Oral diseases as emerging risk factors for Alzheimer’s disease: A scoping review

Abstract

This scoping review examined current evidence on the relationship between oral diseases and Alzheimer’s disease (AD). Systematic searches were conducted in PubMed, Scopus, Web of Science, Google Scholar, and KMbase for studies published from 1990 to December 2024, using terms of Alzheimer’s disease, dementia, oral health, periodontal disease, dental caries, and tooth loss. Human and validated animal studies investigating microbiological, immunological, inflammatory, genetic, or functional links between oral health and AD were included. Of 1328 records, 841 remained after duplicates were removed, and 98 were reviewed in full; 45 met inclusion criteria. Findings were organized into four themes: general associations; periodontal disease and AD, including inflammation, amyloid-β pathways, and APOE4-related susceptibility; dental caries; and tooth loss with prosthetic rehabilitation. Evidence indicates that chronic oral diseases, especially periodontitis and tooth loss, are associated with increased risk of AD and its progression through mechanisms involving systemic inflammation, microbial translocation, amyloidogenic processes, genetic predisposition, and impaired masticatory function. Appropriate prosthetic rehabilitation may help reduce dementia risk by restoring chewing function and supporting nutrition. While causality has yet to be established, maintaining oral health throughout life may be a practical, cost-effective component of strategies to promote cognitive health in older adults.

1. Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most prevalent cause of dementia, affecting over 57 million older adults worldwide [1]. With a rapidly aging population, the global burden of AD is expected to escalate significantly in the coming decades, posing major challenges to public health and healthcare systems [2] While the precise etiology of AD remains incompletely understood, it is recognized that the pathogenesis of AD is complex and multifactorial, encompassing interactions between genetic predisposition, environmental exposures, vascular risk factors, and chronic systemic inflammation [3], [4], [5], [6].

Among the emerging modifiable risk factors, oral diseases have recently attracted attention as potential contributors to AD development [7], [8], [9]. Poor oral health is frequently observed in individuals with AD [10], [11], a phenomenon often attributed to the decline in cognitive function that limits personal oral hygiene and dental care access [5], [9]. Moreover, difficulties in communication, reduced functional capacity, and behavioral changes may further hinder the maintenance of oral health in dementia patients [9], [12]. However, recent epidemiological studies suggest a bidirectional relationship, where not only does cognitive impairment lead to poor oral health but deteriorating oral conditions may also increase the risk and prevalence of AD [5], [13]. And, a significant association has been reported between tooth loss and AD, independent of age and educational level [14], [15], [16], [17], [18]. These findings have led to the hypothesis that chronic oral infections and their systemic consequences may play a role in the early stages of neurodegeneration.

Oral diseases and AD are both associated with systemic inflammation. Inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF- α) are elevated in both oral diseases and neurodegenerative disorders [19], [20], [21]. Recent studies reported changes in the oral microbiome composition in AD patients, suggesting that specific microbial shifts may influence brain health via immune, metabolic, or neural pathways [18], [22].

Despite growing interest in the oral-systemic health connection, the current evidence base remains fragmented across disciplines and methodologies. Therefore, a scoping review is appropriate to comprehensively analyze the existing literature, clarify the biological and clinical basis of the association to guide future interdisciplinary research.

The aim of this scoping review is to systematically identify and integrate existing research on the association between oral diseases and AD, to clarify the current state of evidence and inform future research direction.

2. Methods

2.1. Review design and framework

This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. This approach enables a comprehensive examination of existing literature to identify the scope and main features of evidence on the association between oral diseases and AD, with a focus on potential biological mechanisms, microbial links, inflammation, and cognitive outcomes. A PRISMA-ScR checklist is presented in supplementary Table 1.

2.2. Research questions

The review was guided by the overarching research question: “What is the current state of evidence regarding the association between oral diseases and Alzheimer’s disease, and what biological or clinical mechanisms may underlie this relationship?” To explore this topic in greater detail, the following sub-questions were addressed: (1) What types of oral conditions are associated with AD?; (2) What inflammatory or microbial pathways have been proposed in the literature?; (3) What is the role of genetic susceptibility in the link between oral diseases and AD?; (4) What evidence exists regarding the number of remaining teeth and its association with AD?

2.3. Search strategy

A comprehensive literature search was conducted by two independent reviewers (C-H. L and H-S. S) in five databases (PubMed, Scopus, Web of Science, Google Scholar, and KMbase) for studies published between January 1990 and December 2024. The search strategy combined Medical Subject Headings (MeSH) and free-text keywords, utilizing Boolean operators (“AND”, “OR”) and truncation symbols where appropriate (see Supplementary Table 2). Search terms were tailored to the indexing or controlled vocabulary system of each database. Only peer-reviewed articles published in English or Korean were included.

2.4. Eligibility criteria

Inclusion criteria:

• (1)Original studies reporting the association between oral diseases and AD or dementia.
• (2)Studies on microbiological, immunological, inflammatory, genetic, or behavioral mechanisms that may link oral health to AD.
• (3)Studies reporting cognitive or neurological outcomes in relation to oral health status.
• (4)Research conducted in human populations or validated animal models.

Exclusion criteria:

• (1)Conference abstracts, editorials, letters, or narrative review without primary data.
• (2)Studies focusing exclusively on other forms of dementia (e.g. Parkinsons’s, vascular dementia).
• (3)Case reports or anecdotal evidence without analytic data.

2.5. Study selection

After removal of duplicates, title and abstract screening was conducted independently by two reviewers to identify potentially relevant studies. Full-text articles of selected records were then assessed for eligibility based on the predefined inclusion and exclusion criteria. Discrepancies were resolved by discussion or consultation with a third reviewer (Y. Y). The study selection process is presented in Fig. 1.

Fig. 1.

Flowchart of the study selection process.

2.6. Data extraction

The extracted data included the following items: authorship, year of publication, population characteristics, type of oral disease examined, outcome measures, key findings and proposed mechanisms. Two reviewers independently performed data extraction and cross-checked the entries for accuracy. Discrepancies were resolved through discussion and consensus.

2.7. Data synthesis

A narrative synthesis approach was employed to organize and interpret the findings according to key thematic domains: (1) General association between oral health and AD; (2) Periodontal disease and AD; (2.1) Proinflammatory cytokines and AD; (2.2) Amyloid-β and periodontal disease; (2.3) Genetic susceptibility: periodontitis, APOE4 genotype, and AD; (3) Dental caries and AD; (4) Tooth loss, denture use, and AD risk. Summary tables were generated to facilitate thematic comparison across studies.

3. Results

A total of 1328 records were identified through searches of five databases. After the removal of 487 duplicates, 841 titles and abstracts were screened, and 98 full-text articles were assessed for eligibility. Ultimately, 45 studies met the inclusion criteria and were included in the final analysis (Table 1).

Table 1.

Summary of studies included in this review.

Study	Study design	Study population (n)	Follow-up	Intervention / Assessment	Main findings
Kulkarni et al. (2023) [5]	Cross-sectional, retrospective database cohort (TriNetX)	“Poor oral health” cohort n = 1232,751 vs “normal oral health” n = 31,418,814	N/A	Oral health status (DMFT index, periodontal health), cognitive function (MMSE)	Poor oral health associated with > 2-fold higher AD risk (RR≈2.36; tooth-loss related conditions RR≈3.19).
Hamza et al. (2021) [13]	Narrative review	N/A	N/A	Synthesis of 22 studies (2012–2020) on oral health in AD/dementia	AD/dementia patients often show worse oral hygiene, higher periodontal disease/inflammation; care needs highlighted.
Cicciù et al. (2013) [23]	Cross-sectional “supportive care trial”	AD patients n = 158	N/A	Clinical exam (DMFT, probing depth, bleeding, mobility); OHIP−14	Periodontitis, gingival bleeding, probing depth > 4 mm associated with worse OHRQoL in AD; molar absence worsened chewing ability.
de Souza Rolim et al. (2014) [24]	Case-control	AD n = 29 vs controls n = 30 (age/sex matched)	N/A	Oral exam; TMD evaluation; McGill pain; DMFT; full periodontal eval.	AD group had more orofacial pain (20.7 %), TMJ abnormalities, and periodontal infections vs controls.
Aragón et al. (2018) [25]	Multicenter case-control	AD n = 70 vs controls n = 36	N/A	Oral indices (DMFT/DMFS, CPI), hygiene, prosthetic status, saliva flow/pH, caries-risk microbiology	AD patients had fewer teeth, worse hygiene, more removable prostheses, lower salivary flow/buffering, and more mucosal lesions (candida, cheilitis).
Noble et al. (2013) [18]	Narrative review	N/A	N/A	Literature review on oral health as modifiable risk factor for dementia	Poor oral health, especially periodontitis, may contribute to dementia through systemic inflammation and vascular pathways
Uppoor et al. (2013) [26]	Narrative review	N/A	N/A	Literature review of periodontal–systemic links with focus on AD	Summarized growing evidence linking periodontitis to AD via systemic inflammation, microbial dissemination, and cytokine activity.
Passoja et al. (2010) [28]	Case-control	Chronic periodontitis n = 90 vs controls n = 90	N/A	Serum IL−10, TNF-α measurement; periodontal status	CP patients had significantly higher TNF-α and lower IL−10 vs controls, supporting systemic inflammatory role in AD pathogenesis.
Lewis & Trempe (2017) [32]	Book chapter (narrative synthesis)	N/A	N/A	Review of AD mechanisms beyond amyloid cascade; included oral health/microbiome aspects	Proposed multifactorial etiology of AD including oral microbial/endocrine influences and vascular factors.
Harding et al. (2017) [33]	Narrative review	N/A	N/A	Cross-disciplinary synthesis: oral microbiology, endocrinology, nutrition	Suggested microbial endocrinology as pathway linking oral pathogens to neurodegeneration in AD.
Stein et al. (2007) [16]	Longitudinal cohort with neuropathology	144 participants (Milwaukee cohort)	∼10 yrs cognitive follow-up	Dental history/tooth loss; neuropathology at autopsy	Edentulism/tooth loss associated with greater AD-type pathology and dementia risk.
Kamer et al. (2009) [34]	Case-control	AD n = 18, controls n = 16	N/A	Serum TNF-α; antibodies to Pg, Tf; neuropsychological status	AD group had higher antibodies to Pg and Tf and elevated TNF-α; immune markers discriminated AD vs controls.
Dominy et al. (2019) [8]	Human post-mortem + mouse experiments	AD brains vs controls (post-mortem); Pg-infected mice	N/A (human); 6-week infection period (mice)	Detection of P. gingivalis/gingipains in brain; gingipain-inhibitor tests in mice	Pg and gingipains detected in AD brains; small-molecule inhibitors reduced neurodegeneration/Aβ in mice.
Rivière et al. (2002) [35]	Postmortem brain study	AD brains n = 14, control brains n = 13	N/A	PCR/immunohistochemistry for Treponema DNA/antigens	Detected Treponema DNA/antigens in AD brains; supports oral spirochete invasion hypothesis.
Poole et al. (2013) [36]	Postmortem brain tissue analysis	AD brains n = 10, controls n = 10	N/A	PCR for periodontal virulence factors (e.g., Pg gingipains, fimA)	Periodontopathic virulence genes detected in AD brains but not controls; supports translocation hypothesis.
Singhrao & Olsen (2018) [37]	Narrative review	N/A	N/A	Conceptual discussion on Pg outer membrane vesicles (OMVs)	Proposed that Pg OMVs act as “microbullets,” delivering virulence factors to brain cells and triggering AD pathology.
Hu et al. (2020) [38]	Animal study (rat)	Sprague-Dawley rats (n not specified per group)	12 weeks	Induced periodontitis via Pg-LPS injections; behavioral & histologic assays	Periodontitis increased neuroinflammation, impaired learning/memory; elevated brain TNF-α and IL−1β.
Ilievski et al. (2018) [39]	Animal study (mouse)	Wild-type mice (n = 10 per group)	22 weeks	Chronic oral application of Pg	Caused brain inflammation, neurodegeneration, amyloid-β accumulation; supports causal link.
Zhang et al. (2018) [40]	Animal study (mouse)	C57BL/6 mice (n = 10 per group)	4 weeks	Pg-LPS injection; TLR4 pathway assessment	Pg-LPS induced neuronal inflammation, cognitive dysfunction via TLR4 activation.
Sheng et al. (2003) [41]	Animal study (mouse)	APPswe transgenic mice (n not specified)	Acute (hours–days)	LPS-induced neuroinflammation	LPS increased APP and Aβ accumulation in neurons; links infection to amyloidogenesis.
Sochocka et al. (2017) [42]	Cross-sectional	Elderly n = 128	N/A	Periodontal exam; cognitive tests; cytokine profile	Poor periodontal health correlated with worse cognitive scores and elevated systemic inflammatory markers.
Ide et al. (2016) [43]	Prospective cohort	AD patients n = 59	6 months	Periodontal assessment; cognitive decline (ADAS-Cog)	Periodontitis associated with faster cognitive decline over follow-up.
Cestari et al. (2016) [44]	Cross-sectional	AD & MCI n = 30, controls n = 30	N/A	Oral exam; serum cytokines	Higher pro-inflammatory cytokines in AD/MCI groups; oral infections correlated with systemic inflammation.
Naruishi & Nagata (2018) [45]	In vitro cell study	Human gingival fibroblasts (cell cultures)	N/A	IL−6 stimulation; cytokine regulation assays	IL−6 modulated cytokine production in gingival fibroblasts, suggesting a mechanistic link between periodontitis inflammation and systemic effects.
Shoemark & Allen (2015) [46]	Narrative review	N/A	N/A	Literature synthesis on oral microbiome, aging, AD	Proposed that dysbiosis of the oral microbiome contributes to neurodegeneration via inflammation and microbial byproducts.
Liu et al. (2018) [47]	Animal study (mouse)	CX3CR1 + /GFP mice (n = 12 per group)	N/A	Exposure of microglia to P. gingivalis → activation of PAR−2 via gingipains	P. gingivalis infection promoted microglial migration and inflammatory cytokine release, contributing to neuroinflammation
Kubota et al. (2014) [53]	Cross-sectional (lab-based)	Gingival tissue samples from periodontitis patients (n = 15)	N/A	Immunohistochemistry for APP in gingiva	APP expression elevated in periodontitis-affected gingival tissues, suggesting peripheral amyloid sources.
Gil-Montoya et al. (2017) [54]	Cross-sectional	Elderly with/without cognitive impairment (n = 180)	N/A	Periodontal exam; salivary/blood Aβ measurement	Periodontitis associated with higher systemic and salivary Aβ levels; stronger in cognitively impaired subjects.
Zeng et al. (2021) [55]	In vitro cell study / Animal study (mouse)	hCMEC/D3 cell line, C57BL/6 mice (n = 12, experimental 6 control 6)	N/A	P. gingivalis infection; assessment of RAGE expression and Aβ deposition	Pg infection upregulated RAGE in cerebral endothelial cells, facilitating cerebrovascular Aβ accumulation.
Hafezi-Moghadam et al. (2007) [65]	Animal experiment (ApoE knockout mice)	ApoE-deficient vs. wild-type mice (n not specified)	Age-dependent (up to ∼12 months)	Evans blue dye BBB permeability assay	ApoE deficiency led to progressive, age-related blood–brain barrier leakage, supporting vascular pathway links to AD.
Singhrao et al. (2016) [66]	Narrative review	N/A	N/A	Literature review on ApoE-related comorbidities	Summarized evidence linking ApoE genotype, systemic diseases, and AD, including periodontal connections.
Jones et al. (1993) [67]	Prospective cohort	Dementia patients (n = 43)	12 months	Dental exams every 6 months	Higher caries incidence in dementia patients compared to age-matched controls.
Ellefsen et al. (2008) [68]	Cross-sectional	Older adults ≥ 65 years (n = 1077)	N/A	Oral exam; dementia status assessment	Dementia associated with higher caries prevalence and untreated decay.
Syrjälä et al. (2012) [69]	Cross-sectional	≥ 75 years old (n = 364)	N/A	Oral exam; cognitive testing	Dementia linked with poorer oral health, higher plaque scores, and more tooth loss.
Ellefsen et al. (2012) [70]	Cross-sectional	AD patients (n = 158)	N/A	Root caries assessment; medical records	Recently diagnosed AD patients had higher root caries prevalence and severity than controls.
Sun et al. (2015) [71]	Cross-sectional	Taiwan NHIRD database (n = 20,000 +)	N/A	Dental amalgam exposure vs. AD diagnosis	No significant association between amalgam fillings and AD after adjusting for confounders.
Tiisanoja et al. (2019) [72]	Cross-sectional	≥ 75 years old (n = 300)	N/A	Oral exam; inflammatory markers; cognitive status	Higher oral disease burden correlated with elevated systemic inflammation and increased AD prevalence.
Lee & Choi (2019) [14]	Population-based cross-sectional (Korean NHIS)	Older adults ≥ 65 using 2017 NHIS dental data (nationwide)	N/A	Periodontitis & denture status vs dementia (ICD−10) with multivariable models	Dementia less common with periodontitis (adjusted OR ∼0.80) and more common with denture use (adjusted OR ∼1.26); tooth loss implicated.
Chen et al. (2017) [15]	Retrospective matched cohort (Taiwan NHIRD)	Taiwanese adults ≥ 50, CP cohort n = 9291 vs matched non-CP n = 18,672	Up to 10 yrs	CP exposure and subsequent AD using Cox models	10-year CP exposure linked to higher AD risk (adj. HR 1.707, 95 % CI 1.152–2.528).
Okamoto et al. (2010) [17]	Cross-sectional community study	n = 4031 (controls 3696; MMI 121; low MMSE 214)	N/A	Remaining teeth count; edentulous years; MMSE; regression models	Fewer teeth associated with MMI (OR 1.68 for 0–10 vs 22–32 teeth) and low MMSE (OR 2.18); longer edentulism linked to low MMSE.
Syrjälä et al. (2007) [73]	Cross-sectional (Health 2000 Survey, Finland)	Adults ≥ 30 years (n = 6939)	N/A	Oral health exam; MMSE cognitive test	Cognitive impairment associated with fewer teeth, poor oral hygiene, and periodontal disease.
Matsumoto et al. (2023) [74]	Cross-sectional	n = 51 (AD 19; MCI 13; healthy control 19)	N/A	Remaining teeth count; MMSE cognitive test; MRI and PET imaging of Ab and tau deposition in AD-related brain regions	Tooth loss was directly associated with higher tau accumulation in the medial temporal lobe and memory-related areas.
Kim et al. (2007) [75]	Cross-sectional	Korean community-dwelling elderly (n = 525)	N/A	Dental exam; nutritional status; dementia diagnosis	Dementia linked to tooth loss, poor oral status, and malnutrition risk.
Miyano et al. (2024) [76]	Prospective cohort (Japanese LIFE study)	Adults ≥ 65 years (n = 22,687)	Mean 12.2 months	Assessment of posterior occlusal contact and AD onset	Reduced posterior occlusal contact significantly increased AD onset risk, highlighting the role of mastication.
Cho (2016) [77]	Cross-sectional	Elderly women at senior centers (n = 236)	N/A	Number of remaining teeth; dementia screening	Fewer remaining teeth significantly associated with higher dementia prevalence.

The 45 studies included in this scoping review employed diverse methodologies, including population-based cohort studies [14], [15], [17], [71], [72], [73], [74], [75], [76], [77], case-control studies [23], [24], [25], [44], [54], cross-sectional analyses [13], [18], [26], [46], [67], [68], [69], [70], postmortem brain examinations [8], [35], [36], biomarker and cytokine profiling [28], [34], [38], [39], [40], [41], [42], [43], [45], [52], [65], [66], microbial detection [8], [33], [35], [37], and validated animal models [38], [39], [40], [41], [47], [55]. Human studies accounted for the majority, with only a limited number of experimental animal investigations exploring biological pathways [38], [39], [40], [41]. Most human studies were conducted in older adult populations [13], [14], [17], [23], [25], [43], [44], [67], [68], [69], [70], [72], [73], [74], [75], [76], [77], though some involved middle-aged cohorts [15], [34] or long-term institutionalized individuals [67], [68]. Follow-up durations in longitudinal studies ranged from 1.1 years to over 10 years [14], [15], [17], [71], [72], [73], [74], [75], while cross-sectional and case-control studies provided single-timepoint assessments [13], [18], [23], [24], [25], [26], [44], [46], [67], [68], [69], [70], [74], [77]

Interventions and assessments varied widely, encompassing periodontal examination and diagnosis [14], [15], [17], [23], [25], [28], [38], [39], [40], [42], [43], [44], [53], [56], [72], tooth loss quantification [16], [17], [25], [68], [69], [70], [73], [74], [75], [77], and posterior occlusal contact quantification [76]. Dental caries assessment [67], [68], [69], [70], [72], prosthetic rehabilitation status [16], [17], [73], [75], [77], systemic inflammatory and immunological markers [28], [34], [38], [39], [40], [42], [43], [44], [45], [53], [65], [66], [72], amyloid-β (Aβ) detection in brain or gingival tissues [8], [35], [36], [47], [53], [54], [55], and cognitive evaluations using standardized tools [14], [15], [16], [17], [18], [23], [24], [25], [26], [42], [43], [44], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77]. Several studies utilized national health insurance or registry databases [14], [15], [71], [74], [75] to investigate large-scale associations between oral diseases and AD, while others employed neuropathological approaches such as Aβ and tau burden quantification in brain tissue [8], [35], [36], [53], [54].

Of the 45 included studies, 24 reported funding sources [5], [14], [15], [16], [17], [23], [25], [28], [34], [38], [39], [40], [42], [43], [44], [46], [47], [54], [55], [71], [72], [74], [75], [76], 10 provided no funding disclosure [24], [26], [33], [35], [36], [37], [41], [45], [53], [65], and 11 did not specify funding information [8], [13], [18], [32], [66], [67], [68], [69], [70], [73], [75]. Most reported support came from national research agencies, university research grants, or public health programs. None of the included studies reported receiving commercial or industry sponsorship.

3.1. Association between Alzheimer’s diseases and oral health

Multiple studies have reported a significant association between AD and compromised oral health. A recent large-scale cohort study by Kulkarni et al. [5] analyzed data from over 30 million patients and found that individuals with poor oral hygiene had more than twice the risk of developing AD compared to those with normal oral health. Notably, tooth-loss-related conditions were identified as the strongest oral health-related risk factor (RR: 3.19; 95 % CI: 3.01–3.38). Hamza et al. [13] conducted a narrative review reporting that individuals with AD and dementia showed worse oral hygiene. Although the DMFT index did not differ significantly in some reports, periodontal disease was more common and severe in AD patients, often progressing alongside cognitive decline. And reduced salivary flow, coated tongue, stomatitis, and diminished chewing function were frequently noted, all of which may contribute to poorer quality of life. Earlier studies also support this link. Cicciù et al. [23] found that AD patients exhibited poorer periodontal status and reduced oral health-related quality of life, as assessed using the Oral Health Impact Profile (OHIP-14). Similarly, de Souza Rolim et al. [24] reported a higher prevalence of orofacial pain and periodontal disease in AD patients compared to cognitively healthy controls. Aragón et al. [25] consistently shown that patients with AD are more susceptible to various oral health problem, including increased rates of periodontal disease, greater prosthetic needs, dental caries, hyposalivation, and oral mucosal pathologies. Noble et al. [18] conceptualized poor oral health as a modifiable risk factor for dementia and emphasized the need for public health strategies that integrate oral health promotion with cognitive screening protocol.

3.2. Periodontal diseases and AD

Periodontitis was the most frequently studied oral disease in relation to AD, with numerous studies reporting increased prevalence and severity of periodontal disease in AD patients [5], [13], [23], [24], [25], [26]. As a chronic bacterial infection, periodontitis triggers local inflammation in the gums and can contribute to systemic inflammatory response. It is associated with elevated proinflammatory cytokines such as C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α), while reducing anti-inflammatory mediators, interleukin-10 (IL-10) [27], [28]. Periodontal pathogens could spread through the bloodstream or respiratory tract, a process linked to various systemic inflammatory conditions including cardiovascular disease and diabetes [29], [30], [31]. Their potential to invade the brain raises concern for neurodegenerative consequences such as AD [32], [33].

Serologic studies have reported higher immune responses to oral pathogens such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola in AD patients, indicated by elevated serum IgG levels, an indicator of prolonged microbial exposure before the onset of cognitive decline [16], [34]. Postmortem examinations of AD brains identified P. gingivalis, Treponema DNA, and lipopolysaccharides (LPS) in the cerebral cortex and trigeminal ganglia, suggesting the possibility of oral pathogens to invade the brain through the bloodstream or cranial nerves [8], [35], [36], [37]. Several animal studies showed that P. gingivalis infection induces neuroinflammation, microglial activation, Amyloid-β (Aβ) accumulation, and tau phosphorylation (p-tau) which are hallmark pathologies of AD [38], [39], [40], [41].

3.2.1. Proinflammatory cytokines and AD

Periodontitis is a chronic inflammatory disease which can cause systemic inflammation through the release of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, while reducing anti-inflammatory mediators such as IL-10 [28], [42], [43]. This systemic inflammatory state has been associated in the pathogenesis of AD. In a prospective cohort study by Ide et al. [43] found that AD patients with periodontitis experienced significantly accelerated cognitive decline, which was associated with increased levels of serum CRP, TNF-α, and IL-6, suggesting systemic inflammation as a possible mediator. Cestari et al. [44] reported similar findings that patients with AD and mild cognitive impairment (MCI) had elevated serum IL-6 levels, and those with concurrent periodontitis exhibited higher TNF-α levels. Their findings highlighted a strong association between periodontal infection, cytokine dysregulation, and cognitive decline. Sochocka et al. [42] reported that poor periodontal health and cognitive impairment together exacerbated systemic inflammation, which may accelerate neurodegenerative changes.

Naruishi and Nagata [45] demonstrated that human gingival fibroblasts (HGFs) stimulated by P. gingivalis lipopolysaccharide (Pg-LPS) and calprotectin produce IL-6 through TLR4/NF-κB pathway. This response contributes not only to local periodontal tissue damage but also to systemic inflammation [45]. These systemic cytokines may disrupt the blood-brain barrier (BBB), allowing translocation of microbial products and inflammatory mediators into the central nervous system (CNS) [26]. Shoemark and Allen [46] suggested that chronic TNF- α elevation from oral microbial overgrowth in older adults could compromise BBB integrity, facilitating the spread of bacteria and their products into the brain, thereby contributing to amyloid-β (Aβ) accumulation, tau phosphorylation (p-tau), and neuroinflammation. In line with this, Liu et al. [47] showed that P. gingivalis infection directly activates microglia, promoting their migration and inflammatory responses via gingipain-mediated protease-activated receptor-2 (PAR-2) signaling, highlighting a cellular mechanism by which periodontal pathogens drive neuroinflammation. Thus, the systemic inflammatory load from periodontal disease may act as a trigger that accelerates neurodegenerative changes in AD.

3.2.2. Amyloid-β and periodontal disease

Amyloid-β (Aβ) accumulation is a neuropathological hallmark of AD, forming extracellular plaques that impair neuronal signaling and contribute to neurodegeneration [48], [49]. Aβ is produced when amyloid precursor protein (APP) is sequentially cleaved by β-secretase (BASE1) and γ-secretase, a process that is well-controlled under normal physiological conditions [50], [51]. With aging, oxidative stress, or chronic systemic inflammation, this regulatory balance can be disrupted, resulting in excessive Aβ production and deposition [50], [51], [52].

Several studies suggest that periodontal disease may contribute to Aβ accumulation through both peripheral and central pathways. In a mouse study by Sheng et al. [41], systemic LPS exposure induced by periodontal pathogens increased APP expression and Aβ accumulation in the hippocampus, indicating that neuroinflammation can accelerate amyloid formation. Consistently, gingival tissues from periodontitis patients exhibited elevated APP expression, supporting the role of chronic local inflammation in peripheral Aβ dysregulation [53]. Karmer et al. [34] presented in their case-control study that AD patients had higher serum antibody levels against periodontal bacteria and increased levels of proinflammatory cytokines (TNF-α), which may facilitate Aβ aggregation via neuroimmune activation. Moreover, salivary Aβ-42 levels were found to be elevated in elderly patients with periodontitis, especially in those with cognitive impairment, suggesting a potential link between oral inflammation and systemic or central Aβ burden [54]. Extending these findings, Zeng et al. [55] demonstrated that P. gingivalis infection upregulates receptor for advanced glycation end products (RAGE) in cerebral endothelial cells, which in turn promotes cerebrovascular Aβ accumulation. These findings support the hypothesis that periodontal disease may promote amyloidogenic processes, both peripherally through chronic inflammation and centrally by facilitating Aβ deposition, thereby contributing to AD pathogenesis.

3.2.3. Genetic susceptibility: periodontitis, APOE4 genotype, and AD

The apolipoprotein E (APOE) gene encodes a protein involved in lipid metabolism and transport, playing a critical role in neuronal repair and synaptic maintenance [56]. Among its three allelic variants (APOE2, APOE3, and APOE4), the APOE4 allele is the most strongly associated with an increased risk of late-onset AD. APOE4 carriers are more prone to Aβ aggregation, tau phosphorylation (p-tau), and blood-brain barrier (BBB) disruption, all of which can accelerate neurodegenerative changes [56], [57], [58], [59], [60], [61], [62], [63], [64].

Recent studies suggest a possible gene-environment interaction between the APOE4 genotype and chronic periodontitis, contributing to neurodegeneration. Hafezi-Moghadam et al. [65] found that APOE-deficient mice (apoE-/-) exhibited progressive, age-related leakage of the BBB, suggesting that APOE deficiency increases the vulnerability of the CNS to inflammatory signals from the peripheral inflammation. Poole et al. [36] identified that in APOE4 transgenic mice, oral infection with P. gingivalis (Pg) resulted in the detection of Pg DNA in the brain tissue, indicating the pathogen can reach the brain in genetically susceptible host. Singhrao et al. [66] reported that Pg infection through gingival tissue in APOE4 mice accelerated the formation of age-related granule in the hippocampus, consistent with early AD pathology.

These findings suggest that individuals carrying the APOE4 allele may be more susceptible to brain invasion by periodontal pathogens and the resulting neuroinflammatory cascade. However, further studies are required to clarify the extent to which this gene-environment synergy contributes to AD progression.

3.3. Dental caries and AD

Several studies have reported greater prevalence and progression of dental caries in AD patients. Patients with moderate to severe AD exhibit a higher prevalence and annual progression rate of dental caries compared to cognitively normal individuals [67], [68], [69]. Jones et al. [67] reported that veterans with AD exhibited over twice the annual increment in coronal and root caries compared to matched controls. In the early stages of AD diagnosis, the presence of multiple progressive coronal caries has been identified as a predictor of future root caries development [70]. A large population-based study in Taiwan found that individuals with a history of dental mercury amalgam restorations after caries removal had a significantly higher risk of developing AD compared to those who had never received such treatments, with the association being more pronounced in women [71]. Tiisanoja et al. [72] suggested that the inflammatory burden associated with dental caries may contribute to the development of AD and, in some cases, might even exceed that of periodontal disease. However, recent studies have concentrated on the microbiological, immunological, and genetic links between periodontal disease and AD. This trend reflects a growing scientific view that chronic periodontitis, through its possibility to cause systemic inflammation and enable microbial translocation, may have a greater influence on AD pathogenesis than dental caries.

3.4. Tooth loss, denture use, and AD risk

There is growing evidence suggesting an association between tooth loss and the development of AD. In a Korean population-based cohort study, Lee and Choi [14] reported that older adults with fewer remaining teeth had a higher risk of developing dementia, suggesting that tooth loss could be an early clinical sign of cognitive decline. Likewise, Chen et al. [15] found that patients with chronic periodontitis, the main cause of tooth loss, had a significantly greater risk of AD, highlighting the role of oral inflammation in neurodegenerative process.

Neuropathological findings from the Nun Study by Stein et al. [16] revealed that individuals with complete edentulism exhibited greater AD-related brain pathology, including Aβ plaques and neurofibrillary tangles (NFTs). Okamoto et al. [17] also reported a strong inverse relationship between the number of teeth and mild memory impairment, suggesting that tooth loss may contribute to early cognitive dysfunction even before the clinical diagnosis of dementia. Syrjälä et al. [73] similarly found that Finnish individuals with cognitive impairment tended to have fewer teeth and worse periodontal status. More recently, a Positron Emission Tomography (PET) study by Matsumoto et al. [74] demonstrated that tooth loss in older adults was directly associated with increased tau accumulation in AD-related brain regions. Individuals with fewer remaining teeth exhibited significantly greater tau deposition in the medial temporal lobe and other areas critical for memory function. These findings provide evidence that oral status may not only reflect past disease burden but also be linked to specific neuropathological processes of AD, thereby reinforcing the biological plausibility of this link.

Kim et al. [75] conducted a prospective cohort study with 686 elderly aged ≥ 65 in Korea, and found that a lower number of remaining teeth was significantly associated with a higher risk of dementia, particularly among those who did not wear dentures. This suggests that factors such as reduced chewing ability and poor nutrition, in addition to inflammation, might help explain this relationship. Denture use appeared to attenuate the dementia risk, indicating a potential protective effect. Supporting this functional perspective, Miyano et al. [76] reported that reduced posterior occlusal contact was significantly associated with the onset of AD in older Japanese adults, highlighting the role of preserved mastication in maintaining cognitive health. Cho [77] observed that elderly women with fewer remaining teeth had significantly higher prevalence of dementia, further supporting the hypothesis that oral health status, particularly the number of natural teeth, is closely linked with cognitive function. These findings suggest that tooth loss and prosthetic status may be not only indicators of past oral disease but also modifiable factors in cognitive aging. Public health strategies should incorporate oral rehabilitation, including denture provision and nutritional support, as part of comprehensive dementia prevention program.

4. Discussion

This scoping review comprehensively examined current evidence on the association between oral diseases and Alzheimer’s disease (AD). Findings from the literature suggest a bidirectional relationship in which poor oral health could contribute to cognitive deterioration, while cognitive impairment can in turn worsen oral health status.

Periodontal disease has been most extensively studied. Many studies report that periodontitis is linked to elevated levels of systemic inflammatory markers, including TNF-α, IL-6, and IL-1β, which have been associated with faster cognitive decline in both animal and human studies [26], [42], [43], [44], [45], [46], [47]. These inflammatory mediators can compromise the integrity of the blood-brain barrier (BBB), facilitating the translocation of microbial products and toxins to enter the central nervous system (CNS), promoting neuroinflammation and AD-related changes [26], [46]. And also, P. gingivalis infection has been shown to directly activate microglia, enhancing cell migration and inflammatory cytokine release, which contribute to neuroinflammatory processes in AD pathogenesis [47].

Several experimental studies indicate that periodontal pathogens can influence amyloid-β (Aβ) production and deposition. In mice experiments, lipopolysaccharide (LPS) from P. gingivalis increased the expression of amyloid precursor protein (APP) and its processing enzymes (BASE1 and γ-secretase), resulting in greater Aβ accumulation [41], [53]. Clinical studies also found higher Aβ levels in plasma and gingival tissues of patients with periodontitis, including those without diagnosed cognitive impairment, suggesting that chronic oral inflammation might contribute to early amyloid pathology [34], [54]. Furthermore, P. gingivalis infection have been revealed to promotes upregulation of receptor for advanced glycation end products (RAGE) in cerebral endothelial cells, which facilitates cerebrovascular Aβ deposition [55].

Genetic factors, particularly the presence of the APOE4 allele, appear to further modulate the oral-neurodegenerative relationship. APOE4 is associated with greater susceptibility to BBB disruption and neuroinflammatory responses [56], [62], [63], [64]. In APOE4-transgenic mice, oral infection with P. gingivalis accelerated early neurodegenerative changes, indicating the possibility of a gene-environment interaction [36], [65], [66]. While these findings are noteworthy, more well-designed human studies are needed to clarify causality.

Compared with periodontal disease, the link between dental caries and AD has been less thoroughly investigated. Some observational studies reported that AD patients, particularly in advanced stages, have higher rates of coronal and root caries [67], [68], [69], [70]. Sun et al. [71] reported a higher risk of AD in women with mercury amalgam restorations. Furthermore, systemic inflammation associated with active caries lesions may contribute to neurodegenerative processes, although this hypothesis remains to be comprehensively validated [72]. Recent research trends appear to focus more on periodontitis, likely because its microbial and immune pathways provide a stronger biological rationale for involvement in AD.

Tooth loss and denture use have also been consistently linked to cognitive impairment. Multiple population-based studies demonstrated that individuals with fewer remaining teeth had significantly higher odds of developing AD [14], [16], [17], [18], [73], [74], [75], [76], [77]. Neuropathological and neuroimaging studies also provide biological support for this association, with evidence of increased AD-related pathology among edentulous individuals [16], [74]. The risk appears to be modulated by prosthetic rehabilitation: denture use and preservation of occlusal support may lessen the adverse effects of tooth loss by restoring masticatory function, improving nutrition, and maintaining sensory input [75], [76]. Furthermore, longitudinal evidence indicates that chronic periodontitis, the primary cause of tooth loss, significantly increases the risk of AD development [15]. These findings suggest that oral health status is not only an indicator of past disease but also a potentially modifiable factor in cognitive aging.

The reviewed literature indicates a well-supported and clinically relevant connection between oral diseases and AD. Several interaction pathways have been suggested, including systemic inflammation, microbial invasion, amyloid-related changes, genetic susceptibility, and functional decline associated with tooth loss. Although a clear cause-and-effect relationship has to be confirmed, preserving good oral health throughout life could be a practical and economical way to help lessen the impact of dementia in aging populations.

4.1. Limitations and future research directions

While this review has provided valuable insights into the relationship between oral diseases and AD; however, several limitations should be acknowledged. The included studies varied considerably in diagnostic criteria for both oral diseases and AD, study design, and follow-up duration, which complicates direct comparisons and synthesis. The predominance of observational and cross-sectional research limits the ability to determine which condition occurs first or whether one directly causes the other. And many studies did not adequately adjust for important confounders such as socioeconomic status, systemic comorbidities, medication use, and lifestyle factors, which may influence both oral health and cognitive function. A further limitation is the lack of standardized assessment tools for oral health status, inflammatory biomarkers, and cognitive performance across studies.

Current evidence on the mechanisms linking specific oral pathogens, systemic inflammation, amyloid-related processes, and genetic susceptibility to AD is still limited. Only a limited number of studies have combined microbiological analysis, molecular biomarker profiling, and neuroimaging, which are essential to understand the mechanisms. Moreover, the possible influence of prosthetic rehabilitation, nutritional status, and chewing ability on cognitive outcomes have not been comprehensively investigated.

Consequently, future research should focus on:

• ●Conducting large-scale, long-term cohort studies using standardized diagnostic criteria for both oral diseases and cognitive impairment.
• ●Integrating molecular, microbiological, and neuroimaging methods to clarify the biological mechanisms.
• ●Exploring gene-environment interactions, particularly the role of the APOE4 genotype on the brain’s response to periodontal pathogens.
• ●Assessing the long-term effects of oral disease related systemic inflammation on neurodegenerative changes.
• ●Investigating whether early oral disease prevention, periodontal treatment, and appropriate prosthetic rehabilitation can slow or reduce cognitive decline.
• ●Examining the role of chewing function and adequate nutrition as possible mediators between oral health and cognitive performance.

5. Conclusion

Based on the available evidence, chronic oral diseases, especially periodontitis and tooth loss, appear to play a possible role in the onset and progression of Alzheimer’s disease (AD). Several mechanisms have been proposed, including systemic inflammation, spread of oral pathogens into bloodstream, disruption of the blood-brain barrier (BBB), and interactions with genetic factors such as APOE4 allele. Loss of teeth without prosthetic rehabilitation may further increase dementia risk by reducing chewing efficiency and altering nutritional status. In contrast, appropriate oral rehabilitation could help preserve cognitive function. However, heterogeneity in study design, diagnostic criteria, and follow-up periods make it difficult to draw definitive conclusions. Further longitudinal and interventional studies are required to determine the sequence of events, measure the degree of risk, and assess whether maintaining good oral health can meaningfully lower the incidence and progression of AD in different populations.

Declaration of Competing Interest

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

Appendix A. Supplementary material

Supplementary material

Supplementary material