Severe periodontitis with tooth loss as a modifiable risk factor for the development of Alzheimer, vascular, and mixed dementia: National Health Insurance Service-National Health Screening Retrospective Cohort 2002–2015

Dementia is a condition that involves damage to cerebral neurons by progressive, degenerative, and cerebrovascular diseases, resulting in declining language skills, declining judgment, memory loss, and behavioral changes [1, 2]. Approximately 10% of elderly people aged 65 years or older are reported to have Alzheimer dementia (AD); as such, AD is the most common form of dementia, accounting for 60%–80% of all dementia cases [3]. Approximately half of these patients have only AD, whereas in the other half of patients, AD is accompanied by vascular dementia (VaD) or another type of dementia [3].

The brains of AD patients present with extraneuronal plaques formed by the buildup of the amyloid β-peptide (Aβ) protein, as well as intraneuronal tau tangles, which are abnormal tangled bundles of the phosphorylated tau (P-tau) protein [4, 5]. The known major risk factors for AD are traumatic brain injury, age, family history, education level, the apolipoprotein E ε4 allele, cardiovascular disease, hypertension, and diabetes mellitus [6].

VaD is the second most common form of dementia after AD, accounting for approximately 10% of all dementia cases. VaD is caused by brain injury resulting from cerebral hemorrhage, vascular obstruction, or stroke. VaD is strongly affected by the patient's stroke history and age, and 20%–25% of patients who experience a stroke develop VaD within 3 months [7]. Mixed dementia (MD) refers to dementia with multiple etiologies [8]. Previously, a diagnosis of AD was often excluded in patients with a history of VaD, but reports from around the world have recently revealed that 50% or more of AD cases are concurrent with other etiologies [3, 9].

Periodontitis is a chronic inflammatory disease occurring in the alveolar bone and the soft tissue supporting the dentition [10]. This condition leads to elevated levels of endovascular inflammatory mediators, which in turn increase the risk of systemic inflammatory diseases, such as diabetes mellitus, coronary artery disease, rheumatoid arthritis, erectile dysfunction, osteoporosis, and systemic cancers [11, 12, 13, 14]. Age is a major risk factor for dementia, irrespective of etiology, and the condition typically occurs in elderly patients. These patients experience difficulties managing their oral hygiene because of decreased motor and cognitive ability, and several epidemiological studies have reported that the risk and severity of periodontitis are higher in patients with dementia than in patients without it [15, 16].

The various anaerobic Gram-negative bacteria that cause periodontitis can also directly infiltrate the central nervous system and may affect the development or progression of AD [17]. In addition, some studies have already reported a close association of periodontitis with cardiovascular and cerebrovascular diseases, which are in turn closely related to the onset of VaD [18, 19, 20]. To our knowledge, despite this steady interest, few studies have examined the association between dementia and periodontitis with and without tooth loss [21, 22]. Therefore, the purpose of this study was to evaluate severe periodontitis with tooth loss as a modifiable risk factor for AD, VaD, and MD based on a retrospective analysis of a large population-level dataset.

For statistical analysis of the NHIS-HEALS data, which were updated and newly released in 2018, we conducted multivariate analyses with adjustment for various sociodemographic factors, anthropomorphic measurements, lifestyle factors, and comorbidities that are known risk factors for or indicators of dementia. We found that a diagnosis of severe periodontitis with few remaining teeth (1–9) was significantly associated with relatively high risks of AD, VaD, and MD.

Several previous studies have reported an association between tooth loss and cognitive impairment [25, 26, 27, 28]. Impaired masticatory function caused by tooth loss leads to decreases in cerebral blood supply, cerebral cortical activity, and the concentration of oxygen in the blood. Lower masticatory efficiency also leads to inappropriate nutritional intake, which can increase the risk of dementia [25, 26]. Moreover, peri-radicular mechanoreceptors convey spatial information to the brain during mastication, helping to maintain neuronal activity. After tooth loss, this function decreases, which can result in reduced brain activity [26]. This evidence validates that severe periodontitis, which is considered to be the most common cause of tooth loss in the elderly, increases the risk of dementia.

Recent studies have demonstrated that periodontitis affects the development and/or progression of several types of dementia, including AD and VaD [21, 22]. In one of those studies, after adjusting for the various sociodemographic and medical risk factors in the multivariate analysis, chronic periodontitis was found to be significantly associated with an increased risk of developing dementia (overall dementia: HR, 1.06; 95% CI, 1.01–1.11; AD: HR, 1.05; 95% CI, 1.00–1.11; VaD: HR, 1.10; 95% CI, 0.98–1.22) [21]. Another study by Yoo et al. [22], which included 209,806 participants aged ≥60 years, showed that participants with tooth loss had a higher risk of developing dementia than those without tooth loss (odds ratio, 1.18; 95% CI, 1.14–1.21). The findings that VaD is more closely associated with periodontitis than other types of dementia and that the risk of dementia increases with tooth loss are consistent with the results of this study.

Severe periodontitis causes elevated levels of inflammatory proteins, such as C-reactive protein, interleukin (IL)-1β, IL-6, prostaglandin E2, and tumor necrosis factor alpha, and these immune/inflammatory reactions can affect the development and progression of various systemic diseases [29, 30]. Similarly, plasma from AD patients also shows increased levels of inflammatory markers, and this relationship remains consistent even after adjustment for confounding factors such as age, sex, and education level [31]. The circulation of systemic inflammatory proteins induced by periodontitis activates the central nervous system, particularly glial cells in the brain. This leads to the production of the amyloid β-peptide 1–42 (Aβ 42) and P-tau proteins, which form intra- and extra-neuronal plaques and increase the risks of neurodegeneration and AD [17].

A previous study demonstrated that Prevotella intermedia and Fusobacterium nucleatum, major causative bacteria of periodontitis, are potential risk factors for AD [32]. Foschi et al. [33] reported that the persistent deposition of bacterial dental plaque caused by poor oral hygiene directly increases the risk of systemic bacteremia. In particular, the anaerobic bacteria commonly observed in moderate-to-severe periodontitis can affect the development of AD by directly entering the central nervous system via systemic circulatory or peripheral neural pathways. Treponema denticola, another of the major periodontal pathogens, is often detected in the trigeminal ganglion and is known to increase the synthesis of the Aβ 42 and P-tau proteins by glial and neuronal cells after entering the central nervous system [34].

In patients with severe periodontitis, lipopolysaccharides released by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis induce the activation of systemic inflammatory factors and aggravate intimal hyperplasia in the carotid arteries, ultimately increasing the risk of atherosclerosis and stroke [19]. Higher levels of antibodies targeting periodontal pathogenic bacteria are associated with the accelerated formation of atheroma in the aorta. The treatment of progressive periodontitis has been shown to lead to clear decreases in the circulating concentrations of inflammatory substances and considerable improvement in vascular endothelial function [35].

Although VaD and MD have lower prevalence and incidence rates than AD, approximately 50% of AD patients show concurrent pathological findings of stroke or cerebrovascular disease, indicating a higher likelihood of being diagnosed with VaD and MD [36, 37]. Mortality from VaD is higher than that from AD, with an extremely short mean survival time of 3–5 years. This seems to be due to the effects of concurrent coronary artery disease, which has a relatively high mortality rate [38]. This short survival time is one of the major reasons that long-term and large cohort studies examining the association between periodontitis and VaD are highly limited and lacking.

This study had several limitations. First, calibrated public health dentists examined the number of remaining teeth during oral health examinations but did not ask the reason for tooth loss. Although severe periodontitis is considered the main cause of tooth loss in adults, several other causes exist, such as dental caries, trauma, orthodontic treatment, and iatrogenic factors. Therefore, the association between severe periodontitis and tooth loss in the current study may have been exaggerated [39, 40]. Second, the severity of dementia was not evaluated because of insufficient diagnostic and treatment records. Third, although the most common causes of dementia are multifactorial and heterogeneous, the current study considered only limited factors and did not include various genetic and familial factors such as the apolipoprotein E ε4 allele and family history. Therefore, the association between severe periodontitis and dementia may also have been exaggerated or underestimated.

Although our study had some limitations, severe periodontitis with very few remaining teeth may be considered a potential risk indicator or modifiable risk factor for the development of AD, VaD, and MD in Korean adults. Further comparative randomized controlled clinical studies with longer follow-up periods are required to strengthen the evidence for this conclusion and to determine the underlying mechanism of linkage between periodontitis and dementia.