points. For non-comparative studies, with a maximum of 20 points, poor quality studies received 0–6 points, medium quality—7–14 points and good quality—15–20 points.
2.4. Oral Assessment
The oral health of the participants in the included studies was assessed using a comprehensive evaluation. This evaluation included the following parameters:
- Number of teeth: the total number of teeth present in each participant’s mouth was recorded.
- Periodontal status: periodontal health was assessed by examining the presence of periodontal pockets and measuring their depth. The presence of gingival bleeding on probing, an indicator of gingival inflammation, was also measured.
- Smoking status: participants were asked about their smoking habits, and this information was categorized as current smoker, former smoker or non-smoker.
3. Results
3.1. Search Result
The database search resulted in 623 hits (Figure 1). After removing duplicates, 437 papers remained. After the title and abstract screening, 45 articles seemed to be relevant, of which 32 had to be excluded after full-text reading according to the inclusion and exclusion criteria (Figure 1). Hence, 13 studies were included for quality/risk of bias assessment and data extraction. Involvement of the third reviewer was not necessary.
3.2. Quality
The quality assessment, conducted using the MINORS criteria (Supplementary Table S1), categorized the included articles into three groups: good quality, medium quality or poor quality, indicated by the color (green, orange and red). After careful consideration of the MINORS criteria, with specific factors related to the oral health of the patients added (Table 1), six articles were deemed ‘good quality’, five ‘medium quality’, and two were labeled ‘poor quality’.
3.3. Study Characteristics
Of the thirteen included papers, two were characterized as non-comparative studies, describing different aspects related to the oral microbiota in patients with AD, and eleven were classified as comparative studies. As shown in Table 2, there was considerable clinical heterogeneity in sample size, age and study methods. Most of the microbiological data were obtained via an open-ended method using 16S rRNA gene amplicon sequencing (ten articles), while three articles used a qPCR technique targeting selected oral taxa.
The number of included patients in the studies varied from 20 to 195, with a total of 1016 participants (427 patients diagnosed with AD and 589 patients with Mild Cognitive Impairment (MCI) or Subjective Cognitive Decline (SCD) or healthy controls). The reported age varied among the studies. The mean age of the AD group was 74.0 years, while the control group had a mean age of 69.8.
3.4. Oral Health Assessment
In the analysis of the selected studies, it was observed that five studies did not include any oral health assessments. Of the eight studies that included an oral health assessment, seven included only partial assessments, and one included a comprehensive oral health assessment. Besides clinical oral assessments, one study also examined the frequency of tooth brushing, dental visits and the educational level of the participants [20].
3.5. Alpha Diversity
Alpha diversity characterizes the structural aspects of an ecological community by quantifying either the richness (number of taxa) or the distribution of abundance among different taxa. Of the thirteen studies, six assessed alpha diversity. Two of these studies consistently showed a significant decrease in the diversity of salivary microbiota in AD patients compared to controls [21,22]. However, the studies by Qui et al. [23] and Holmer et al. [24] found no significant differences in the alpha diversity of oral microbiota between cognitively normal individuals and AD patients. Conversely, Cirstea et al. [25] and Issilbayeva et al. [26] observed increased alpha diversity in the oral microbiota of AD patients compared to healthy controls.
3.6. Beta Diversity
Beta diversity comprises the composition of the oral microbial community in patients. Several studies found significant differences in the taxa observed in AD patients compared to controls (Table 3). Shuttleworthia was found at a higher relative abundance in AD patients in two studies [22,26], as were Firmicutes in the studies by Wu et al. [22] and Guo et al. [27]. Additionally, Holmer et al. [24] and Moghadam et al. [28] reported increased levels of Prevotella intermedia. Two studies found Actinomycetales [24,25] at a lower relative abundance in AD patients compared to controls, while Fusobacteria were lower in both studies by Wu et al. [22] and Guo et al. [27]. Furthermore, three studies demonstrated a lower abundance of Rothia dentocariosa [20,21,24], and two studies reported a lower abundance of Haemophilus parainfluenzae in AD patients compared to controls [26,27]. Inconsistencies in observed differences in taxa were also found. For example, Streptococcus was higher in AD patients in the study by Wu et al. [22] but lower in Cirstea et al. [25]. Similarly, F. nucleatum was higher in AD patients in Panzarella et al. [29] and Moghadam et al. [28] but lower in Guo et al. [27]. Finally, P. gingivalis was significantly higher in three studies [24,25,28] and lower in one study [30]. In three studies, no significant differences in bacterial taxa were found in AD patients compared to controls [18,19,23].
4. Discussion
This systematic review aimed to provide an overview of the current scientific knowledge on the associations between oral microbiota and AD. In summary, it can be stated that there is considerable heterogeneity among the studies in terms of sample size, age distribution and study design. This variability highlights the challenges of studying the oral microbiota in AD and emphasizes the importance of robust methodologies to draw meaningful conclusions. In addition, the quality of the included studies was mostly assessed as reasonable to good according to the MINORS criteria, which undermines confidence in the reliability of their findings. Although the table suggests that the quality of the studies is reasonable to good, this impression is influenced by modifications to the MINORS criteria. Specifically, items 6 and 7 were excluded from the scoring, leading to an overestimation of the overall quality of the articles.
In the literature, a review on a similar topic was published in 2021 [31]. However, despite what the title suggests, that study did not focus only on the oral microbiota but also examined cytokines, antibodies and other factors [31]. Furthermore, only four of the articles included in this review were discussed in the previous article. In this present review, we only focused on the oral microbiota of patients with AD, preferably compared to healthy controls, and it includes 11 new articles published in the years after the publication of Maitre et al. [31].
4.1. Oral Microbiota
Key findings regarding α-diversity were contradictory and therefore inconclusive: two studies found higher α-diversity, two—no difference and two—lower alpha diversity in the salivary microbiota of AD patients compared to healthy controls. The studies that did not demonstrate differences in alpha diversity between AD patients and controls likely reflect the exploratory and descriptive nature of their research, as these studies lacked sufficient power to detect a difference [23,24]. The sequencing methods used in this review varied, with ten studies analyzing the whole microbiome and three studies focusing on specific species, which is the equivalent of ‘finding only what you are looking for’ and may lead to an underestimation of the differences. The use of targeted methods may have resulted in the omission of oral microbiota, which could be influential or significant. This makes it difficult to effectively compare the results of these studies. Different sampling methods may also influence the results, as different sites in the oral cavity harbor different microbiota. If sample sites were the same, it would be easier to draw conclusions about differences between the groups. In this review, some articles only analyzed the saliva of the included patients, and there are studies that assessed supra- or subgingival dental plaque, buccal or tongue mucosal swabs instead of or besides saliva. It is of great importance to know the oral health of the included patients, as the dynamic (im)balance of the oral microbiota is strongly influenced by lifestyle and diet [32,33]. Finally, not all the included articles mentioned the oral health status of their patients. Without knowing which important confounders, such as the number of remaining teeth or periodontal status, are influencing the data, it is difficult to conclude that the results regarding the oral microbiota are unbiased.
4.2. Oral Health Assessment
The importance of oral health assessment lies in its ability to promote early detection, prevent systemic complications, educate patients and provide an overview of an individual’s health [34,35,36]. Regular assessment is essential for maintaining optimal oral and general health [34,35,36]. It is, therefore, important that oral health is assessed in routine clinical practice and that oral health is reported and discussed in the literature to enable comparison of the effects of oral health assessment.
However, only one study examined the brushing habits and dental visits of the patients, making it challenging to compare the studies, as there was no valid basis for comparison. Similarly, 12 out of the 13 studies either did not conduct or conducted incomplete oral health assessments, further complicating comparisons. Many articles also lacked general important aspects of oral health, such as the number of teeth. Additionally, not all studies considered diet and lifestyle factors that influence the microbiota, nor did they account for antibiotic use in the past six months. The lack of oral health and oral hygiene status may have contributed to the contradictory findings in alpha and beta diversity among the included studies.
4.3. Strengths and Limitations
The quality of the included studies, as described in the MINORS qualification, was mostly reasonable to good [17]. As a result of the omission of two of the criteria, the quality results may have been overestimated. Limitations of this systematic review were that the studies differed in study design (cross-sectional and prospective) and study protocol, e.g., the lack of oral health assessment and differences in microbiological methods. Furthermore, in most studies, it remained unclear whether patients, for example, engaged in smoking or were using antibiotics—both known to affect oral microbial composition [22,23,27,30]. This could potentially explain the contradictory findings of our study. Also, not all articles compared the included patients with healthy controls [18,19]. In addition, the average age within the AD groups was often higher than that of the control groups, and in the majority of studies, the control group consisted of fewer people (Table 2) or even had better oral health [24]. In some studies, the control group also had a higher BMI and a different smoking status compared to the AD group, so it is not clear what is being compared [24,25,26].
5. Conclusions
There is yet no conclusive evidence regarding whether and which oral microbiota are associated with AD since many conflicting results have been reported. Although the overall quality of the studies was acceptable, the studies differed in study design (cross-sectional and prospective) and study protocols. These papers showed a large variation in alpha diversity, the oral health assessments were incomplete and the microbiological methods varied. There is a need for further studies on the well-recorded oral health and oral hygiene status of the study participants.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/app14198869/s1, Table S1. Explanation of the Methodological Index for Non-Randomized Studies (MINORS) criteria. Scores are assigned as follows: 0 if not reported, 1 if reported but inadequate, and 2 if reported and adequate. The criteria are adapted from Slim et al. [17].
Author Contributions
All listed authors (S.M.P., L.A.L., E.Z., A.V. (Arjan Vissink) and A.V. (Anita Visser)) have made substantial contributions to (1) the conception or design of the work or the acquisition, analysis or interpretation of data for the work; (2) drafting the work or revising it critically for important intellectual content; (3) giving final approval of the version to be published; and (4) agreeing to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.
Funding
Funding was provided by Orange Health.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
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Figure 1.
Flow diagram of the study process and article selection.
Table 1.
Methodological index for non-randomized studies (MINORS) score (0 if not reported; 1 when reported but inadequate; and 2 when reported and adequate). * The maximum score is 10 for non-comparative studies (0–3: poor quality (red), 4–7: medium quality (orange) and 8–10: good quality (green)) and 20 for comparative studies (0–6: poor quality (red), 7–14: medium quality (orange) and 15–20: good quality (green). Non-comparative studies, c.g., longitudinal and prospective studies, and comparative studies, c.g., case-control studies.
Table 1.
Methodological index for non-randomized studies (MINORS) score (0 if not reported; 1 when reported but inadequate; and 2 when reported and adequate). * The maximum score is 10 for non-comparative studies (0–3: poor quality (red), 4–7: medium quality (orange) and 8–10: good quality (green)) and 20 for comparative studies (0–6: poor quality (red), 7–14: medium quality (orange) and 15–20: good quality (green). Non-comparative studies, c.g., longitudinal and prospective studies, and comparative studies, c.g., case-control studies.
| References | 1. Clearly Stated Aim | 2. Inclusion of Consecutive Patients | 3. Prospective Data Collection | 4. Endpoints Appropriate to Study Aim | 5. Unbiased Assessment of Endpoints | 6. Follow-Up Appropriate to Study Aim | 7. <5% Lost to Follow-Up | 8. Prospective Calculation of Study Size | 9. Adequate Control Group | 10. Contemporary Groups | 11. Baseline Equivalence of Groups | 12. Adequate Statistical Analyses | Total * |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Non-comparative studies | |||||||||||||
| Leblhuber et al. [18] | 0 | 0 | 0 | 1 | 0 | NA | NA | NA | NA | NA | NA | NA | 1 |
| Chen et al. [19] | 1 | 2 | 1 | 2 | 2 | NA | NA | NA | NA | NA | NA | NA | 8 |
| Comparative studies | |||||||||||||
| Fu et al. [20] | 2 | 2 | 2 | 2 | 0 | NA | NA | 1 | 2 | 2 | 1 | 2 | 16 |
| Liu et al. [21] | 2 | 2 | 2 | 2 | 0 | NA | NA | 0 | 0 | 2 | 0 | 1 | 11 |
| Wu et al. [22] | 2 | 2 | 2 | 2 | 0 | NA | NA | 0 | 0 | 2 | 0 | 2 | 12 |
| Qiu et al. [23] | 2 | 2 | 2 | 2 | 0 | NA | NA | 0 | 2 | 2 | 1 | 2 | 15 |
| Holmer et al. [24] | 2 | 2 | 2 | 2 | 0 | NA | NA | 0 | 2 | 2 | 1 | 2 | 15 |
| Cirstea et al. [25] | 2 | 2 | 2 | 2 | 0 | NA | NA | 0 | 2 | 2 | 0 | 2 | 14 |
| Issilbayeva et al. [26] | 1 | 2 | 2 | 2 | 0 | NA | NA | 0 | 2 | 2 | 0 | 2 | 13 |
| Guo et al. [27] | 0 | 2 | 2 | 2 | 0 | NA | NA | 0 | 2 | 2 | 2 | 2 | 14 |
| Moghadam et al. [28] | 2 | 2 | 2 | 2 | 0 | NA | NA | 0 | 2 | 2 | 1 | 2 | 15 |
| Panzarella et al. [29] | 2 | 2 | 2 | 2 | 0 | NA | NA | 0 | 2 | 2 | 1 | 2 | 15 |
| Bathini et al. [30] | 1 | 0 | 2 | 2 | 0 | NA | NA | 0 | 0 | 0 | 0 | 0 | 5 |
Table 2.
Characteristics of the included studies.
| Reference | Study Design | Type of Subjects | Microbiological Method | Main Findings (Microbiota Related to AD) | MINORS * | Limitations |
|---|---|---|---|---|---|---|
| Non-comparative studies | ||||||
| Leblhuber et al., 2020 [18] | Prospective | AD (N = 20): 78.1 ± 2.2 y.o. Non-smokers Austria Gingival Crevicular Fluid and paperpoints | Detection (>104 cells) of Treponema denticola, Tannerella forsythia, Porphyromonas gingivalis, Prevotella intermedia and Aggregatibacter actinomycetemcomitans (PerioPOC®) | A significant association between the salivary presence of P. gingivalis and lower MMSE. | 1 | No oral health status assessed. No cognitively healthy control group included. No assessment in time. |
| Chen et al., 2022 [19] | Longitudinal | AD (N = 66): 82.85 ± 6.00 y.o. divided into Intervention (N = 33) 82.70 ± 6.03 and Control (N = 33) group 83.00 ± 6.04 y.o. Intervention: oral health intervention for 24 weeks Non-smokers China Kayser-Jones Brief Oral Health Examination (BOHSE) Subgingival plaque samples by paperpoints | V3-V4 region of 16S rRNA gene amplicon sequencing (Illumina MiSeq) | The intervention group had a higher proportion of the relative abundance of Alphaproteobacteria, Betaproteobacteria and Flavobacteria compared to the control group, while Actinobacteria, Spirochaete and Synergistes were lower in the intervention group. | 8 | No cognitively healthy control group included.Oral microbiota affected by oral health intervention. |
| Comparative studies | ||||||
| Fu et al., 2022 [20] | Cross-sectional | AD (N = 20): 74.65 ± 1.75 y.o. Controls (N = 20): 73.00 ± 1.71 y.o. Smoking 5% of AD 5% of Controls Taiwan Periodontal status, plaque index, nr of teeth Unstimulated saliva | Amplicon sequencing of V3-V4 region of 16S rRNA gene (Illumina MiSeq) | The relative abundance of Capnocytophaga, Eubacterium infirmum, Prevotella buccae and Selenomonas artemidis were significantly in- creased in the AD group. The relative abundance of Streptococcus mutans and Rothia dentocariosa—significantly lower in AD group. | 16 | The control group exhibited more frequent toothbrushing (p = 0.006), dental visits (p < 0.001) and higher education level (p = 0.027) than the AD patients. |
| Liu et al., 2019 [21] | Cross-sectional | AD (N = 39): 64.28 ± 9.28 y.o. Healthy controls (N = 39): 63.90 ± 9.36 y.o. Non-smokers China 2 mL of unstimulated saliva | Amplicon sequencing of V3-V4 region of 16S rRNA gene (Illumina Hiseq2500) | Significantly lower alpha diversity in AD vs. controls. In AD: Moraxella catarrhalis (high), Leptotrichia buccalis (high) and Sphaerochaeta multiformis (high) In controls: Rothia dentocariosa (high) | 11 | No oral health assessment. |
| Wu et al., 2021 [22] | Cross-sectional | AD (N = 17): 77.9 ± 10.5 y.o. Controls (N = 18): 65.2 ± 24.6 y.o. Taiwan Decayed, Missing, and Filled Teeth and dental plaque weight Pooled supra-gingival plaque from all buccal and lingual/palatal surfaces of all teeth. By periodontal curettes | Amplicon sequencing of full 16S rRNA gene (PacBio, SMRT) | AD patients had significantly lower alpha diversity than healthy controls. The proportion of Lactobacillales, Streptococcaceae and the Firmicutes/Bacteroidetes ratios were significantly higher, whereas Fusobacterium and Proteobacteria were significantly lower in patients with AD compared to the controls. | 12 | The number of missing teeth and dental plaque weight significantly higher in AD group. No mention of the smoking status of the patients. |
| Qiu et al., 2024 [23] | Cross-sectional | AD (N = 32): 76.03 ± 8.23 y.o. Amnestic mild cognitive impairment (aMCI) (N = 32): 72.31 ± 8.07 y.o. Cognitively normal people (N = 32): 65.75 ± 6.33 y.o. China Functional tooth number of ≥6, periodontal probing depth (PPD), clinical attachment level (CAL), percentage of CAL > 3 mm, gingival index, plaque index and percentage of bleeding on probing. Subgingival plaque and gingival crevicular fluid samples were obtained from Ramfjord index teeth ** and teeth with moderate and deep periodontal pockets (PPD > 3 mm). Sterile paper points into the gingival sulcus or periodontal pockets. | Amplicon sequencing of full 16S rRNA gene (PacBio and SMRT) | Veillonella parvula, Lancefieldella parvula, Prevotella melaninogenica, Megasphaera micronuciformis, Anaeroglobus geminatus, Streptococcus anginosus, Campylobacter gracilis and Dialister pneumosintes were negatively correlated with cognitive function. (Eubacterium) yurii, Pseudoleptotrichia goodfellowii, Campylobacter rectus, Leptotrichia buccalis, Streptococcus sanguinis, Actinomyces massiliensis, Haemophilus parainfluenzae and Campylobacter concisus were positively correlated with cognitive function. None of them were significant. | 15 | No mention of the smoking status of the patients. Controls significantly younger. In AD group: significantly lower nr of teeth, higher PPD, CAL, CAL > 3 mm, PLI and BOP |
| Holmer et al., 2021 [24] | Cross-sectional | AD (N = 46): 71 y.o. Controls (N = 63): 69 y.o. Mild cognitive impairment (MCI) (N = 40): 70 y.o. Subjective cognitive decline (SCD) (N = 46): 61 y.o. Current smoking AD: 8.7% Previous smoking AD: 47.8% Current smoking Controls: 7.9% Previous smoking Controls: 44.4% Sweden Nr of teeth, periodontal status Subgingival microbial sampling | Amplicon sequencing of V3-V4 region of 16S rRNA gene (Illumina MiSeq) | Alpha diversity: higher in males and individuals with PPD ≥ 6 mm; Significantly higher alpha diversity in MCI group; Actinomyces and Rothia were more common among controls with healthier periodontal status than in the diagnostic subgroup of AD with poorer periodontal status; In AD, higher abundance of Slackia exigua and Lachospiraceae [G-7]. | 15 | Control group had significantly higher BMI, AD group had significantly more sites with periodontal pocket depth (PPD) ≥ 6 and higher bleeding on probing (BoP). |
| Cirstea et al., 2022 [25] | Cross-sectional | AD (N = 45): 74 (65–78) y.o. Controls (N = 54): 70 (66–74) y.o. Ever smoker AD: 42.2% Ever smoker Control: 46.3% Current smoker AD: 2.2% Current smoker Control: 7.4% Canada Sampling via bilateral swabbing the oral mucosa over the opening of the ductus of parotis salivary gland and below the tongue using a cotton swab | Amplicon sequencing of V4 region of 16S rRNA gene (Illumina MiSeq) | Alpha-diversity: higher in the AD. A higher relative abundance of Weeksellaceae in AD; A lower abundance of Streptococcaceae and Actinomycetaceae in AD; Porphyromonas gingivalis—5 times more prevalent among patients with AD. | 14 | No oral health status assessed. No mention of the number of teeth in both groups. |
| Issilbayeva et al., 2024 [26] | Cross-sectional | AD (N = 64): 68 (63–74) y.o. Controls (N = 71): 67 (61–72) y.o. Kazakhstan History of smoking AD: 20.3% History of smoking Controls: 14.1% Bone loss, bleeding on probing (BoP), periodontal probing depth (PPD), clinical loss of attachment, gingival recession and number of remaining teeth were indicated. Unstimulated saliva, supragingival and subgingival plaque, tongue dorsum, hard palate, buccal mucosa, keratinized gingiva, palatine tonsils and throat | Amplicon sequencing V3-V4 region of 16S rRNA gene (Illumina NovaSeq 6000) | Alpha-diversity and Beta-diversity were higher in the AD group. Four species were significantly decreased in the AD group: Haemophilus parainfluenza, Prevotella melaninogenica, Prevotella histicola and Actinomyces oris. Enrichment in the AD group and the leading prediction features are Bacteroides, Methylobacterium-methylorubrum, Anaerostipes, Shuttleworthia and Lactobacillus. | 13 | No mention of the smoking status of the patients. Unclear data from which sample type is presented in the results. |
| Guo et al., 2021 [27] | Cross-sectional | AD (N = 26): 71.96 ± 7.92 y.o. Control (N = 26): 70.04 ± 6.44 y.o. China Number of teeth > 7 Periodontal status Citric-acid stimulated saliva; Gingival crevicular fluid of four teeth with the deepest pocket by sterile paperpoints. | Full-length 16S rRNA gene amplicon sequencing (SMRTbell and PacBio) | In saliva: A significantly higher relative abundance of Firmicutes and Deinococcus-Thermus, and a significantly lower relative abundance of Fusobacteria and Proteobacteria in AD patients. At the species level, Veillonella parvula, Prevotella denticola and Lactobacillus salivarius enriched in the AD group. Aggregatibacter aphrophilus, Haemophilus parainfluenzae, Haemophilus haemolyticus and Cardiobacterium valvarum—lower in the AD group. In CGF, a positive correlation between AD and Veillonella parvula. | 14 | No mention of the smoking status of the patients. |
| Moghadam et al., 2022 [28] | Cross-sectional | AD (N = 15): 69.47 ± 6.88 y.o. Healthy controls (N = 15): 64.33 ± 3.73 y.o. Smokers, non-smokers and ex-smokers Iran Sampled from mucosa, teeth, supra- and sub-gingival spaces, tongue and keratinized gingiva using sterile paper points. | qPCR of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Prevotella intermedia and Streptococcus mutans | Significantly higher amount of P. gingivalis F. nucleatum and P. intermedia in AD group | 15 | No oral health assessment. Significant difference between the control and AD groups: AD older, higher frequency of hypertension, diabetes, hyperlipidemia and lower education level |
| Panzarella et al., 2022 [29] | Cross-sectional | AD (N = 20): 83.5 ± 7.7 y.o. Amnestic mild cognitive impairment (aMCI) (N = 20): 78.0 ± 9.5 y.o. Controls (CONS) (N = 20): 78.8 ± 8.1 y.o. Smoking: 20% in controls and 0% in AD Italy Oral health assessment Subgingival plaque samples | Quantitative determination of Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola and Tannerella forsythia via RT-PCR analysis (Carpegen® Perio Diagnostics kit) | F. nucleatum was higher in the AD group compared to the control group. T. denticola was higher in the MCI group compared to the AD group. | 15 | The number of smokers different in each group. Significantly higher DMFT in AD group Significantly higher M (missing teeth) in AD group |
| Bathini et al., 2020 [30] | Cross-sectional | AD (N = 17): 71.1 ± 6.6 y.o. Cognitive Normal Healthy Controls—CNh (N = 27): 67.0 ± 9.2 y.o. Switzerland 2 mL of unstimulated saliva | Amplicon sequencing of V3-V4 region of 16S rRNA gene (Illumina MiSeq) | Prevotella tannerae (low), Filifactor villosus (low), P. gingivalis (low) and Cardiobacterium valvarum (high) are significantly different in AD as compared to CNh. Filifactor villosus and P. tannerae—the best differentiators in patients with AD | 5 | No oral health status assessed. No mention of the number of teeth in both groups. No mention of the smoking status of the patients. |
* Green: good quality, orange: medium quality and red: poor quality. ** Ramfjord index teeth: the maxillary right and mandibular left first molars, maxillary left and mandibular right first premolars, and maxillary left and mandibular right central incisors. y.o—years old, AD—Alzheimer Disease, MMSE—Mini Mental State Examination, PPD—Periodontal pocket depth, BoP—Bleeding on probing, CAL—Clinical attachment level, DMFT—Decayed, missing, and filled teeth, PLI—Plaque Index.
Table 3.
Taxa in the AD group. Significant differences compared to the control group (p < 0.05). p: Phylum, c: Class, o: Order, f: Family, g: Genus, s: Species.
Table 3.
Taxa in the AD group. Significant differences compared to the control group (p < 0.05). p: Phylum, c: Class, o: Order, f: Family, g: Genus, s: Species.
| Taxa in the AD Group | Higher Relative Abundance | Lower Relative Abundance |
|---|---|---|
| Firmicutes (p) | [22,27] | |
| Bacteriodetes (p) | [22] | |
| Proteobacteria (p) | [27] | |
| Fusobacteria (c) | [22,27] | |
| Lactobacillales (o) | [22] | |
| Actinomycetales (o) | [24,25] | |
| Cardiobacteriales (o) | [22] | |
| Porphyromonadaceae (f) | [22] | |
| Streptococcaceae (f) | [22] | [25] |
| Lachnosporaceae (f) | [24] | |
| Weeksellaceae (f) | [25] | |
| Bacteriodes (g) | [26] | |
| Streptococcus (g) | [22] | |
| Deinococcus-Thermus (g) | [27] | |
| Lactobacillus (g) | [26] | |
| Shuttleworthia (g) | [22,26] | |
| Moraxella (g) | [21] | |
| Leptotrichia (g) | [30] | |
| Methylobacterium-methylorubrum (g) | [26] | |
| Anaerostipes (g) | [26] | |
| Actinomyces oris (s) | [26] | |
| Corynebacterium durum (s) | [24] | |
| Prevotella oulorum (s) | [24] | |
| Prevotella denticola (s) | [27] | |
| Prevotella tannerae (s) | [30] | |
| Prevotella melaninogenica (s) | [26] | |
| Prevotella histicola (s) | [26] | |
| Prevotella intermedia (s) | [24,28] | |
| Slackia exigua (s) | [24] | |
| Porphyromonas gingivalis (s) | [24,25,28] | [30] |
| Fusobacterium nucleatum (s) | [28,29] | [27] |
| Filifactor alocis (s) | [30] | |
| Filifactor villosus (s) | [30] | |
| Streptococcus mutans (s) | [20] | |
| Treponema denticola (s) | [29] (MCI > AD) | |
| Eubacterium infirmum (s) | [20] | |
| Prevotella buccae (s) | [20] | |
| Selenomonas artemidis (s) | [20] | |
| Rothia dentocariosa (s) | [20,21,24] | |
| Veillonella parvula (s) | [27] | |
| Haemophilus parainfluenzae (s) | [26,27] | |
| Aggregatibacter aphrophilus (s) | [27] | |
| Porphyromonas endodontalis (s) | [27] | |
| Lactobacillus salivarius (s) | [27] | |
| Streptococcus aginosus (s) | [27] | |
| Bifidobacterium dentium (s) | [27] | |
| Atopobium parvulum (s) | [27] | |
| Cardiobacterium valvarum (s) | [30] | [27] |
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Pruntel, S.M.; Leusenkamp, L.A.; Zaura, E.; Vissink, A.; Visser, A. Oral Microbiota in Patients with Alzheimer’s Disease: A Systematic Review. Appl. Sci. 2024, 14, 8869. https://doi.org/10.3390/app14198869
AMA Style
Pruntel SM, Leusenkamp LA, Zaura E, Vissink A, Visser A. Oral Microbiota in Patients with Alzheimer’s Disease: A Systematic Review. Applied Sciences. 2024; 14(19):8869. https://doi.org/10.3390/app14198869
Chicago/Turabian StylePruntel, Sanne M., Lauren A. Leusenkamp, Egija Zaura, Arjan Vissink, and Anita Visser. 2024. "Oral Microbiota in Patients with Alzheimer’s Disease: A Systematic Review" Applied Sciences 14, no. 19: 8869. https://doi.org/10.3390/app14198869
APA StylePruntel, S. M., Leusenkamp, L. A., Zaura, E., Vissink, A., & Visser, A. (2024). Oral Microbiota in Patients with Alzheimer’s Disease: A Systematic Review. Applied Sciences, 14(19), 8869. https://doi.org/10.3390/app14198869
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