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Physical Activity and Risk of Cognitive Impairment and Dementia in Elderly Persons
Danielle Laurin, MSc;
René Verreault, MD, PhD;
Joan Lindsay, PhD;
Kathleen MacPherson, MD;
Kenneth Rockwood, MD
Arch Neurol. 2001;58:498-504.
ABSTRACT
Context Dementia is common, costly, and highly age related. Little attention
has been paid to the identification of modifiable lifestyle habits for its
prevention.
Objective To explore the association between physical activity and the risk of
cognitive impairment and dementia.
Design, Setting, and Subjects Data come from a community sample of 9008 randomly selected men and
women 65 years or older, who were evaluated in the 1991-1992 Canadian Study
of Health and Aging, a prospective cohort study of dementia. Of the 6434 eligible
subjects who were cognitively normal at baseline, 4615 completed a 5-year
follow-up. Screening and clinical evaluations were done at both waves of the
study. In 1996-1997, 3894 remained without cognitive impairment, 436 were
diagnosed as having cognitive impairment–no dementia, and 285 were diagnosed
as having dementia.
Main Outcome Measure Incident cognitive impairment and dementia by levels of physical activity
at baseline.
Results Compared with no exercise, physical activity was associated with lower
risks of cognitive impairment, Alzheimer disease, and dementia of any type.
Significant trends for increased protection with greater physical activity
were observed. High levels of physical activity were associated with reduced
risks of cognitive impairment (age-, sex-, and education-adjusted odds ratio,
0.58; 95% confidence interval, 0.41-0.83), Alzheimer disease (odds ratio,
0.50; 95% confidence interval, 0.28-0.90), and dementia of any type (odds
ratio, 0.63; 95% confidence interval, 0.40-0.98).
Conclusion Regular physical activity could represent an important and potent protective
factor for cognitive decline and dementia in elderly persons.
INTRODUCTION
DEMENTIA represents a major health problem in aging societies.1 Apart from hormonal replacement therapy2, 3
and antihypertensive4, 5 and nonsteroidal
anti-inflammatory drug6 treatments, few preventive
strategies for dementia and its leading cause, Alzheimer disease, have been
explored.7, 8, 9 Comparatively
little attention has been paid to the identification of modifiable environmental
factors such as diet and lifestyle habits, including physical fitness.
Physical activity has well-known benefits for several chronic disorders,1, 10, 11 including coronary
artery disease, stroke, diabetes mellitus, and osteoporosis. While its influence
on premature mortality among both young and old segments of the elderly population
is also well established,12, 13, 14, 15
the evidence that physical activity may delay cognitive loss and impairment
is more equivocal.10, 16, 17
In clinical settings, beneficial effects of physical fitness interventions
on memory and other aspects of cognition have been documented in elderly persons,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30
although inconsistently.31, 32, 33, 34
Few epidemiological studies have examined the role of physical activity
on the risk of cognitive impairment and dementia in elderly persons. Suggestions
that exercise may be protective for dementia, and for Alzheimer disease in
particular, have been made in some case-control studies using prevalent cases,35, 36 but again these findings have not
consistently been replicated.37, 38, 39
In these studies, retrospective assessment of physical activity limits the
validity of the results. Discordant results have also been reported in a few
prospective studies.40, 41, 42
This study evaluates the association between regular physical activity
and subsequent occurrence of cognitive impairment and dementia, within the
Canadian Study of Health and Aging (CSHA), a large-scale, prospective cohort
study, based on a representative sample of the elderly Canadian population.
SUBJECTS AND METHODS
Data come from the community sample of the CSHA, a national, multicenter,
prospective cohort study, designed to focus on the prevalence, incidence,
and risk factors for dementia and Alzheimer disease in elderly Canadians.
Methodological details of the study have been described elsewhere.43, 44, 45 Briefly, during the
first wave of the study conducted in 1991-1992 (CSHA-1), representative samples
of men and women 65 years or older were drawn from population-based listings
for 36 urban and surrounding rural areas in all 10 Canadian provinces. Of
the 10 263 people involved, 9008 were living in the community and constituted
our initial pool of subjects. All subjects were interviewed to ascertain their
perceived health status, general chronic conditions, and functional ability
in basic and instrumental activities of daily living, based on a modified
version of the Older Americans Research Survey scale.46
Participants were screened for dementia using the Modified Mini-Mental State
(3MS) Examination.47, 48 Subjects
who screened positive (3MS Examination score  77), and a random sample
of those who screened negative (3MS Examination score  78) were asked to
attend an extensive standardized 3-stage clinical evaluation.49
A nurse first screened for hearing and vision problems, and collected information
about medication regimen and medical and family histories. Next, a physician
carried out standardized physical and neurologic examinations. Third, a psychometrist
administered a neuropsychological test battery50
to all individuals deemed testable (3MS Examination score 50), the results
of which were interpreted by a neuropsychologist. Preliminary diagnoses were
made independently according to Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition criteria51 by the physician and the neuropsychologist who subsequently
arrived at a diagnosis in a consensus conference. Consensus diagnoses constituted
the following: no cognitive impairment, cognitive impairment–no dementia
[CIND],52 Alzheimer disease (probable or possible)
according to NINCDS-ADRDA (National Institute of Neurological Disorders and
Stroke–Alzheimer's Disease and Related Disorders Association) criteria,53 vascular dementia according to World Health Organization International Classification of Diseases, 10th Revision
criteria,54 other specific dementia and unclassifiable
dementia. All subjects without dementia were asked to complete and return
by mail a self-administered risk factor questionnaire covering specific expositions
for which prior hypotheses existed. This questionnaire included questions
about demographic characteristics, occupational and environmental exposures,
lifestyle, and medical and family histories.
Follow-up was carried out in 1996-1997 (CSHA-2). All subjects who could
be contacted and who agreed to participate in the second wave were reinterviewed
to measure changes in health status and functioning following a 5-year period
on average. Subjects took part in the same diagnostic process as in CSHA-1,
including screening and clinical evaluation. Diagnoses from consensus conferences
in CSHA-2 were made without knowledge of CSHA-1 diagnoses. Two final diagnoses
were made for dementia and vascular dementia, one according to the same criteria
used in CSHA-1, and the other according to more recent Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition55 and NINDS-AIREN (National Institute of Neurological
Disorders and Stroke–Association Internationale pour la Recherche et
l'Enseignement en Neurosciences) criteria.56
Exercise data were collected as part of CSHA-1 when subjects were not
demented and represent a proxy for earlier activity up until the time of baseline.
The level of physical activity was assessed by combining 2 questions from
the risk factor questionnaire regarding frequency and intensity of exercise
for subjects who reported regular physical activity. A composite score rating
physical activity as either low, moderate, or high, was obtained by summing
answers to the frequency question (3 times per week, weekly, or less than
weekly) and the intensity question (more vigorous, equal to, or less vigorous
than walking). A high level of physical activity corresponded to an exercise
engaged 3 or more times per week at an intensity greater than walking, while
a moderate level of physical activity corresponded to exercise also engaged
3 or more times per week, but of an intensity equal to walking. All other
combinations of frequency and intensity were considered as a low level of
physical activity. Subjects who reported no regular exercise constituted the
reference category. The measurement properties of this index were assessed
with an independent sample of 738 elderly individuals, to whom the risk factor
questionnaire was administered by an interviewer. Construct validity was assessed
by comparing the combined score with other reported markers of health hypothesized
to be related to exercise and self-rated health. The average intraclass coefficient
for the combined score was 0.76 (95% confidence interval [CI], 0.72-0.79; P = .002), while the combined score demonstrated satisfactory
construct validity, and seemed to be well associated with mortality over 5
years.57
Ethical approval for the study was obtained from ethics review boards
in all participating centers. Subjects living in the province of Newfoundland
had to be excluded from CSHA-2 final analyses, because of recent provincial
legislation restricting the possibility of obtaining consent from proxies
for participation of mentally incompetent subjects.
DESIGN
The effect of physical activity on cognitive impairment and dementia
was analyzed using a case-control approach within the CSHA-1 cohort, with
incident cases and controls selected at the end of CSHA-2. To be included
in the analysis, subjects initially had to be screened negative or without
dementia or CIND according to the clinical evaluation. The following 4 outcomes
were examined according to CSHA-2 final diagnoses: CIND, Alzheimer disease,
vascular dementia, and any type of dementia. The diagnosis of dementia for
these analyses was based on the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition criteria.55
Subjects who remained without cognitive impairment or dementia in CSHA-2,
according to the screening test and/or the clinical evaluation, served as
controls. A fifth end point was examined among controls only and consisted
of whether they experienced a reduction of 5 points or more on the 3MS Examination
score from CSHA-1 to CSHA-2.
STUDY POPULATION
Of the 9008 subjects in the original sample at CSHA-1, 442 subjects
from Newfoundland were excluded from the analyses as were 826 subjects diagnosed
as having CIND or dementia in CSHA-1. Of the remaining 7740 eligible subjects,
6434 (83.1%) subjects had a risk factor questionnaire available. Subjects
who died during the follow-up period (n = 1172), who refused to participate
in CSHA-2 (n = 374), or who were lost to follow-up (n = 273) also were excluded,
leaving 4615 subjects. Of these, 3894 were still not cognitively impaired
in CSHA-2 (controls) and 436 were diagnosed as having CIND, 194 Alzheimer
disease, 61 vascular dementia, and 30 other specific or unclassifiable dementia.
STATISTICAL ANALYSIS
Five separate analyses were performed to assess the associations between
exercise and incident cognitive loss, CIND, Alzheimer disease, vascular dementia,
and any type of dementia. Univariate and multivariate logistic regression
models were used to analyze the crude and adjusted odds ratios (ORs) for the
5 end points. Age, sex, and education were included in all multivariate models
as potential confounders; age and education were entered as continuous variables.
Other variables examined as potential confounders included the following:
family history of dementia; regular smoking; regular alcohol consumption;
use of nonsteroidal anti-inflammatory drugs; a summation score for the 7 items
of activities of daily (ie, eating, transferring [ie, the capacity to get
in and out of bed], toileting, grooming, dressing, walking, and bathing);
a summation score for the 7 items of instrumental activities of daily living
(ie, self-medicating, telephone use, handling money, meal preparation, walking
outside, shopping, and housework); self-rated health; and number of reported
chronic diseases from a list of 10 conditions (ie, heart disease, hypertension,
cancer, stroke and other neurologic diseases, arthritis, ulcer, diabetes mellitus,
thyroid disease, kidney disease, and depression). Modification of risk by
age, sex, education, and family history of dementia was investigated using
interaction terms.  2 Tests for linear trend were performed
using the 4-level physical activity variable as an ordinal variable in adjusted
models.
RESULTS
Unimpaired subjects were younger and had completed more years of education
(medians of 72 and 11 years, respectively) than those with CIND (medians of
78 and 9 years) or dementia (medians of 80 and 10 years) (Table 1). The sex distribution was similar across categories. Reported
regular exercise was more frequent for controls than for subjects with CIND
or dementia. Table 1 also lists
the distribution of these characteristics for eligible subjects in CSHA-1
who died during follow-up or did not participate in CSHA-2. Decedents and
nonrespondents were older, less educated, and less physically active at baseline
than subjects in the control group, and were generally similar to the group
of subjects with CIND or dementia.
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Table 1. Characteristics at Baseline of Study Population, Decedents,
and Nonrespondents*
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After adjusting for age, sex, and education, low, moderate, and high
levels of physical activity were related to lower risks for CIND compared
with no physical activity (Table 2).
Likewise, moderate and high levels of physical activity were associated with
significantly lower risks for Alzheimer disease and for dementia of any type.
A similar but nonsignificant effect was observed with vascular dementia. Significant
trends for lower risk with a higher level of physical activity were observed
in the groups with CIND (P<.001), Alzheimer disease
(P = .02), and dementia of any type (P = .04).
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Table 2. Relationship Between Physical Activity and Risk of Cognitive
Impairment–No Dementia (CIND) and Dementia
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Associations between physical activity and risk of CIND and dementia
were examined separately for men and women (Table 3). Among women, after adjusting for age and education, regular
exercise was associated with significantly lower risks of CIND, Alzheimer
disease, and dementia. The ORs were lowest for the highest level of physical
activity, showing approximately 50% reductions in risk of CIND and dementia,
and a 60% reduction for Alzheimer disease, as compared with no physical activity.
Trends in decreasing risk with increasing levels of activity were significant
for CIND (P<.001), Alzheimer disease (P = .03), and dementia (P = .02). Among men,
associations between levels of physical activity and decreased risk of CIND
and dementia were observed, but none were of statistical significance. No
interaction was found between regular physical activity and age, education,
or family history of dementia (data not shown). The association between physical
activity and risk of CIND, Alzheimer disease, and dementia, according to sex
and adjusted for several potential confounders, is given in Table 4. Estimates of ORs for men and women were similar to those
reported earlier, but some lost statistical significance. Among women, tests
for trend remained significant for CIND (P<.003)
and Alzheimer disease (P = .05), but did not reach
statistical significance for dementia of any type (P
= .18).
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Table 3. Relationship Between Physical Activity and Risk of Cognitive
Impairment–No Dementia (CIND) and Dementia, According to Sex
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Table 4. Relationship Between Physical Activity and Risk of Cognitive
Impairment-No Dementia (CIND) and Dementia, According to Sex and Adjusted
for Several Potential Confounders
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Table 5 gives the association
between physical activity and risk of a 5-point loss on the 3MS Examination,
according to sex among controls only. After adjusting for age and education,
no association was found for men, whereas a significant protective effect
was observed for the highest level of physical activity among women (OR, 0.58;
95% CI, 0.40-0.82). A significant trend for an increased protective effect
with higher level of physical activity was noted in women (P<.01), but not in men.
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Table 5. Relationship Between Physical Activity and Risk of Cognitive
Loss, According to Sex, Among Cognitively Normal Subjects
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COMMENT
This large-scale, prospective cohort study showed a significant protective
effect of regular physical activity on the risk of cognitive impairment and
dementia, particularly of the Alzheimer type, in a representative sample of
the Canadian elderly population. These associations were observed mainly in
women and revealed a significant dose-response relationship showing decreasing
risk with increasing level of physical activity. We also found a lower risk
of cognitive loss associated with intensive regular physical activity among
elderly women who remained cognitively normal during the study period.
Few other prospective studies have examined the association of regular
exercise with the risk of dementia in elderly populations. In Japan, Yoshitake
et al41 followed up a cohort of 828 people
for 7 years and reported a relative risk of 0.20 for Alzheimer disease in
physically active compared with nonactive subjects, but did not find any association
for vascular dementia. These analyses were based on small samples of incident
cases, and measurement of physical activity was limited to a 4-category question
on intensity of physical activities from leisure to work. Li et al40 completed a 3-year follow-up study of 1090 people
in China and found a relative risk of 8.7 for dementia in subjects limited
to indoor activities, compared with those without such limitations. The study,
however, was based on only 13 incident cases of dementia and did not include
specific measures of physical exercise. Finally, Broe et al42
conducted a 3-year follow-up study of 327 people in Australia and reported
no association between physical exercise (ranging from gardening to sports
or walking) and risk of dementia or performance to a series of cognitive tests.
Our results are based on a large representative sample, using a rigorous
prospective design, avoiding biases related to retrospective assessment of
regular exercise and other exposures. In addition, participation rates remained
high58 throughout all phases of the study44 and, subjects were assessed using an extensive standardized
diagnostic protocol including clinical evaluations by a physician and a neuropsychologist.
Our study also has limitations. Of all eligible subjects at baseline
for whom a risk factor questionnaire was available, 1172 (18.2%) died during
the 5-year follow-up period and were excluded from the analyses. These subjects
were, at baseline, generally older, less educated, less physically active,
and suffered more frequently from chronic diseases than subjects who completed
follow-up. Excluding decedents may have produced distortions in the results,
if they were both less physically active at baseline and at high risk of developing
cognitive impairment or dementia. In a recent article by CSHA investigators
presenting incidence figures for dementia in Canada,44
an effort was made to estimate the probability of dementia for subjects who
died during follow-up, from the following 3 sources: (1) the mention of dementia
on death certificates; (2) information from proxies about a diagnosis of memory
problem, Alzheimer disease, or senile dementia prior to death; and (3) a logistic
regression model estimating the probability that the deceased person was demented
prior to death, based on an analysis of 71 people who died within 2 to 5 months
of undergoing a complete diagnostic evaluation. These estimates could be obtained
for most decedents, but were unavailable for nonrespondents. Using one or
more of these criteria, 21.2% of decedents could be classified as having developed
dementia during follow-up. When analyses were redone including 249 decedents
as demented cases and 773 as nondemented controls, the observed associations
between physical activity and risk of dementia persisted and were even more
statistically significant. This suggests that exclusion of deceased subjects
from our study had little effect on our results, if anything making estimates
somewhat conservative.
It might be argued that engaging in regular physical activity does not
per se play a protective role on cognition and cognitive disorders, as suggested
by our study, but rather can be viewed merely as a marker of good health,
being itself related to lower risk of cognitive impairment and dementia. We
tried to examine this hypothesis by adding in our logistic models variables
related to health status, and observed that risk estimates remained very similar
to those reported for men and women when controlling for age and education
only.
Despite the prospective nature of the study, our results might possibly
be explained by some preclinical cognitive decline (not yet detectable by
screening and clinical evaluations at CSHA-1) among subjects who later developed
CIND or dementia by CSHA-2. If so, lower physical activity could then be a
consequence of CIND or dementia at its preclinical state rather than a risk
factor. In this context, we reanalyzed our data excluding subjects who reported
early cognitive symptoms in the first 2 years of follow-up and obtained practically
unchanged results. Moreover, the fact that the protective effect of exercise
on cognitive loss persisted among subjects who remained without CIND or dementia
during the whole 5-year follow-up period does not favor this hypothesis of
a preclinical state for explaining our results, although it cannot be ruled
out.
Several mechanisms may underlie the potentially protective effects of
physical activity on cognitive function. It has been shown that physical activity
sustains cerebral blood flow19 by decreasing
blood pressure, lowering lipid levels, inhibiting platelet aggregability,
or enhancing cerebral metabolic demands. There is also evidence that exercise
may improve aerobic capacity and cerebral nutrient supply.24, 59
More recently, experimental studies in rodents indicated that growth factors
could be involved.60 To our knowledge, our
results suggest, for the first time, that exercise may be protective especially
for women. Apparent lack of association between exercise and CIND and dementia
in men could be attributed to insufficient numbers of cases. Stronger associations
found in women could also be related to some interaction between exercise
and hormone metabolism. Endurance exercise training has been shown to have
an independent but complementary effect to hormone replacement therapy on
serum lipid profiles in healthy postmenopausal women.61
Our study suggests that engaging in regular physical activity, among
other health benefits, may delay or prevent the onset of cognitive impairment
and dementia in the elderly, especially in women. Although these findings
will need confirmation in further epidemiological and intervention studies,
this study suggests that regular practice of physical activity could represent
an important and potent protective factor for cognitive impairment, Alzheimer
disease, and other dementia in the elderly population.
AUTHOR INFORMATION
Accepted for publication November 29, 2000.
Data reported in this article were collected as part of the CSHA. The
core study was funded by the Seniors' Independence Research Program, through
the National Health Research and Development Program (NHRDP) of Health Canada
(Project No. 6606-3954-MC [S]). Additional funding was provided by Pfizer
Canada Inc through the Medical Research Council/Pharmaceutical Manufacturers
Association of Canada Health Activity Program, NHRDP (Project No. 6603-1417-302
[R]), Bayer Inc, and the British Columbia Health Research Foundation (Project
Nos. 38 [93-2] and 34 [96-1]). Ms Laurin was supported in part by a National
Health PhD Fellowship provided by the NHRDP (Project No. 6605-5228-47) and
by the Laval University Chair for Geriatric Research. Dr Verreault is supported
by the Laval University Chair for Geriatric Research.
This study was coordinated through the University of Ottawa and the
Division of Aging and Seniors, Health Canada.
We are grateful to Susan Kirkland, PhD, for her comments on an earlier
draft of the manuscript.
From the Laval University Geriatric Research Unit, Centre d'hébergement
St-Augustin du Centre hospitalier affilié universitaire de Québec,
Beauport, and Department of Social and Preventive Medicine, Laval University,
Sainte-Foy, Quebec (Ms Laurin and Dr Verreault); Department of Epidemiology
and Community Medicine, University of Ottawa, Ottawa, Ontario, and Aging-Related
Diseases Division, Laboratory Center for Disease Control, Health Canada, Ottawa
(Dr Lindsay); and Department of Community Health and Epidemiology, Dalhousie
University, Halifax, Nova Scotia, and Division of Geriatric Medicine, Dalhousie
University, Queen Elizabeth II Health Sciences Center, Halifax (Drs MacPherson
and Rockwood).
Corresponding author and reprints: René Verreault, MD, PhD,
Laval University Geriatric Research Unit, Centre d'hébergement St-Augustin
du Centre hospitalier affilié universitaire de Québec, 2135
Terrasse Cadieux, Beauport, Quebec, Canada G1C 1Z2 (e-mail: Rene.Verreault{at}msp.ulaval.ca).
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