Salivaomics: New Frontiers in Studying the Relationship Between Periodontal Disease and Alzheimer’s Disease
Abstract
1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Eligibility Criteria and PICO Framework and Research Question
- Population: Human subjects of any age diagnosed with Alzheimer’s disease (AD) or mild cognitive impairment (MCI), or cognitively healthy controls, with or without a diagnosis of periodontal disease (PD).
- Intervention/Exposure: Assessment of salivary metabolomic or microbiome profiles, including techniques such as LC-MS/MS, GC-MS, NMR, and 16S rRNA sequencing. Studies analyzing gingival crevicular fluid (GCF) were also considered if saliva was included.
- Comparison: Studies comparing subjects with AD versus healthy controls, or patients with periodontitis versus those without, or studies examining within-group correlations (e.g., between salivary markers and cognitive scores).
- Outcomes: Diagnostic or prognostic relevance of salivary biomarkers, correlation with clinical measures (e.g., MMSE, MoCA, periodontal indices), or characterization of oral microbial/metabolomic signatures in systemic disease contexts.
- Study Design: Observational studies including cross-sectional, case–control, and cohort designs, as well as randomized controlled trials (RCTs) where applicable.
- Language and Access: Published in English and available in full text.
- Were conducted using in vitro or animal models;
- Were narrative or systematic reviews, editorials, case reports, or conference abstracts lacking sufficient methodological detail;
- Did not include salivary (or GCF) analysis relevant to AD or PD;
- Focused exclusively on unrelated conditions without addressing oral–systemic interactions.
2.3. Data Extraction and Analysis
3. Results
3.1. Study Selection and Characteristics
3.2. Synthesis of Findings Across Studies
3.3. Risk of Bias Assessment
3.4. Summary of Findings, Evidence Certainty (GRADE), Publication Bias, Heterogeneity, and Meta-Analysis Considerations
3.4.1. GRADE Assessment
3.4.2. Publication Bias
3.4.3. Meta-Analysis
3.4.4. Heterogeneity
4. Discussion
5. Limitation
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Aβ | Amyloid beta |
AD | Alzheimer’s disease |
AUC | Area Under the Curve |
aMCI | Amnestic mild cognitive impairment |
BOP | Bleeding on probing |
CAL CHC | Clinical attachment level Cognitively healthy control |
DIABLO | Data Integration Analysis for Biomarker discovery using Latent cOmponents |
GCF | Gingival crevicular fluid |
IL-1 | Interleukin-1 |
IL-6 | Interleukin-6 |
LC-MS/MS | Liquid chromatography coupled to tandem mass spectrometry |
MoCA | Montreal Cognitive Assessment |
PD | Periodontal disease |
PgAgD | Agmatine deiminase from Porphyromonas gingivalis |
PI | Plaque index |
pTau181 | Phosphorylated Tau protein at threonine 181 |
rRNA | Ribosomal ribonucleic acid |
TNF-α | Tumor necrosis factor-alpha |
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Database | Search String | Number of Record Retrieved |
---|---|---|
Pubmed | (metabolome OR metabolite OR saliva OR salivome) AND (“Alzheimer disease” OR “periodontal disease”) | 41 |
Web of science | (metabolome OR metabolite OR saliva OR salivome) AND (“Alzheimer disease” OR “periodontal disease”) | 40 |
Scopus | (metabolome OR metabolite OR saliva OR salivome) AND (“Alzheimer disease” OR “periodontal disease”) | 158 |
References | Type of Study | N. of Patients | Aim of the Study | Outcomes |
---|---|---|---|---|
François et al. (2024) [95] | Cross-sectional, observational | 80 participants: 40 CHC, 20 MCI, 20 AD |
|
|
François et al. (2021) [96] | Observational, cross-sectional pilot study | 80 participants: 40 CHC, 20 with MCI, 20 with AD |
|
|
Issilbayeva et al. (2024) [97] | Case–control study | 135 participants: 64 with AD, 71 CHC |
|
|
Sansores-España et al. (2022) [98] | Clinical observational pilot study | 30 participants: CHC, periodontitis without AD, and periodontitis with AD |
|
|
Qiu et al. (2024) [33] | Cross-sectional, observational study | 96 participants: 32 CHC, 32 MCI, and 32 AD |
|
|
Guo et al., 2023 [28] | Observational (cross-sectional) study | 60 participants (33 with AD, 27 CHC) | To investigate oral microbiomes of Alzheimer’s disease patients and controls. | AD patients had an altered oral microbiome composition, with increased pathogenic bacteria (P. gingivalis, F. alocis) and reduced beneficial bacteria (R. mucilaginosa, C. matruchotii). Changes were more pronounced in subgingival plaque and seemed independent of oral hygiene status. |
Ide et al., 2016 [91] | Observational cohort (6 months) | 60 participants | To investigate the correlation between periodontitis and AD. | Periodontitis is associated with significantly faster cognitive decline and heightened systemic inflammation in AD patients. |
Na et al., 2024 [99] | Cross-sectional observational study | 43 participants (21 with AD + PD; 22 with PD only) | To investigate the influence between AD and periodontitis. | AD influences oral microbiota and may worsen periodontal condition. |
Hamdi et al., 2024 [100] | Observational, cross-sectional | 54 participants (27 AD patients, 27 CHC) | To investigate the dysregulation of Porphyromonas gingivalis agmatine deiminase (PgAgD) expression in Alzheimer’s disease and its correlation with periodontitis and cognitive decline. | Correlation between decreased PgAgD expression and lower Mini-Mental State Examination (MMSE) scores. |
Chen et al. (2024) [74] | Cross-sectional study | 165 older adults | To explore differences in subgingival microbiota composition and function across cognitive states. | Decreased microbial richness with cognitive decline; specific bacterial signatures associated with cognitive level. |
Yang et al. (2023) [3] | Observational case–control study | 79 participants (60 for saliva analysis) | To investigate the correlation between periodontal status and identify salivary metabolic biomarkers in AD. | AD linked with worse periodontal status; four salivary biomarkers identified. |
Study | Confounding | Selection of Participants | Classification of Interventions | Deviations from Intended Interventions | Missing Data | Measurement of Outcomes | Selection of Reported Results | Overall Risk |
---|---|---|---|---|---|---|---|---|
François et al. (2024) [95] | Moderate risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
François et al. (2021) [96] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Low risk |
Issilbayeva et al. (2024) [97] | Moderate risk | Moderate risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Sansores-España et al. (2022) [98] | Serious risk | Moderate risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | High risk |
Qiu et al. (2024) [33] | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Guo et al. (2023) [28] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Low risk |
Ide et al. (2016) [91] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Na et al. (2024) [99] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Hamdi et al. (2024) [100] | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Chen et al. (2024) [74] | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Yang et al. (2024) [3] | Moderate risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Key Finding | Inference/Implication |
---|---|
↓ Oral microbial diversity in AD ↑ P. gingivalis, F. alocis, ↑ Firmicutes | Oral dysbiosis is associated with cognitive decline and may precede clinical signs of Alzheimer’s Disease (AD) |
↑ Salivary metabolites (e.g., L-tyrosine, 3-chlorotyrosine, taurine, 3-hydroxybutyric acid) | Oral metabolic changes reflect oxidative stress and inflammation, potentially linked to neurodegenerative processes |
↑ Inflammatory cytokines (IL-1β, IL-6, TNF-α) in saliva and GCF | Local oral inflammation may contribute to systemic neuroinflammation, particularly in genetically susceptible individuals (e.g., ApoE-ε4 carriers) |
↓ Expression of beneficial microbial genes (e.g., PgAgD) | Microbial functional changes suggest an active role of the oral microbiome in AD pathophysiology |
Coexistence of AD and periodontitis = ↑ Inflammatory profile + ↑ Cognitive decline | Periodontal disease may be a modifiable risk factor for the progression of Alzheimer’s Disease |
Gradual microbial and metabolic changes from healthy aging → MCI → AD | Oral biofluids could serve as early biomarkers for the diagnosis and monitoring of cognitive decline |
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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Malcangi, G.; Marinelli, G.; Inchingolo, A.D.; Trilli, I.; Ferrante, L.; Casamassima, L.; Nardelli, P.; Inchingolo, F.; Palermo, A.; Inchingolo, A.M.; et al. Salivaomics: New Frontiers in Studying the Relationship Between Periodontal Disease and Alzheimer’s Disease. Metabolites 2025, 15, 389. https://doi.org/10.3390/metabo15060389
Malcangi G, Marinelli G, Inchingolo AD, Trilli I, Ferrante L, Casamassima L, Nardelli P, Inchingolo F, Palermo A, Inchingolo AM, et al. Salivaomics: New Frontiers in Studying the Relationship Between Periodontal Disease and Alzheimer’s Disease. Metabolites. 2025; 15(6):389. https://doi.org/10.3390/metabo15060389
Chicago/Turabian StyleMalcangi, Giuseppina, Grazia Marinelli, Alessio Danilo Inchingolo, Irma Trilli, Laura Ferrante, Lucia Casamassima, Paola Nardelli, Francesco Inchingolo, Andrea Palermo, Angelo Michele Inchingolo, and et al. 2025. "Salivaomics: New Frontiers in Studying the Relationship Between Periodontal Disease and Alzheimer’s Disease" Metabolites 15, no. 6: 389. https://doi.org/10.3390/metabo15060389
APA StyleMalcangi, G., Marinelli, G., Inchingolo, A. D., Trilli, I., Ferrante, L., Casamassima, L., Nardelli, P., Inchingolo, F., Palermo, A., Inchingolo, A. M., & Dipalma, G. (2025). Salivaomics: New Frontiers in Studying the Relationship Between Periodontal Disease and Alzheimer’s Disease. Metabolites, 15(6), 389. https://doi.org/10.3390/metabo15060389