This community-based survey revealed that the prevalence of a low MMSE score was significantly increased in association with the decrease in the number of remaining teeth (Figure 2). After adjustment for other explanatory variables (Table 2), a significant relationship between the decrease in the number of remaining teeth and a low MMSE score was observed. These results are consistent with those of previous reports demonstrating that tooth loss was associated with decreased cognitive function [21, 22]. We also revealed that a decrease in the number of remaining teeth was associated with the risk of MMI.
Four limitations of the present study merit consideration. The principal limitation was that the data were derived from a cross-sectional study; thus, we can only hypothesize for the biological credibility of the effect of tooth loss on MMI and a low MMSE score. Second, we did not investigate when tooth loss started or its causes. We also did not investigate markers of inflammation in the gingival crevicular fluid or alveolar bone loss measurements, by which the severity of periodontal disease can be evaluated more precisely than with the CPI code. Third, our criteria for identifying subjects with MMI were different from Ishikawa's criteria  as we identified the absence of dementia or depression using the MMSE and GDS screening tests; however, the prevalence of MMI in our study (2.9%: 121/4,206) was similar to the prevalence of Japanese community-based mild cognitive impairment (MCI) [23, 24] identified using the criteria of Petersen et al. . Therefore, the MMI subjects in this study are considered to approximate individuals with MCI. Fourth, apolipoprotein E (APOE) genotyping was not examined. Individuals with dementia had a higher frequency of APOE ε4 compared with non-demented individuals in Japanese-American men . The frequency of APOE ε4 was also higher in MCI subjects than in non-MCI individuals in a Japanese community . These findings indicate that APOE ε4 is an important risk factor for cognitive decline. The statistical relationship between tooth loss and cognitive function will weaken relatively among subjects with APOE ε4; therefore, our findings may have overestimated the relationship between tooth loss, MMI, and a low MMSE score.
The basis of the relationship between tooth loss and a low MMSE score was considered as given below. Older adults with a low MMSE score do not regularly use dental services . In addition, older adults with dementia have increased plaque accumulation . There may be other biological bases separate from the deterioration of dental health induced by cognitive impairment among tooth loss, MMI, and a low MMSE score, considering that a significant relationship was also found between tooth loss and MMI subjects who maintained the basic and instrumental ADL. Four further plausible biological explanations for the relationship between tooth loss and cognitive function can be proposed. First, periodontal disease, which is the cause of approximately 50% of all extractions in the elderly , may be associated with cognitive function through systemic inflammation. It has been hypothesized that inflammatory cytokines induced by periodontal disease can enter or influence the brain [9, 29]. Second, genetic risk factors related to periodontal disease and cognitive function may be present; an interleukin 1 gene polymorphism has been reported to be associated with the severity of periodontal disease  and the risk of AD . Third, a decrease in the number of periodontal mechanoreceptors due to tooth loss , which are sensory receptors, may result in a memory learning disorder. The functional deterioration of the cholinergic neuronal system in the parietal cortex has been observed in molar-loss rats . In addition, the number of high-affinity tyrosine kinase B mRNA-positive cells in the hippocampal CA3 area was negatively affected by the duration of tooth loss and the number of teeth extracted . However, these findings are based on animal models, and further investigations will be needed. Fourth, other risk factors may be related to tooth loss and cognitive function. Low socioeconomic status, negative events earlier in life, head traumas with maxillofacial injuries, and limitations on the choice of a healthy diet may be related to tooth loss and cognitive function.
Among edentulous subjects, a significant relationship was found between the length of the edentulous period and the risk of a low MMSE score after adjustment for their age at the baseline examination and other variables (Table 3). A history of "lost all teeth or lost half of teeth before age 35" was a significant risk factor for AD . We observed a higher prevalence of individuals who were edentulous for 15 years or more in the MMI group (50.0%) than in the control group (34.4%), although no significant relationship was found; therefore, tooth loss may have a cumulative detrimental effect on the brain.
While there was a significant relationship between the number of remaining teeth with the risk of MMI and a low MMSE score, no significant relationship was found between the CPI code, MMI, and a low MMSE score (Table 1 and Figure 2). The CPI is a marker of the current status of periodontal tissue, and it appears to underestimate the relationship between cognitive function and the cumulative burden of periodontal disease. We consider that tooth loss or periodontal disease may be associated with cognitive function because the prevalence of "Ineligible for CPI" was higher and the prevalence of "Code 0, 1, or 2" was lower in the MMI and low MMSE score groups than in the control group.