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J Am Dent Assoc, Vol 138, No 10, 1314-1322.
© 2007 American Dental Association
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COVER STORY

JADA Continuing Education

Tooth loss, dementia and neuropathology in the Nun Study

Pamela Sparks Stein, DMD, Mark Desrosiers, PhD, Sara Jean Donegan, SSND, DDS, Juan F. Yepes, DDS, MD, MPH and Richard J. Kryscio, PhD


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background. Numerous studies have linked dementia to the subsequent deterioration of oral health. Few investigators, however, have examined oral disease as a potential risk factor in the development of dementia. The authors conducted a study to investigate a potential association between a history of oral disease and the development of dementia.

Methods. Longitudinal dental records supplemented data collected from 10 annual cognitive assessments of 144 Milwaukee participants in the Nun Study, a longitudinal study of aging and Alzheimer disease, who were 75 to 98 years old. Neuropathologic findings at autopsy were available for 118 participants who died.

Results. A low number of teeth increased the risk of higher prevalence and incidence of dementia.

Conclusion. Participants with the fewest teeth had the highest risk of prevalence and incidence of dementia.

Clinical Implications. Edentulism or very few (one to nine) teeth may be predictors of dementia late in life.

Key Words: Epidemiology; periodontal disease; Alzheimer disease

Abbreviations: apoE4: Apolipoprotein E4 allele.

Many cross-sectional studies1–14 and some longitudinal studies15,16 have shown that patients with dementia are more likely to have poor oral health. Few investigators,17–19 however, have attempted to relate oral disease to the subsequent risk of developing cognitive impairments and dementia. Such an association is biologically plausible.20 Potential mechanisms include inflammatory mediators produced in response to periodontal pathogens,21–28 which produce chronic systemic inflammation and neuropathology; increased risk of stroke and cerebrovascular injury in those with periodontal disease29–34; and dissemination of oral gram-negative bacteria to the brain35–46 via a transient bacteremia. Oral bacteria also may spread to the brain via neuronal pathways. Riviere and colleagues47 suggested that oral bacteria may use branches of the trigeminal nerve to reach the brain. In their postmortem examination of brain tissues, they detected antigens of oral treponemes more often in samples from subjects with Alzheimer disease (14 of 16) than in samples from control subjects (four of 18).

The Nun Study, a longitudinal study of aging and Alzheimer disease, offers a unique model for the study of oral health and cognitive function. Participants in the Nun Study are Roman Catholic sisters who are members of the international congregation of the School Sisters of Notre Dame. At the first examination, conducted from 1991 through 1993, the 678 sisters who agreed to participate in all phases of the study—including annual cognitive assessments and brain donation on death—were 75 to 102 years old (mean age, 83 years). Two hundred of these Nun Study participants were members of the Milwaukee province (region) of the congregation, and 165 had been dental patients of the Milwaukee province dentist (S.J.D.). We limited this study to Nun Study participants in the Milwaukee province because it was the only province that had an on-site dental clinic and a full-time dental staff. The Milwaukee province dentist began practicing in 1964 and has remained the dentist for the sisters since that time. Combining 40 years of longitudinal dental data from a private practice and 12 years of longitudinal findings from annual cognitive assessments with brain autopsies from the Nun Study provides an unparalleled opportunity to study dental health, dementia and neuropathology.

Dementia is a complex and multifactorial disease, and it is unlikely that any one mechanism is completely causal. However, specific risk factors have been identified that increase the probability for developing Alzheimer disease. In 1993, a polymorphism in the apolipoprotein E4 allele (apoE4) was discovered to be a major risk factor for late-onset Alzheimer disease.48 This gene promotes the deposition of beta-amyloid protein in the brain, contributing to the formation of senile plaques. People who have inherited a single E4 allele of apolipoprotein (APOE) experience a twofold to fivefold increase in risk of developing Alzheimer disease.49

We investigated the relationships between tooth loss, dementia and neuropathology in participants in the Nun Study, a study that already has yielded much data on dementia and neuropathology.50–58


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Study population. Of the 165 Nun Study participants who were patients of the Milwaukee province dentist (S.J.D.), 148 were patients before and after they participated in the first cognitive assessment in the Nun Study. For two of those patients, there were no data on the presence or absence of apoE4. Two additional patients who were found to have dementia at the first examination had a history of psychiatric conditions dating back to early adult life. Elimination of these four patients resulted in a final sample of 144 Nun Study participants.

Characteristics of our sample of 144 participants were similar to those of the total Nun Study population of 678 sisters. The 144 participants in this study were 75 to 98 years old (mean age, 84 years) at their first cognitive examination. This differs only slightly from the entire population of 678 participants, who ranged in age from 75 to 102 years. Eighty-five percent of the participants in our subset had attained at least a bachelor’s degree, 88 percent had been teachers most of their lives, and 22 percent had one or more copies of the major genetic risk factor for Alzheimer disease, the apoE4 allele. Of the other Nun Study participants not included in our sample, 84 percent had attained at least a bachelor’s degree, 90 percent had been teachers most of their lives, and 23 percent had one or more copies of apoE4.

Nun Study participants live in one of seven provinces throughout the United States. These provinces are located in rural areas such as Chatawa, Miss., Wilton, Conn., and Mankato, Minn, and urban areas such as Chicago, St. Louis, Baltimore and Milwaukee, the province from which we obtained our subset. Although these sisters live in different areas throughout the United States, their living conditions, diet and medical care are similar.

Oral and dental health. Information contained in the dental records included clinical notes made by the Milwaukee province dentist (S.J.D.) regarding treatment, as well as the charting of missing, carious and restored teeth. In most cases, the records contained radiographs. Documented or written information regarding the periodontal status of the patients (probing depths, clinical attachment level, percentage of sites with bleeding at probing and periodontal diagnoses) was not available in the patients’ records. Another dentist (P.S.S.) reviewed each participant’s dental record, documenting the number of teeth observed and lost across time during the participant’s tenure as a patient. She recorded the date and reason for each extraction. Reasons included periodontal disease, caries, breakage, periapical disease, pain, failed restoration and multiple causes.

Using these longitudinal data, we determined the number of non–third molars for the date of the first cognitive examination. The primary consideration in categorizing the number of non–third molars present was to create groups of at least 10 participants at the extremes of the continuum of the number of teeth present. A group with one to nine non–third molars was at one end of that continuum. (We kept the edentulous separate from this group because they did not have active periodontal disease or other dental diseases.) At the other end of the continuum, we created a group with 17 to 28 non–third molars. We created a middle category with 10 to 16 non–third molars.

Medical history assessment. Most of the dental records contained medical histories. A dentist (P.S.S.) reviewed the medical histories, documenting for each subject the presence or history of any medical conditions known to be associated with an inflammatory process. Five physicians collaborated to create the list of inflammatory conditions, which included allergies, rheumatoid arthritis, asthma, cardiovascular disease, Crohn disease, eczema, lupus erythematosus, psoriasis, rosacea, temporal arteritis and ulcerative colitis.

Radiographic examination. We used full-mouth radiographs obtained before the first cognitive examination to assess alveolar bone loss and damage to periodontal tissues. One of the authors (J.F.Y.) performed all radiographic examinations under ideal conditions (in a dark-room using a magnifier and a viewing box). The same independent observer, who had experience in radiograph interpretation, measured the marginal bone level by means of a calibrated rule.

We based the radiographic measurements on alveolar bone loss from the cementoenamel junction. We classified the degree of periodontal damage of the participants by using methodology and criteria previously described by Jansson and colleagues.59 We classified participants who had 4 to 6 millimeters of alveolar bone loss in 33 percent or more of their teeth as having moderate periodontal damage and those with more than 6 mm of alveolar bone loss in 33 percent or more of their teeth as having severe periodontal damage. Because of the low number of participants classified as having severe periodontal damage (1.3 percent), we combined the moderate and severe categories.

Cognitive function and dementia. Two field-trained gerontologists assessed the participants’ cognitive function annually by a battery of tests. These tests evaluated memory, concentration, language, visuospatial ability, and orientation to time and place.60 The gerontologists assessed social and daily physical functions by means of performance-based testing.61,62 Participants classified as having intact (high) cognitive function had normal global cognitive and physical function (as measured by the Mini-Mental State Examination and Activities of Daily Living), as well as scores within normal limits on tests of memory, language and visuospatial ability (as measured by scores on the Delayed Word Recall Test,60 the Boston Naming Test,60,63 the verbal fluency test and constructional praxis test60) (as described by Riley and colleagues55). Participants considered to have dementia according to Nun Study criteria had each of the following conditions:

– impairment in memory;
– impairment in at least one other area of cognition, such as language or visuospatial ability;
– impairment in social or daily function, such as inability to use a phone or handle money.55

apoE genotyping. Two scientists performed genotyping by using genetic material from buccal cells collected from living participants by a field-trained gerontologist or from frozen or paraffin-embedded brain specimens obtained at autopsy by the neuropathologist for the Nun Study according to a protocol already described.64,65 On the basis of the six standard apoE genotypes (2/2, 2/3, 2/4, 3/3, 3/4, 4/4), we used a binary variable coded as presence or absence of any E4 allele.

Neuropathology. A neuropathologist who was blinded to the participants’ cognitive test scores performed standard gross and microscopic evaluations of the participants’ brains (n = 118) according to previously described protocol.56 He identified brain infarcts by examining the intact brain and 1.5-centimeter–thick coronal sections of the cerebral hemispheres, brain stem and cerebellum. He classified infarcts visible to the naked eye as either lacunar (< 1.5 cm) or large (> 1.5 cm) (a classification described by Snowdon and colleagues50). He determined the severity of Alzheimer disease neuropathology using the staging method of Braak and Braak.66 Braak stage 0 includes cases without any entorhinal or hippocampal neurofibrillary tangles or only extremely rare transentorhinal tangles; stages I and II indicate neurofibrillary disease in the entorhinal cortex; stages III and IV involve increasing neurofibrillary disease in the entorhinal cortex and in other medial temporal lobe structures, including the hippocampus and the amygdala; and stages V and VI involve additional neurofibrillary disease in the neocortex.66,67

Statistical methods. We used logistic regression to analyze prevalence data and derive adjusted odds ratios (ORs). The main independent variable was the number of non–third molars. We coded categories of teeth as 0 for the edentulous group, 1 for those with one to nine teeth, 2 for those with 10 to 16 teeth, and 3 for those with 17 to 28 teeth. We used Cox proportional hazards regression to calculate hazards ratios for incidence data.68 We coded the following covariates as binary variables: college education, presence of apoE4, brain infarct identified at autopsy, presence of moderate-to-severe damage to periodontal tissues and presence of any medical inflammatory condition. All correlations were Spearman rank correlations. A test for trend was based on the Cochran-Armitage statistic for the percentage who lost a tooth owing to periodontitis as well as on a test for linearity in a one-way analysis of variance for the mean number of teeth lost due to periodontitis. We used two-tailed P values in all analyses. The statistical package we used was SAS/STAT (Version 9, SAS System for Windows, SAS Institute, Cary, N.C.). The {alpha} level of significance for our analysis was .05.

Approximately one-third of the participants with no teeth or very few teeth (one to nine) had dementia at the first cognitive examination.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
In the subset of 144 participants in our study, the first cognitive examinations took place between October 1991 and October 1992.

The number of non–third molars teeth present had a strong inverse association with past tooth loss due to periodontal disease as determined by clinician’s notes (Table 1Go). The number of non–third molars also was inversely correlated with age (r = –0.41; P < .0001) and positively associated with attained education ({chi}2 = 24.3; P < .0001), but was not associated with the presence of apoE4 ({chi}2 = 2.7; P = .44).


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  		TABLE 1 The relationship of number of non–third molars at the last dental visit to past tooth loss due to periodontal disease as determined by clinician’s notes.*

 
Approximately one-third of the participants with no teeth or very few teeth (one to nine) had dementia at the first cognitive examination (Table 2Go). In those with 10 or more teeth, the percentage with dementia was 17 percent or less. Adjusting for age and education, we found that the number of non–third molars present was not significantly associated with dementia prevalence at the first cognitive assessment in the total population of all participants. We tested for effect sizes and found a significant interaction between the number of teeth and apoE4 (P = .04)—that is, the allele was a statistically significant modifier of the association between tooth loss and dementia prevalence. The interactions between number of teeth and age or education were not statistically significant. Table 2Go shows the prevalance of dementia in the total population of participants (n = 144) and two subsets, one with apoE4 (n = 32) and one without (n = 112). In the 112 participants without apoE4, a low number of teeth (one to nine) was significantly associated with dementia prevalence after we adjusted for age and education. A combined category (zero to nine), comprising the edentulous and group with a low number of teeth (one to nine), also was significantly associated with dementia prevalence (OR = 4.3, 95 percent confidence interval [CI] = [1.16–15.60], P = .03).


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  		TABLE 2 Prevalence of dementia at the first examination, by number of non–third molars.

 
Medical histories were available for 133 participants. Sixty had one or more medical conditions associated with documented inflammatory disease. Adding the risk factor of inflammatory disease did not alter the significance of the association between those with one to nine teeth and the prevalence of dementia in the subset of the population without apoE4, but in fact increased the OR (OR = 8.2, 95 percent CI = [1.34–49.80] P = .02). The categories of the number of teeth were not associated with the presence of one or more inflammatory conditions ({chi}2 = 1.5; P = .67).

Full-mouth radiographs obtained before the first cognitive examination were available for 76 participants. All participants had some alveolar bone loss; 68 percent had slight periodontal damage, 30 percent had moderate periodontal damage, and 1 percent had severe periodontal damage. There was a significant inverse relationship between the number of teeth and moderate-to-severe periodontal damage as assessed via radiographic examination (r = –0.31, P = .01). Adjusting for age, education and apoE4, we found that moderate-to-severe periodontal damage, as evidenced by alveolar bone loss, was not associated with dementia at the first cognitive examination (OR = 1.5, 95 percent CI = [0.37–5.8]) or incidence of dementia (hazards ratio = 2.4, 95 percent CI = [0.86–6.6). Nor was it related to Alzheimer disease neuropathology ({chi}2 = 1.1, P = .29) or brain infarcts (2 0.21, P = .65).

We based our incidence analysis on the 101 participants who did not have dementia at the first examination and who had undergone at least one additional cognitive examination. We further collapsed the four tooth categories into two categories, a low number of teeth (zero to nine) and a high number of teeth (10 to 28), owing to the similarities of these categories found in the prevalence analysis. Adjusting for age, education and presence of apoE4, we found that presence of a low number of non–third molars (zero to nine) was associated with the incidence of dementia during the subsequent 12 years of observation in the Nun Study (Table 3Go). Only 15 of the 101 participants had apoE4; no one in the zero-to-nine tooth category in this group developed dementia. Thus, we could not test for an interaction between the number of teeth and apoE4 and, therefore, did not create apoE4 subgroups.


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  		TABLE 3 Incidence of dementia after the first cognitive examination, by number of non–third molars.

 
Of the 144 participants in our study, 15 were living and 129 were deceased. Neuropathologic examination results were available for 118 of the deceased participants. In this subset, adjusting for age, education and presence of apoE4, we found no association between the number of teeth and the severity of Alzheimer neuropathology, Braak stage (OR = 1.1, 95 percent CI = [0.49–2.7], P = .75) and no association between number of teeth and brain infarcts (OR = 1.14, 95 percent CI = [0.49–2.66], P = .76).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Only a few studies17–19 have explored a potential link between oral disease and the subsequent risk of developing dementia. Data from two case-control studies suggest that tooth loss may be a significant risk factor for Alzheimer disease.17,19 In our prospective longitudinal study, we found an association between the presence of a low number of teeth and the prevalence and incidence of dementia.

Thirty-two of the 144 participants in our study had dementia at the first cognitive examination in the Nun Study. (Eleven participants did not have more than one cognitive examination.) We do not know how long these sisters had had dementia. They may have had dementia when some of their teeth were extracted, in which case the dentist may have thought it was easier to extract than to restore their teeth. However, we excluded from our incidence analysis the participants who had dementia at the first examination and followed only those participants who did not have dementia at the first examination. Of the participants who did not have dementia at the first examination, those with few teeth (zero to nine) had an increased risk of developing dementia during the study compared with those who had 10 or more teeth. It is interesting that we found this increase in risk only in those without apoE4.

Additionally, in participants without apoE4, a low number of teeth (one to nine) significantly increased the risk of having dementia at the first cognitive examination (OR = 6.4) compared with participants in the reference group, who had 17 to 28 teeth. This increase in odds did not occur in the participants with apoE4. Perhaps apoE4 is such a strong risk factor for Alzheimer disease that it significantly modifies the association between tooth number and dementia.

We assessed damage to alveolar bone from periodontal disease and other conditions of an inflammatory nature to investigate the potential role of inflammation in our findings. Inflammation has been suggested as playing a role in the pathophysiology of Alzheimer disease.69 Chronic "trickling" of periodontal pathogens into the systemic bloodstream may result in a sustained elevation of inflammatory products within the circulation.21 In addition, inflammatory cytokines produced in the periodontal tissues may disseminate into the bloodstream.70–72 The potential role of cytokines in neurological changes relating to psychiatric disorders, including Alzheimer disease, has been highlighted in the literature.73 The presence of interleukin-6, a cytokine significantly elevated in severe periodontal disease,28 has been demonstrated in and around senile plaques.74 This cytokine may regulate the production of beta-amyloid protein found in senile plaques.75 Interleukin-1 (IL-1), another cytokine associated with periodontal disease,76 also has been implicated in Alzheimer pathogenesis.77 Furthermore, several studies have linked polymorphisms (variations) in the IL-1 gene family to periodontal disease78–85 and Alzheimer disease.86–89 Although these polymorphisms are found at different loci, one might consider the possibility that these polymorphisms reflect a hyperinflammatory genotype that could be an underlying trait common to people with periodontal disease and people with dementia.

Although not statistically significant, the adjustment for one or more inflammatory diseases increased the odds of dementia at the first cognitive examination in those with few teeth (one to nine) from OR = 6.4 to OR = 8.2. However, we found no significant association between dementia and a history of periodontal disease, as marked by alveolar bone loss. Moderate-to-severe periodontal damage to the alveolar bone was not a significant predictor of dementia, nor was it related to Alzheimer disease or brain infarcts. Documenting the amount of alveolar bone loss from full-mouth radiographs does not present a comprehensive evaluation of the true periodontal disease burden of the participants. It only provides information about their history of periodontal disease. Full-mouth radiographs were not available for all participants; the final radiographic sample included 76 participants. Limitations of radiographic analysis have been described previously90 and include variability of technique including angulation and patient positioning, variations in opacity and contrast, differences in film speed and processing and masking of alveolar bone by other anatomical structures. Periodontal data, therefore, must be interpreted with caution. Further studies are necessary for a more comprehensive investigation of the potential role of periodontal disease in the association between tooth loss and dementia.

Besides periodontal disease, there are other possible explanations for the observed association between number of teeth and dementia in our study. Because the brain is undergoing final maturation in childhood, adolescence and even young adulthood, oral diseases in early life might be particularly damaging to the brain. One must consider the cumulative burden of all oral infections throughout the participant’s lifetime, both odontogenic and periodontal. Alternatively, the association may be due to some unmeasured or unobserved confounding factor. For example, tooth loss could be marking early life stressors and low socioeconomic status, which may have played a role in development of dementia in late life. Nutritional deficiencies, infections or chronic diseases in early life may result simultaneously in tooth loss and damage to the brain.

Although unmeasured confounding is a potential limitation of any observational study, our unique study population minimized many confounding factors. Our sample was composed of a relatively highly educated population of primarily teachers, living in similar housing, who did not smoke, who did not drink heavily, and who had the same marital and reproductive history, similar medical and nursing care, and dental care from the same dentist for an average of 21 years.


   CONCLUSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Regardless of the issues of confounding and biological mechanisms, our findings suggest that a low number of teeth has an association with dementia late in life. However, one should not ascribe causality on the basis of the findings of this investigation. It is not clear from our findings whether the association is causal or casual. Further studies are necessary to determine the true nature of the association between tooth loss and dementia.


   FOOTNOTES
 

Dr. Stein is assistant professor, Department of Anatomy and Neurobiology, College of Medicine, MN 210 Chandler Medical Center, University of Kentucky, Lexington, Ky. 40536, e-mail "pam.stein{at}uky.edu". Address reprint requests to Dr. Stein.


Dr. Desrosiers is a scientist III, Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington.


Dr. Donegan is a professor, Department of General Dental Sciences, School of Dentistry, Marquette University, Milwaukee.


Dr. Yepes is an assistant professor, Department of Oral Health Practice, Division of Oral Diagnosis, Medicine and Radiology, Department of Diagnostic Radiology, College of Dentistry and Medicine, University of Kentucky, Lexington.


Dr. Kryscio is the director, Biostatistics and Data Management, Alzheimer’s Disease Center, Sanders-Brown Center on Aging; the chair, Department of Biostatistics, College of Public Health; and a professor, Department of Statistics, College of Arts and Sciences, University of Kentucky, Lexington.


This study was funded by grants R01AG09862, K04AG00553 and 1P30AG028383 from the U.S. National Institute on Aging, Bethesda, Md., and grants from the Abercrombie Foundation, Versailles, Ky., and The Robert J. Jr. and Helen C. Kleberg Foundation, San Antonio. Additional funding was provided by grant K30HL04163 and grant P20 RR020145 from the National Center for Research Resources, Bethesda, Md., a component of the National Institutes of Health.


This study would not have been possible without the generous and enthusiastic support of the members and leaders of the School Sisters of Notre Dame congregation, their health care providers and particularly the dental staff at the Milwaukee convent. The authors thank the Nun Study personnel for providing the data for this study and for their assistance in this project.


More information about the Nun Study may be obtained at "www.nunstudy.org".


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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
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