1 Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
2 Surveillance and Risk Assessment Division, Health Canada, Ottawa, ON, Canada.
3 Laval University Geriatric Research Unit, Beauport, QC, Canada.
4 Department of Social and Preventive Medicine, Laval University, Quebec, QC, Canada.
5 Sherbrooke University Geriatric Institute, Sherbrooke, QC, Canada.
6 Elisabeth Bruyère Health Centre, Ottawa, ON, Canada.
Received for publication December 14, 2001; accepted for publication May 9, 2002.
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ABSTRACT |
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Alzheimer disease; anti-inflammatory agents, non-steroidal; apolipoproteins; cohort studies; education; exercise; risk factors; wine
Abbreviations:
Abbreviations: APOE, apolipoprotein E; APOE4, apolipoprotein E 4 allele; CI, confidence interval; CSHA, Canadian Study of Health and Aging; EURODEM, European Community Concerted Action on Epidemiology and Prevention of Dementia; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; 3MS, Modified Mini-Mental State.
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INTRODUCTION |
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Even though investigations using prospective designs should reveal a more defined picture of the pathogenesis of Alzheimers disease, results obtained so far are not consistent. The European Community Concerted Action on Epidemiology and Prevention of Dementia (EURODEM) group associated smoking with a higher risk of Alzheimers disease (3), whereas other studies did not observe any significant relation between smoking and the onset of Alzheimers disease (46). The EURODEM group also found that female sex and low educational level were associated with increased risks of Alzheimers disease. Conversely, sex and education were not reported as risk factors for incident Alzheimers disease in other studies (7, 8). Methodological differences, such as duration of follow-up, and selection and number of study participants may account for these discrepancies.
The Canadian Study of Health and Aging (CSHA) is a large, national, multicenter, longitudinal study of dementia in elderly people focusing on its prevalence (1), incidence (9), and risk factors (1012). As part of the first phase (CSHA-1), a case-control study was conducted. Age, family history of dementia, educational level, arthritis, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) were significantly related to Alzheimers disease (10). We report here the results of a prospective analysis of risk factors for incident cases of late-onset Alzheimers disease, which were based on risk factor data collected at CSHA-1 from those who were cognitively normal and on diagnosis of incident Alzheimers disease 5 years later at CSHA-2.
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MATERIALS AND METHODS |
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Initial assessment (CSHA-1)
In 19911992, representative samples of men and women aged 65 years or older were drawn from 36 urban and surrounding rural areas; all 10 Canadian provinces were covered. Of the 10,263 participants, 9,008 lived in the community while 1,255 resided in institutions and were excluded from this analysis. Those in the community were interviewed about their health, presence of specific disorders, and limitations in performing basic and instrumental activities of daily living based on the Older Americans Resources and Services Activities of Daily Living scale (13). All participants were screened for dementia by using the Modified Mini-Mental State (3MS) Examination (14, 15). Those who screened positive (a 3MS Examination score of below 78/100) and a random sample of those who screened negative (a score of 78 or above) were invited to participate in an extensive clinical evaluation, which followed a three-stage protocol. A nurse first readministered the 3MS Examination and collected information on the participants medical and family history. Next, a physician conducted a standardized physical and neurologic examination. Finally, for those participants deemed testable (a 3MS Examination score of 50 or above), a psychometrist administered a series of neuropsychological tests (16), which were interpreted later by a neuropsychologist.
Independent preliminary diagnoses were made by the physician and neuropsychologist, which was followed by a case conference in which a consensus diagnosis was reached according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria for dementia (17); the National Institute of Neurological and Communicative Disorders and StrokeAlzheimers Disease and Related Disorders Association (NINCDS-ADRDA) criteria for Alzheimers disease (18); and other specific criteria for cognitive impairment (19) and vascular dementia (20). Diagnoses comprised the following categories: no cognitive impairment; cognitive impairment, no dementia; probable and possible Alzheimers disease; vascular dementia; other specific dementia; and unclassifiable dementia.
Detailed information about risk factors was gathered from a self-administered questionnaire completed at CSHA-1 by those participants found to be cognitively normal on the basis of either the screening test or clinical examination. The risk factor questionnaire covered sociodemographic characteristics, occupational and environmental exposures, lifestyle (smoking, alcohol consumption, intake of selected food items, and regular exercise), and family and medical history (prior head injury with and without loss of consciousness, chronic diseases, and medication use). Participants were asked whether they engaged in regular exercise (yes/no), but "regular" was not explicitly defined. Regular consumption of beer, wine, and spirits was defined as at least once a week. Regular consumption of tea and coffee was defined as nearly every day.
Follow-up study (CSHA-2)
In 19961997, all subjects who could be contacted and who agreed to participate in the second wave of the study were interviewed to measure changes in their health status and functioning an average of 5 years after CSHA-1. Participants took part in the same diagnostic process as the one used at CSHA-1, including the screening test, the nurse evaluation, and the clinical evaluation. Two diagnoses of dementia were made at a consensus conference, one according to the same criteria used at CSHA-1 and the other according to the more recent Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria (21) for Alzheimers disease and the National Institute of Neurological Disorders and StrokeAssociation Internationale pour la Recherche et lEnseignement en Neurosciences (NINDS-AIREN) criteria for vascular dementia (22). The more recent criteria were used to define cases for the current analysis. Blood samples were collected, and apolipoprotein E (APOE) allele status was determined in a subsample of subjects examined clinically (23).
For participants who died before the follow-up study was conducted, the date and cause of death were obtained from the relevant provincial Registrar of Vital Statistics, and a relative or other informant was interviewed to assess the subjects physical and cognitive status 3 months prior to death. For subjects who died during follow-up, the probability of dementia was estimated from three different sources (9): 1) mention of dementia on death certificates; 2) information from proxies about a diagnosis of memory problems, Alzheimers disease, or senile dementia prior to death; and 3) a logistic regression model, based on an analysis of 71 people who died within 25 months of a complete diagnostic evaluation, estimating the probability that the deceased person was demented prior to death. These estimates were available for 1,022 decedents (87.2 percent). Because this procedure did not permit diagnosis of the type of dementia, decedents were omitted from the main analysis. A secondary analysis was then conducted to assess the potential impact of omitting decedents; all deaths classified as due to dementia were included as Alzheimers disease cases, and deaths not due to dementia were considered controls.
Both phases of the CSHA were approved by the ethics review committees in all 18 participating study centers as well as at the coordinating center. Participants or their proxies provided informed consent for each component of the study. However, residents of the province of Newfoundland had to be omitted from the prospective analysis because a 1996 legal interpretation of the provinces advance directives legislation prohibited the use of proxy consent for persons unable to give full, informed consent to participate in research studies. This interpretation meant that people with dementia could not provide consent for the clinical examination (i.e., the outcome measure could not be obtained). Therefore, all Newfoundland participants were excluded.
Analysis
This analysis included only those participants living in the community as of CSHA-1. A case-control analysis was conducted, with incident cases and controls selected at CSHA-2. To be included, participants initial screening results had to be negative or, at CSHA-1, participants had to be clinically diagnosed without 1) cognitive impairment, no dementia or 2) dementia. Cases were diagnosed with probable or possible Alzheimers disease at CSHA-2. Comparisons were made with controls who, at CSHA-2, remained without cognitive impairment, no dementia or dementia according to the clinical evaluation or screening test at follow-up.
Differences between cases and controls regarding means and proportions were compared by using the t test and the chi-square test, respectively. Univariate and multivariate logistic regression models were used to calculate crude and adjusted odds ratios for the various risk factors. Under the rare disease assumption, the odds ratio can be considered a valid estimate of the relative risk. Age, sex, and education (age and education both as continuous variables with 1-year increments) were introduced into all multivariate models as potential confounders. Modification of risk by age, sex, and APOE 4 allele (APOE4) status was examined by using interaction terms.
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RESULTS |
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Demographic characteristics of the subjects are summarized in table 2. The distributions of age, sex, and education across cases and controls were significantly different. The cases were older than the controls (median age and range at CSHA-2 screening: 87 years; range, 69105 vs. 78 years; range, 70100). The cases had also completed fewer years of education (median, 10 vs. 11 years). Table 2 also presents the adjusted odds ratios for age, sex, and education. As expected, advanced age was strongly associated with higher risk of Alzheimers disease after we controlled for sex and education. When age was treated as a continuous variable, the risk of Alzheimers disease increased by 23 percent (95 percent confidence interval (CI): 1.19, 1.26) per additional year of age. The age- and sex-adjusted risk of Alzheimers disease for those with the lowest level of education was almost twice that for more educated participants. No association was observed between sex and risk of Alzheimers disease.
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DISCUSSION |
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We found that increasing age, low educational level, and the APOE4 allele were associated with increased risks of incident Alzheimers disease, while arthritis, regular use of NSAIDs, wine consumption, coffee consumption, and regular physical activity were associated with reduced risks. Of note, family history of dementia and smoking were not related to the risk of Alzheimers disease. In addition, estrogen was not shown to be protective.
However, our results are subject to potential limitations. First, of all eligible community subjects at baseline for whom a risk factor questionnaire was available, 1,172 (18.2 percent) died during the 5-year follow-up period and were not included in the main analyses. This group of decedents included proportionately more men, was generally older, was less educated, and suffered more frequently from chronic diseases than did subjects who completed follow-up. Exclusion of these participants may have distorted the results if, for example, these subjects were both more frequently exposed to a particular risk factor and at higher risk of developing Alzheimers disease. Results from the simulation that included those subjects who died suggest that, although arthritis, NSAID use, wine consumption, and coffee consumption might be potentially valid protective factors for Alzheimers disease, some bias due to exclusion of decedents during follow-up might also partially explain these associations.
Another limitation of our analysis is the possibility of bias in assessing risk factor exposures. In spite of the prospective nature of the study, our results could be explained, at least in part, by some preclinical cognitive decline (not yet detectable by screening and clinical evaluations at CSHA-1) among subjects who had developed Alzheimers disease by CSHA-2. Although it cannot be ruled out, this explanation seems improbable in view of the extensive screening and clinical evaluation process that was used at CSHA-1 to diagnose cognitive impairment, no dementia as well as dementia, along with the relatively long follow-up period. Nevertheless, to test this possibility, results were reanalyzed by excluding cases whose symptoms of Alzheimers disease were reported by their proxies to have started within 2 years after CSHA-1 (up to the end of 1993). The persistence of a protective effect on Alzheimers disease of NSAIDs (odds ratio (OR) = 0.61, 95 percent CI: 0.40, 0.97), wine (OR = 0.55, 95 percent CI: 0.30, 1.03), coffee (OR = 0.69, 95 percent CI: 0.48, 0.99), and physical activity (OR = 0.66, 95 percent CI: 0.47, 0.94) does not support the hypothesis that a preclinical decline explains our results.
Since multiple comparisons were performed, it is possible that some statistically significant associations may have occurred because of chance. For new associations that were found, for example, the protective effect of coffee drinking, replication in other studies will be needed to determine the validity of the association. Our results are generalizable to populations of largely European descent. Inclusion of different ethnic groups living in Canada was determined by their ability to speak either English or French.
Family history of dementia, similar to advancing age and the APOE4 allele, frequently has been associated with an increased risk of Alzheimers disease and is generally considered a definite risk factor (24). The CSHA-1 case-control study found an increased risk of Alzheimers disease that increased significantly by two- to threefold for family history of dementia (10). However, as in the EURODEM pooled data set (3), the prospective analysis of CSHA data did not find this association. These contradictory findings might reflect misclassification of the information because of recall bias and/or the uncertainty of information collected with the help of informants in retrospective investigations compared with longitudinal studies. In a case-control study, Mayeux et al. (25) observed that relatives of patients whose onset of Alzheimers disease began at age 70 years or older did not have an increased risk of Alzheimers disease, whereas there was an increased risk for first-degree relatives of patients whose onset occurred prior to age 70 years. Thus, it would seem reasonable that we did not observe this association in our older cohort. It may be surprising that family history of dementia was not associated with Alzheimers disease while an increased risk of Alzheimers disease was observed for subjects who had the APOE4 allele, since family history of dementia is believed to be a potential indicator of this genetic factor. However, it has been suggested that the APOE4 allele does not explain a large part of family history of dementia (26). In this study, 13 percent of those who had at least one APOE4 allele reported a parent with dementia compared with 10 percent of those who had no 4 allele.
The association between low educational level and the risk of Alzheimers disease is consistent with findings from several retrospective and prospective studies (3, 10, 2729). As in other large-scale population-based studies, CSHA cases were ascertained by means of a two-phase diagnostic procedure (screening and clinical examination). The cutpoint for screening with the 3MS Examination was chosen to achieve high sensitivity, even though this cutpoint could have missed mild cases of Alzheimers disease in people with higher levels of education who could still perform well on cognitive screening tests. Whether the risk of Alzheimers disease associated with less education corresponds to an artifact or represents a true risk factor is still unclear. Explanations for the education effect include increased brain reserve (30), selection bias resulting from selective attrition or use of a two-phase diagnostic procedure (27, 31), and confounding by indicators of socioeconomic status linked to education, such as diet, lifestyle, and occupational history (32, 33).
The present analysis supports the hypothesis of a negative association between NSAIDs and the risk of Alzheimers disease. This protective relation was also found in several population-based case-control studies, including the CSHA-1 analysis (34). At least one longitudinal study supports the protective effect of anti-inflammatory drugs against Alzheimers disease and dementia (35), while some studies remain inconclusive (36, 37).
Regular wine consumption was also associated with a reduced risk of Alzheimers disease. Results from the PAQUID Study, a longitudinal study of community residents, showed a similar negative relation between wine consumption and Alzheimers disease (38). This protective effect remained significant after more in-depth statistical analyses were conducted (39). It has been suggested that specific substances in wine, but not in other alcoholic beverages, could be responsible for this positive effect on nerve cells in dementia (40).
In our analysis, regular consumption of coffee seemed to be protective for Alzheimers disease. Low coffee intake was reported to be related to mental disability after a 25-year follow-up of 716 Finnish men (41). Without confirmation from other prospective studies of Alzheimers disease, this finding may have been due to chance.
The potential protective effect of regular physical activity on the risk of Alzheimers disease is important because it represents a modifiable lifestyle habit. Few epidemiologic studies have evaluated the possible protective role of regular physical activity on the risk of cognitive impairment and dementia in the elderly, and results have been inconsistent (7, 42). However, in clinical trials, exercise has been shown to benefit cognitive function (43, 44). More recently, regular physical activity has been found to be protective against cognitive impairment as well as all types of dementia, including Alzheimers disease, and an interaction with sex has been reported, suggesting greater protection in women than in men (45).
In conclusion, this large-scale prospective study of older-age onset of Alzheimers disease confirmed some of the most frequently suggested etiologic hypotheses about the disease, but not all. Intriguing protective associations observed in our study warrant further research. Few preventive strategies for Alzheimers disease have been explored. Regular physical activity could represent a novel and safe preventive strategy against Alzheimers disease and many other conditions, and it should be examined further.
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ACKNOWLEDGMENTS |
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The authors are grateful to Richard Aylesworth and Louis Rochette for statistical assistance.
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NOTES |
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REFERENCES |
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