Wilson RS, Mendes de Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in Cognitively Stimulating Activities and Risk of Incident Alzheimer Disease. JAMA. 2002;287(6):742–748. doi:10.1001/jama.287.6.742
Author Affiliations: Rush Alzheimer's Disease Center and Rush Institute for Healthy Aging and Departments of Neurological Sciences (Drs Wilson, Barnes, Schneider, and Bennett), Psychology (Drs Wilson and Barnes), and Medicine (Drs Mendes de Leon, Bienias, and Evans), Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill.
Context Frequent participation in cognitively stimulating activities has been
hypothesized to reduce risk of Alzheimer disease (AD), but prospective data
regarding an association are lacking.
Objective To test the hypothesis that frequent participation in cognitive activities
is associated with a reduced risk of AD.
Design Longitudinal cohort study with baseline evaluations performed between
January 1994 and July 2001 and mean follow-up of 4.5 years.
Participants and Setting A total of 801 older Catholic nuns, priests, and brothers without dementia
at enrollment, recruited from 40 groups across the United States. At baseline,
they rated frequency of participation in common cognitive activities (eg,
reading a newspaper), from which a previously validated composite measure
of cognitive activity frequency was derived.
Main Outcome Measures Clinical diagnosis of AD by a board-certified neurologist using National
Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's
Disease and Related Disorders Association criteria and change in global and
specific measures of cognitive function, compared by cognitive activity score
Results Baseline scores on the composite measure of cognitive activity ranged
from 1.57 to 4.71 (mean, 3.57; SD, 0.55), with higher scores indicating more
frequent activity. During an average of 4.5 years of follow-up, 111 persons
developed AD. In a proportional hazards model that controlled for age, sex,
and education, a 1-point increase in cognitive activity score was associated
with a 33% reduction in risk of AD (hazard ratio, 0.67; 95% confidence interval,
0.49-0.92). Results were comparable when persons with memory impairment at
baseline were excluded and when terms for the apolipoprotein E ∊4 allele
and other medical conditions were added. In random-effects models that controlled
for age, sex, education, and baseline level of cognitive function, a 1-point
increase in cognitive activity was associated with reduced decline in global
cognition (by 47%), working memory (by 60%), and perceptual speed (by 30%).
Conclusion These results suggest that frequent participation in cognitively stimulating
activities is associated with reduced risk of AD.
Alzheimer disease (AD) is the leading cause of dementia in older persons,
but few risk factors for the disease have been identified. Frequent participation
in cognitively stimulating activities has been hypothesized to reduce risk
of AD,1- 3 but this
hypothesis has not been tested prospectively in longitudinal studies of incident
disease. Support for the hypothesis now comes mainly from retrospective case-control
studies suggesting that mid-life cognitive activity is associated with disease
risk4,5 and from cross-sectional
research showing an association between frequency of cognitive activity and
level of cognitive function in old age.6- 8
In the current study, we used a previously established measure of frequency
of participation in common cognitive activities8
and tested its association with incident AD and decline in cognitive function
in a large cohort of older Catholic clergy members examined annually for up
to 7 years.
All subjects are participants in the Religious Orders Study, an ongoing
longitudinal clinical-pathological study of aging and AD. Older Catholic nuns,
priests, and brothers were recruited from about 40 groups across the United
States (see Acknowledgment). The study was approved by the Human Investigations
Committee of Rush-Presbyterian-St. Luke's Medical Center. Eligibility was
established at baseline and required an age of 65 years or older, absence
of a clinical diagnosis of dementia, and consent to annual clinical evaluations
and to brain donation at the time of death.
At baseline, each person had a uniform structured evaluation that was
repeated annually by examiners blinded to previously collected data. The evaluation
has been previously described.9- 11
It included a medical history, neurological examination, assessment of cognitive
function, and review of brain scan when available. On the basis of this evaluation,
a board-certified neurologist diagnosed AD and other common conditions affecting
cognitive or physical function (eg, stroke). The diagnosis of AD followed
the criteria of the joint working group of the National Institute of Neurological
and Communicative Disorders and Stroke and the Alzheimer's Disease and Related
Disorders Association (NINCDS/ADRDA).12 These
criteria require a history of cognitive decline and impairment in memory and
at least 1 other cognitive domain. Some persons who met these criteria had
another condition impairing cognition (termed "possible" AD in the NINCDS/ADRDA
system). Because exclusion of this subgroup did not affect results, it is
included in all analyses reported in this article.
Of 1003 persons who expressed interest after a presentation about the
Religious Orders Study, 879 agreed to participate and had a baseline evaluation
between January 1994 and July 2001. We excluded 74 persons who met criteria
for dementia at baseline and 4 persons with missing diagnostic or cognitive
activity data. Of the remaining 801 persons, 21 died before the first follow-up
evaluation and 40 had not yet reached the date of their first follow-up. Of
the remaining 740 persons, follow-up information on AD was available in 733
(99%), with a mean of 5.5 evaluations per person (range: 2-8); follow-up composite
cognitive scores were available in 724 (98%), with a mean of 5.4 valid scores
per individual (range: 2-8). Analyses are based on these persons. Nearly all
of them were still active in their order, parish, or community at baseline,
and 70% were working at least part-time.
We used a previously established, composite measure of cognitive activity
frequency in analyses.8 At baseline, persons
were asked about time typically spent in 7 common activities that involve
information processing as a central component: viewing television; listening
to radio; reading newspapers; reading magazines; reading books; playing games
such as cards, checkers, crosswords, or other puzzles; and going to museums.
Frequency of participation in each activity was rated on a 5-point scale,
as follows: 5 points, every day or about every day; 4 points, several times
a week; 3 points, several times a month; 2 points, several times a year; and
1 point, once a year or less. Responses to each item were averaged to yield
the composite measure.
We used a composite measure to reduce floor and ceiling artifacts and
other sources of measurement error. As previously described, it was formed
by averaging responses to each item rather than weighting items by the estimated
cognitive demand involved in the activity because the latter approach yielded
a composite measure that was indistinguishable from a composite based on frequency
alone.8 In a geographically defined population
of older persons, each item was positively correlated with the total score
on the other 6 (range: 0.8-0.46, all P<. 01),
supporting the use of a composite measure. This composite measure had positive
correlations of moderate size with educational attainment and a performance-based
measure of cognitive function, supporting its construct validity.
At each evaluation, 20 cognitive tests were administered in an approximately
45-minute session. One test, the Mini-Mental State Examination (MMSE13) was used only for descriptive purposes. There were
7 tests of episodic memory: immediate and delayed recall of the East Boston
Story,14 Logical Memory Ia and IIa,15 and Word List Memory, Recall, and Recognition16; 4 tests of semantic memory: Boston Naming Test,16 Extended Range Vocabulary,17
Verbal Fluency,16 and National Adult Reading
Test18; 4 tests of working memory: Digits Forward
and Digits Backward,15 Digit Ordering,19 and Alpha Span20;
2 tests of perceptual speed: Symbol Digit Modalities Test21
and Number Comparison17; and 2 tests of visuospatial
ability: Judgment of Line Orientation22 and
Standard Progressive Matrices.23 Composite
measures of global cognition, based on all 19 tests, and of the specific domains
of cognitive function defined above were used in analyses. Each measure was
formed by converting raw scores on component tests to z scores, using the baseline mean and SD and computing the average.
Detailed information about the individual tests and summary measures is published
We assessed participation in physical activities with questions adapted24 from the 1985 Health Interview Survey.25
The activities were walking for exercise, gardening or yardwork, calisthenics
or general exercise, bicycle riding, and swimming or water exercise. Persons
were asked if they had participated in each activity in the last 2 weeks,
and if so, the number of occasions and average minutes per occasion. Minutes
in each activity were summed and divided by 120 to yield a composite measure
of participation in physical activity expressed as hours per week. Because
results were unchanged when activities were weighted by the estimated energy
expended,26 we used total weekly hours in all
analyses. Due to its skewed distribution, we treated it as a categorical variable
in the main analysis with people grouped into quartiles.
Apolipoprotein E (ApoE) genotyping was performed by an investigator
blinded to all clinical data. Blood was collected at each participating Religious
Orders Study site with acid citrate dextrose anticoagulant and stored at room
temperature. It underwent lymphocyte separation within 24 hours of collection.
DNA was extracted from approximately 2 million to 3 million cells and amplified
by the polymerase chain reaction as described by Hixson and Vernier.27 Of 801 eligible persons at baseline, ApoE genotype
was available in 721 (90%), and 186 (26%) had at least 1 ∊4 allele.
Seven medical conditions were identified in at least 5% of study participants
at baseline. Classification of 6 was based on medical history: hypertension,
diabetes, heart disease, cancer, thyroid disease, and head injury with loss
of consciousness. A clinical diagnosis of stroke was made in 53 persons (7%)
based on history, examination, and in 31 of these, review of a prior brain
scan (with evidence of cerebrovascular disease in 18). The number of these
conditions present at baseline was used in analyses.
Depressive symptoms were assessed at baseline with a 10-item form28 of the Center for Epidemiologic Studies Depression
Scale.29 The score was the number of symptoms
experienced in the past week.
The association of cognitive activity with risk of developing AD was
assessed in a Cox proportional hazards model, adjusted for the potentially
confounding effects of age, sex, and education.30
In additional models, we excluded persons with low episodic memory scores
at baseline and added terms for the presence of at least 1 ApoE ∊4 allele
and for the number of medical conditions and depressive symptoms at baseline.
We used random-effects regression models to assess the relation of cognitive
activity with baseline level of cognitive function and annual rate of change.31 Each cognitive function measure was analyzed in a
model with terms for cognitive activity, time, and their interaction, and
for the potentially confounding effects of age, sex, and education. The term
for cognitive activity indicates the mean difference in cognitive function
at baseline associated with a 1-point increase in cognitive activity. The
term for time indicates the average rate of cognitive change per year in a
typical participant with a cognitive activity score of 3, and the interaction
term indicates the effect of a 1-point change in cognitive activity on annual
rate of cognitive change. Further description of the application of these
models to cognitive function data is provided elsewhere.11,32
Comparable analyses were used to examine the relation of the physical
activity measure with incident AD and change in cognitive function. Model
assumptions were assessed graphically and analytically and were found to be
adequately met. All analyses were carried out in SAS.33
A P value of less than .05 was considered significant.
Scores on the composite measure of cognitive activity ranged from 1.57
to 4.71 (mean, 3.57; SD, 0.55), with higher scores indicating more frequent
activity. Cognitive activity had modest correlations with age (r, −0.08; P<.05) and education (r, 0. 20; P<. 01) but was not
associated with sex (t799 = 0.35, P = .73).
Participants were followed up for a mean of 4.5 years. A total of 111
persons developed AD after a mean of 3.0 years; 101 met NINCDS/ADRDA criteria
for probable AD and 10 for possible AD (because of cognitive impairment due
to stroke in 5 and to Parkinson disease in 5). Baseline characteristics of
these persons and of those who did not develop AD are shown in Table 1. Of the 111 persons in the incident disease group, 51 have
died. Brain autopsy results are available for 31, of whom 26 (84%) met Consortium
to Establish a Registry for Alzheimer's Disease pathological criteria for
AD (14 definite, 12 probable) based on ratings of neuritic plaque density
in 3 neocortical regions.34
Three persons with dementia due to other causes were excluded from analyses
of disease incidence. In a proportional hazards model that adjusted for age,
sex, and education, the relative risk (RR) of developing AD decreased by 33%
(hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.49-0.92) for each
1-point increase in the composite measure of cognitive activity (Table 2). Thus, compared with a person
with activity frequency at the 10th percentile (score = 2.86), the RR of disease
was reduced by 28% in a person whose cognitive activity frequency was at the
50th percentile (score = 3.71) and by 47% in a person whose activity frequency
was at the 90th percentile (score = 4.29). Education was not related to disease
risk in this model (HR, 1.02; 95% CI, 0.96-1.08) or when the analysis was
repeated without cognitive activity (HR, 1.01; 95% CI, 0.95-1.07).
We next considered whether the results depended on a subgroup with manifestations
of early AD. Because episodic memory impairment has been shown to be a very
early sign of disease,35,36 we
repeated the analysis excluding 35 persons with a baseline episodic memory
score at or below the fifth percentile, and the association of cognitive activity
with incident AD remained (HR, 0.59; 95% CI, 0.41-0.86). Results were comparable
when we excluded those at or below the 10th percentile (n = 69) (HR, 0.57;
95% CI, 0.38-0.85) or 15th percentile (n = 104) (HR, 0.58; 95% CI, 0.38-0.88).
Because the ApoE ∊4 allele is an established risk factor for AD,
we repeated the analysis with a term for possession of 1 or more ∊4 alleles.
The association of cognitive activity remained significant in this model (HR,
0.67; 95% CI, 0.49-0.92), and in a subsequent model, there was no interaction
of ∊4 with cognitive activity (P = .90).
We also examined whether other medical conditions or depression influenced
the association of cognitive activity with AD. We added terms to the core
model for the number of common medical conditions (mean, 1.1; range: 0-6)
and number of depressive symptoms (mean, 1.0; range: 0-8) at baseline, and
results were not substantially changed (HR for cognitive activity, 0.70; 95%
Another way to assess the impact of preexisting cognitive impairment
on results is to examine the association of cognitive activity with the principal
manifestation of AD, cognitive decline, while controlling for baseline level
of cognition. We did this in a series of random-effects models that examined
the relation of cognitive activity with baseline level of and annual rate
of change in cognitive function. Each model included terms to control for
the potentially confounding effects of age, sex, and education. To make use
of all available data, the initial analysis used the global measure of cognition,
which ranged from –1.765 to 1.374 at baseline, with higher scores indicating
better function. At baseline, each point of cognitive activity score was associated
with 0.128 units in the global cognitive score (P<.001).
On average, the global cognitive score declined 0.043 units per year (P<.001), and this rate decreased by 0.020 units (P<.05), or about 47%, for each 1-point increase in cognitive
activity score. Thus, on average, a person with activity frequency at the
10th percentile declined 0.046 units per year in global cognition; this rate
was reduced by 0.014 units (about 30%) for an activity frequency score at
the 50th percentile and by 0.026 units (about 60%) for an activity frequency
score at the 90th percentile.
To determine whether cognitive activity was related to decline in some
domains of cognition but not others, we repeated the analysis using measures
of function in specific cognitive domains (Table 3). More frequent cognitive activity was associated with higher
baseline function in each cognitive domain. On average, performance declined
in each cognitive domain, as shown by the terms for time. In addition, cognitive
activity was associated with lower rates of decline in working memory, by
0.021 units or about 60% for each 1 point of cognitive activity score, and
perceptual speed, by 0.026 units or about 30%, and a trend toward reduced
decline in episodic memory. By contrast, change in semantic memory and visuospatial
ability was not significantly related to cognitive activity.
To determine whether the effect of cognitive activity reflected a nonspecific
effect of activity, we also examined the association of physical activity
with risk of disease. At baseline, persons spent a median of 3.5 hours per
week in physical activities (interquartile range, 0.5-7.0 ; mean, 5.7; SD,
8.3 hours). Because of the skewed distribution, we divided physical activity
time into quartiles and contrasted those in the lowest quartile with each
of the remaining quartiles in a proportional hazards model that controlled
for age, sex, and education. As shown in Table 4, risk of incident AD was not significantly reduced in any
quartile relative to the lowest quartile. Similar results were obtained when
the analysis was repeated with physical activity treated as a continuous variable
(HR, 1.00; 95% CI, 0.97-1.02). Results were also comparable when cognitive
activity was added to the model. In random-effects models that controlled
for demographic variables, physical activity was not related to decline in
global or specific measures of cognitive function.
We found that frequency of participation in common cognitive activities
was associated with incident AD during a mean of 4.5 years of follow-up. On
average, a person reporting frequent cognitive activity at baseline (90th
percentile) was 47% less likely to develop AD than a person with infrequent
activity (10th percentile). These results suggest that frequent cognitive
activity in old age is associated with reduced risk of incident AD.
A prospective, population-based study found that lower participation
in several leisure activities was associated with higher risk of incident
dementia after 3 years of follow-up.37 However,
few of the activities were cognitive, activity frequency was not assessed,
and education was not controlled for. In 2 retrospective case-control studies,
frequency of cognitive and physical activity in mid-life was associated with
risk of AD.4,5 However, information
about mid-life activity was obtained after disease onset, by informant-report
for cases, and by self-report for controls, potentially biasing results.
Few prospective studies have evaluated the relation of physical activity
to dementia or AD, and their results have been inconsistent.38- 40
We found no evidence that frequency of participation in physical activities
was associated with risk of AD or rate of cognitive decline. This observation
is important because it suggests that the association of cognitive activity
with disease risk reflects mental stimulation rather than a nonspecific result
of being active.
A novel feature of this study is that incident AD and change in different
cognitive abilities were used as separate but complementary outcomes. We found
that the frequency of cognitive activity was not only associated with level
of cognition at baseline, consistent with prior research,6- 8
but also with rate of cognitive decline, suggesting that the association of
cognitive activity with AD is not exclusively due to the association of cognitive
activity with premorbid level of cognitive ability, a known risk factor for
the disease.41,42 A previous study
found that frequency of novel information processing was associated with rate
of cognitive decline during a 6-year period.43
This association was observed for only 1 of 9 cognitive measures, however,
and education was not controlled for.
The basis of the association of cognitive activity with incident AD
is uncertain. One hypothesis is that cognitive activity is protective.1- 3 One version of this
hypothesis is that with repetition some cognitive skills become more efficient
and less vulnerable to disruption by AD pathology.44
Alternatively, frequent cognitive activity may strengthen processing skills
such as working memory and perceptual speed, which may help to compensate
for age-related decline in other cognitive systems.45
That cognitive activity was mainly associated with change in working memory
and perceptual speed in this study, and with working memory in a prior study,43 is consistent with a compensatory mechanism.
Another possibility is that reduced cognitive activity is an early sign
of AD. However, we excluded persons who met clinical criteria for AD at baseline
and obtained comparable results in secondary analyses after excluding those
with low episodic memory scores at baseline. Further, cognitive activity was
related to rate of cognitive decline after controlling for baseline level
of cognition. Nevertheless, because AD is thought to develop slowly over many
years, it is possible that prodromal manifestations of the disease contributed
to the results. Indeed, if cognitive activity is protective, reduced cognitive
activity should be an early sign of disease.
Cognitive activity may also be a proxy for some other less easily modified
variable. However, we controlled for key demographic and clinical variables
that have been associated with disease risk, cognitive activity frequency,
or both. Further, the homogeneity in this cohort substantially reduces the
confounding effect of socioeconomic status and education.46
Education, in fact, was unrelated to incident AD, contrary to many47- 49 but not all50- 52 previous prospective
studies, possibly due to the high level of educational attainment in this
cohort (88% with 16 years or more).
This study has several strengths, including a relatively long study
period with an average of more than 5 evenly spaced observations per individual,
follow-up participation exceeding 95%, use of uniform structured evaluations
and widely accepted criteria applied by board-certified neurologists to diagnose
AD, and use of previously established composite measures of cognitive activity
frequency and cognitive function. In addition, the clinical diagnosis of AD
has been confirmed pathologically in more than 80% of cases evaluated to date.
Our study also has important limitations. The cohort is selected and
differs from older persons in the US population in education, lifestyle, and
perhaps other ways. It will be important, therefore, to replicate these findings
in more diverse cohorts. Furthermore, our findings regarding the association
of cognitive activity with reduced risk of AD only pertain to our composite
measure of cognitive activity. More detailed studies are required to establish
whether there is a differential effect of each of these activities on disease
risk. Finally, the basis of the association of cognitive activity frequency
with incident AD and rate of cognitive decline remains to be established.
Disentangling the complex associations among cognitive activity, AD, and cognitive
function is likely to require longer observational studies, clinical-pathological
research, and evaluations of cognitive interventions.