<h3>Introduction</h3>

<br/>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, characterized by memory loss, cognitive impairment, and functional decline [1]. As the global population ages, the burden of AD continues to rise, underscoring the urgent need for strategies that target modifiable risk factors. While traditional research has focused on genetic predisposition, cardiovascular health, and lifestyle factors, emerging evidence points to an unexpected yet compelling contributor: oral health.

<br/> Recent epidemiological and mechanistic studies have identified a significant association between poor oral health and an increased risk of developing AD. Periodontal disease, dental caries, and tooth loss have all been implicated as potential risk factors, with some large-scale studies reporting more than a twofold increase in AD risk among individuals with poor oral health. In particular, chronic periodontal inflammation and the presence of specific oral pathogens – such as Tannerella forsythia, Fusobacterium nucleatum, Porphyromonas, Prevotella, Leptotrichia, Fusobacteriota, Peptostreptococcaceae, and Candida spp. – appear to play a key role in promoting neuroinflammation and the hallmark neuropathological features of AD, including amyloid-beta plaques and tau tangles [2].

<br/> Moreover, tooth loss has been shown to exert a dose-dependent effect on dementia risk, potentially reflecting reduced cognitive reserve and impaired masticatory function [3]. Not only does poor oral health increase the likelihood of developing AD, but it may also accelerate cognitive decline in patients already diagnosed with the disease.

<br/> This review aims to synthesize current evidence on the link between oral health and AD, explore the underlying biological mechanisms, and highlight the clinical and public health implications of maintaining good oral hygiene as a potential strategy for AD prevention and progression management.

<h4>Alzheimer’s disease: etiology, pathophysiology, and prevalence</h4>

<br/>Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Its etiology is multifactorial, involving a complex interplay between genetic, environmental, and lifestyle factors. While age remains the most significant risk factor – with prevalence doubling every five years after age 65 – modifiable contributors such as cardiovascular disease, diabetes, obesity, smoking, and low educational attainment have also been implicated [4]. Genetic predisposition plays a critical role, particularly in early-onset forms of AD, which are associated with mutations in the APP, PSEN1, and PSEN2 genes. The presence of the APOE e4 allele markedly increases the risk of late-onset AD. Pathophysiologically, AD is characterized by the accumulation of extracellular amyloid-beta (Ab) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein [5]. These changes are accompanied by widespread neuronal loss, particularly in the hippocampus and basal forebrain, and a marked decline in cholinergic transmission. Two main hypotheses – the cholinergic and amyloid hypotheses – have been proposed to explain the underlying mechanisms of neurodegeneration in AD [6]. The global prevalence of AD has risen sharply, with projections estimating that 150 million people will be affected by 2050 [7]. The projected increase in global dementia cases by 2050 is driven primarily by population ageing and growth, with changing prevalence playing a smaller role. While rising body mass index (BMI) and blood glucose levels contribute to increased prevalence in most regions, improvements in education appear to offset these effects somewhat. In high-income Asia Pacific, a decline in dementia-related risk factors is expected, yet population ageing remains a dominant driver. Regionally, sub-Saharan Africa’s increase is mainly attributed to population growth, while in East Asia and Western Europe, ageing plays a more significant role. In some areas, such as Eastern Europe and high-income Asia Pacific, anticipated population declines may partially mitigate the impact of aging (Fig. 1) [8].

<h4>Potential mechanisms linking oral health and Alzheimer’s disease</h4>

<br/>The association between poor oral health and AD is supported by growing clinical and mechanistic evidence. Several biological pathways may underlie this relationship, ranging from direct microbial invasion to systemic inflammation and reduced cognitive reserve. The following key mechanisms have been proposed.

<h4>Oral pathogens and direct neurotoxicity</h4>

<br/>A central player in the oral-brain connection is Porphyromonas gingivalis, a Gram-negative anaerobic bacterium implicated in chronic periodontitis. Studies have shown that P. gingivalis and its virulence factors – particularly the proteolytic enzymes gingipains – can access the brain via systemic circulation, especially when the integrity of the oral mucosa or blood-brain barrier is compromised. Once in the brain, gingipains interact with neuronal tau proteins, promoting their abnormal aggregation into neurofibrillary tangles. Simultaneously, gingipains contribute to the cleavage and accumulation of amyloid-beta, facilitating the formation of extracellular amyloid plaques – a hallmark of AD pathology.

<h4>Systemic inflammation and neuroinflammatory amplification</h4>

<br/>Chronic periodontal disease is a persistent source of systemic inflammation. It leads to elevated circulating levels of inflammatory cytokines (e.g., interleukin 6 [IL-6], tumor necrosis factor a [TNF-a], C-reactive protein [CRP]), which can cross the blood-brain barrier and exacerbate neuroinflammation. This systemic inflammatory state not only promotes AD pathology but may also impair the brain’s ability to clear toxic protein aggregates [9]. Moreover, repeated episodes of bacteremia due to poor oral hygiene can further stimulate peripheral and central immune responses, contributing to progressive cognitive decline.

<h4>Tooth loss and reduced cognitive reserve</h4>

<br/>Tooth loss has been independently associated with a higher risk of dementia, with a clear dose-response relationship reported in epidemiological studies [10]. The loss of teeth may reduce masticatory efficiency, which has been linked to decreased hippocampal activity and reduced neurogenesis in animal models [11]. In addition, individuals with significant tooth loss may experience diminished cognitive reserve, a protective factor against age-related neurodegeneration, thereby increasing vulnerability to AD [12].

<h4>Shared risk factors</h4>

<br/>Several modifiable and non-modifiable risk factors are common to both poor oral health and AD. These include smoking, poor nutrition, low socioeconomic status, chronic systemic illnesses (e.g., diabetes), and genetic susceptibility (e.g., APOE ε4 allele). These shared factors may act synergistically to promote both periodontal degradation and neurodegeneration [13].

<h3>Aim of the study</h3>

<br/>This review aims to explore the potential relationship between oral health and cognitive decline, with a particular focus on AD. By synthesizing current epidemiological and experimental evidence, it seeks to provide an overview of how conditions such as periodontal disease, tooth loss, and chronic oral infections may contribute to cognitive impairment and increase the risk of AD. Special attention is given to the role of oral pathogens and the associated inflammatory responses, which may promote the accumulation of amyloid-beta plaques and tau tangles – hallmarks of AD pathology.

<h3>Material and methods</h3>

<br/>A structured literature search was conducted on June 30, 2025, across four major databases: PubMed, Web of Science, Scopus, and ClinicalTrials.gov. The search strategy combined keywords such as ‘Alzheimer’s disease’, ‘cognitive decline’, ‘oral health’, ‘periodontitis’, ‘tooth loss’, ‘Porphyromonas gingivalis’, ‘gingipains’, and ‘neuroinflammation’, using Boolean operators (AND, OR) to optimize results. The search covered all studies published between database inception and June 30, 2025.

<br/> We included both observational and interventional studies that investigated the association between the oral microbiota and cognitive decline and/or AD. Studies were eligible for inclusion if they employed validated microbial assessment methods – such as quantitative PCR or metagenomic sequencing – and included a cognitively healthy control group. Exclusion criteria encompassed in vitro and animal studies, single-case reports, editorials, narrative reviews, and studies lacking standardized microbiological techniques.

<br/> Titles and abstracts were initially screened, and full texts of potentially relevant articles were subsequently reviewed for eligibility by two independent reviewers. A total of 5,045 records were assessed. After removal of duplicates and application of the inclusion and exclusion criteria, 21 studies were deemed eligible and included in the final qualitative synthesis. The flow diagram illustrating the search and selection process is presented in Figure 2.

<h3>Results</h3>

<br/>A total of 20 studies were included in this review, encompassing various study designs: observational case-control (n = 11), cross-sectional (n = 5), prospective cohort (n = 2), and randomized controlled trials (n = 2). Collectively, these studies assessed the relationship between oral microbiota, periodontal health, and AD or mild cognitive impairment (MCI). A summary of the key findings is presented in Table 1 [3, 9, 10, 13-30].

<h4>Oral microbiota composition</h4>

<br/>Multiple studies reported dysbiosis of the oral microbiome in individuals with AD and MCI. Common findings included increased abundance of specific pathogens such as Fusobacterium nucleatum, Treponema denticola, Lactobacillales, and Streptococcaceae [13, 22, 24]. A decreased relative abundance of beneficial or commensal bacteria such as Rothia, Lautropia, and Actinomyces was also observed [14, 19]. In several studies, oral microbial diversity was reduced in AD patients compared to healthy controls [20], while others reported increased diversity in AD and MCI compared to controls [26].

<h4>Periodontal health and cognitive decline</h4>

<br/>Periodontitis and poor oral hygiene indicators, such as higher DMFT (decayed, missing, and filled teeth) scores, deeper periodontal pockets, and gingival erythema, were consistently associated with cognitive decline and an increased risk of AD [16, 30]. Ide et al. observed that periodontitis was linked to accelerated cognitive decline and elevated systemic inflammatory markers over time [28].

<h4>Immunological findings</h4>

<br/>Several studies have examined antibody titers or pathogen presence in serum and cerebrospinal fluid (CSF) [9]. Elevated IgG levels against oral pathogens such as F. nucleatum, P. intermedia, and Actinomyces naeslundii were associated with increased AD risk [24, 27]. The detection of Treponema spp. in the brain tissue of AD patients [25] and in higher prevalence in serum/CSF further supports a possible infectious etiology [29].

<h4>Intervention outcomes</h4>

<br/>Two interventional studies [3, 15] reported that improving oral hygiene led to enhanced microbiota profiles and reduced cognitive decline. In particular, the largest multicenter trial [3] involving over 32 million individuals showed that poor oral health was associated with more than double the risk of AD (RR = 2.36), with the highest risk linked to tooth-loss-related conditions (RR = 3.19).

<h4>Genetic and molecular correlates</h4>

<br/>One study conducted by L’Heureux et al. linked P. intermedia abundance to the presence of APOE4, a known genetic risk factor for AD. Microbial compositions favoring Prevotella dominance were associated with cognitive decline, whereas Neisseria-Haemophilus dominance appeared to be protective [19].

<h4>Discussion</h4>

<br/>This review synthesizes current evidence on the relationship between oral microbiota, periodontal health, and cognitive impairment, particularly AD.

<br/> The findings reveal a consistent association between oral dysbiosis, characterized by the overgrowth of pathogenic bacteria, and both MCI and AD. Although causality cannot be definitively established, the convergence of microbiological, immunological, and clinical data supports a potential contributory role of oral pathogens in neurodegeneration.

<br/> Several studies have identified an increased abundance of Fusobacterium nucleatum, Treponema denticola, and other periodontopathogens in patients with AD or MCI [13, 17, 22, 24].

<br/> The detection of Treponema spp. in brain tissue [25] and CSF [29] lends support to the hypothesis that oral bacteria may translocate to the central nervous system, where they may exacerbate neurodegeneration.

<br/> Furthermore, poor periodontal health has emerged as a key modifiable risk factor for cognitive impairment. Studies have consistently shown that clinical indicators of periodontitis, such as pocket depth and gingival erythema, were more prevalent in individuals with MCI or AD compared with healthy controls [28, 30]. The association between periodontitis and systemic inflammation, reflected by elevated cytokines and inflammatory markers, suggests a possible mechanism through which chronic oral inflammation may accelerate neuronal damage.

<br/> Interesting findings were derived. In a small-scale study by Leblhuber et al. (n = 20), multispecies probiotic supplementation in patients with advanced AD produced mixed effects, including beneficial anti-inflammatory changes at the gut level, such as reduced fecal zonulin (p = 0.01) and increased Faecalibacterium prausnitzii abundance (p < 0.001), indicating improved intestinal barrier function [23].

<br/> In contrast, at the systemic level, the intervention was associated with immune activation, reflected by increased serum neopterin and kynurenine concentrations (p < 0.05), suggesting activation of macrophages and a Th1-type immune response.

<br/> The results from interventional studies are promising. Chen et al. [15] showed that improved oral hygiene could reduce cognitive impairment and restore microbial balance, while Kulkarni et al. [3] provided large-scale epidemiological evidence linking poor oral health to a significantly increased risk of AD. These findings highlight the potential of oral health interventions as a preventive strategy in at-risk populations.

<br/> Despite consistent associations, most of the included studies were observational, which limits causal inference. Sample sizes varied widely, and methodologies for microbiota analysis were heterogeneous. Confounding factors such as education level, nutrition, and comorbidities were not consistently controlled across studies. In addition, the possibility of reverse causality cannot be excluded, as cognitive decline itself may contribute to reduced oral care and subsequent microbiota changes.

<h3>Conclusions</h3>

<br/>This review highlights a consistent and biologically plausible association between oral health, particularly dysbiosis and periodontal disease, and AD. Alterations in the oral microbiome, heightened systemic and central nervous system immune responses, and poor dental status are recurring features in individuals with cognitive impairment.

<br/> The findings underscore the potential of oral health assessments and microbial profiling as non-invasive tools for early risk identification and disease prevention in AD. Maintaining good oral hygiene and preventing periodontal disease may also represent a modifiable and cost-effective strategy to reduce the burden of dementia.

<br/> Nevertheless, further longitudinal and interventional studies are needed to clarify causal pathways, establish whether microbiota alterations precede cognitive decline, and determine whether oral health interventions can delay or prevent the onset of AD.

<h3>Disclosures</h3>

<br/>This research received no external funding.

<br/>Institutional review board statement: Not applicable.

<br/>The authors declare no conflict of interest.

<h3>References</h3>