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Low dose aspirin and cognitive function in the women’s
health study cognitive cohort
Low Dose Aspirin Does Not Protect Women Against Cognitive Decline
Taking low dose aspirin does not protect older women against cognitive decline, finds a large study published on bmj.com today.
Identifying ways to prevent dementia is a public health priority. Evidence suggests that aspirin and other anti-inflammatory drugs may protect against dementia, but data from randomised studies to date have been inconclusive. So researchers in the US decided to test the effect of long term use of low dose aspirin on overall cognitive decline among a large sample of women.
Jae Hee Kang and colleagues at Brigham and Women's Hospital in Boston, Massachusetts identified 6,377 women aged 65 years or more, who were taking part in the Women's health study between 1998 and 2004.
The women were randomly divided into two groups. Over a period of nearly 10 years, the first group took low dose aspirin (100 mg on alternate days) and the second group took a placebo pill. Each woman had three cognitive assessments at two year intervals to measure general cognition, verbal memory, and category fluency.
At the initial assessment (after 5.6 years of treatment) cognitive performance in the aspirin group was similar to that of the placebo group. Average performance across all tests from the first to the final assessment (after 9.6 years of treatment) was also similar in the aspirin group compared with the placebo group. The risk of substantial decline was also comparable between the groups.
There was some suggestion that women in the aspirin group performed better in the category fluency test than women in the placebo group. However, the authors stress that this result should be interpreted with caution.
They conclude: "In this study, we observed no apparent benefit of low dose aspirin in slowing cognitive decline over four years. Other methods for preserving cognitive function in older people need to be investigated."
"Low dose aspirin and cognitive function in the women's health study cognitive cohort"
BMJ Online First
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Low-Dose Aspirin Won't Help Aging Brain
Major 10-year study of older women shows no differences.
By Amanda Gardner
HealthDay Reporter |
THURSDAY, April 26 (HealthDay News) -- Despite earlier hopes, regular use of low-dose aspirin does not protect older, healthy women against cognitive decline, a major new study concludes.
The findings may lay to rest the notion that aspirin can prevent age-related shortfalls in memory and thinking.
"I certainly don't think that people should look at taking low-dose aspirin as a preventive measure for cognitive decline," said study author Jae Hee Kang, an instructor of medicine at Brigham and Women's Hospital in Boston. "I think that's pretty clear, especially among those women who are healthy."
Another expert agreed.
"It doesn't slam [the door] shut, but it does kind of close it out," said Dr. Gary Kennedy, director of geriatric psychiatry at Montefiore Medical Center in New York City. "They had a large enough sample that, even for a short period of observation, they should have seen the effect." He was not involved in the study, which was published online Thursday in the British Medical Journal.
Previous evidence had suggested that aspirin and other anti-inflammatory drugs might help protect aging brains from dementia. Larger randomized trials, such as this one, however, had been inconclusive.
Low-dose aspirin does have significant cardiovascular benefits. New expert guidelines recommend that women aged 65 and over consider taking low-dose aspirin on a routine basis, regardless of their cardiovascular risk, to help prevent both heart attacks and stroke. Women under 65 should not be taking aspirin routinely.
But this study focused on brain health. Kang and her colleagues looked at almost 6,400 women, aged 65 or over, who were all participating in the Women's Health Study between 1998 and 2004.
Participants were assessed cognitively every two years by phone. These tests tracked general cognition, verbal memory and category fluency (arranging things quickly by kind).
The women were randomly divided into two groups, one of which took a low-dose (100 milligrams) of aspirin on alternate days and the other a placebo pill. The study lasted almost 10 years.
At the first assessment (after 5.6 years of treatment), cognitive performance was similar in the two groups, as it was at the second assessment (after 9.6 years of treatment). Risk of substantial decline in cognitive function was comparable between the two groups.
There was a hint that women taking aspirin performed better on the category fluency test than women in the placebo group, but the association was far from definitive.
The data also suggested that low-dose aspirin might be beneficial among people who are current smokers or who have elevated cholesterol. "However, these might be chance findings, as we could not find other studies that replicate this finding," Kang cautioned.
The data does have some limitations, namely that the population in question was generally "younger old" and white. "The risk of dementia really shoots up after age 85," Kang said. "Unfortunately, the trial had ended, so we can't follow these women when it really starts to go up. Whether or not aspirin may be beneficial in those who are older and high-risk populations is really not known."
"I was not terribly surprised," Kennedy said. "I didn't have high hopes [that aspirin would prove effective], but it's very nice that they've done this. It's a well-run study, with a big sample and careful measures. If there was a relationship, this study would have found it."
"This is a holdover from the flurry of older studies aimed at slowing Alzheimer's progression with cox-2 inhibitors and conventional anti-inflammatories," said Dr. Sam Gandy, chairman of the Medical and Scientific Advisory Council for the Alzheimer's Association. "Some of those studies were terminated prematurely due to risks or side effects, but the negative results from the low-dose aspirin study reinforces the notion that a positive outcome was unlikely, had those studies gone on to their intended endpoints."
More information
There's more on cognitive decline at the Alzheimer's Association.
(SOURCES: Jae Hee Kang, D.Sc., instructor of medicine, Brigham and Women's Hospital, Boston; Gary J. Kennedy, M.D., director, geriatric psychiatry, Montefiore Medical Center, New York City; Sam Gandy, M.D., chairman, Medical and Scientific Advisory Council for the Alzheimer's Association, and director, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia; April 26, 2007, online edition, British Medical Journal)
Jae Hee Kang, instructor,1 Nancy Cook, associate professor,2 JoAnn Manson, professor,2 Julie E
Buring, professor,2 Francine Grodstein, associate professor1
ABSTRACT
Objective To determine whether low dose aspirin protects
women aged 65 or more against cognitive decline.
Design Cohort study within both arms of the women’s
health study, a randomised, double blind, placebo
controlled trial of low dose aspirin for the primary
prevention of cardiovascular disease and cancer, 1992-5.
Setting Women’s health study, 1998-2004.
Participants 6377 women aged 65 or more.
Interventions Low dose aspirin (100 mg on alternate
days) or placebo for a mean of 9.6 years.
Main outcome measures Women had three cognitive
assessments at two year intervals by telephone. The
battery to assess cognition included five tests measuring
general cognition, verbal memory, and category fluency.
The primary prespecified outcome was a global score,
averaging performance across all tests. The key
secondary outcome was a verbal memory score,
averaging performance on four measures of verbal
memory.
Results At the initial assessment (mean 5.6 years after
randomisation) cognitive performance in the aspirin
group was similar to that of the placebo group (mean
difference in global score −0.01, 95% confidence interval
−0.04 to 0.02). Mean decline in the global score from the
first to the final cognitive assessment was also similar in
the aspirin compared with placebo groups (mean
difference 0.01, −0.02 to 0.04). The risk of substantial
decline (in the worst 10th centile of decline) was also
comparable between the groups (relative risk 0.92, 0.77
to 1.10). Findings were similar for verbal memory;
however, a 20% lower risk was observed for decline in
category fluency with aspirin (relative risk 0.80, 0.67 to
0.97).
Conclusion Long term use of low dose aspirin does not
provide overall benefits for cognition among generally
healthy women aged 65 or more.
INTRODUCTION
Identifying ways to reduce the incidence of dementia is
a public health priority. Because preventive measures
may be most effective in the earliest stage of the disease,
increasing research has focused on reducing the
risk of early cognitive decline—a strong predictor of
dementia.1
Aspirin and other anti-inflammatory drugs have
been investigated in previous studies, with mixed findings.
Randomised trials3-7 have generally found no cognitive
benefits of these drugs for patients with
Alzheimer’s disease, although the trials were of short
duration (<2 years) and the disease may have been too
advanced to allow detection of benefits. Observational
studies of cognitive function among healthy participants
have been inconsistent and may be subject to
biases from various sources. A recent meta-analysis8
of four cohort studies reported no relation between
use of non-steroidal anti-inflammatory drugs and cognitive
decline (summary relative risk 1.23, 95% confidence
interval 0.70 to 2.31); thus, existing data on the
relation between these drugs and dementia are inconclusive.
Another limitation of previous observational studies
is that numerous anti-inflammatory agents and drug
doses are often combined in analyses. Several antiinflammatory
drugs have been recently implicated in
the development of cardiovascular disease9 and thus
are unlikely to be viable candidates for neuroprotection.
Low dose aspirin, however, has been shown to
provide vascular benefits, particularly in those aged
65 or more.10 11
We tested the effect of long term use of low dose
aspirin on overall cognitive decline over four years
among a subset of 6377 women aged 65 or more participating
in the women’s health study.11
METHODS
The women’s health study was a randomised, double
blind, placebo controlled 2×2 factorial trial of low dose
aspirin (100 mg on alternate days; Bayer HealthCare)
and vitamin E supplementation (600 IU on alternate
days; Natural Source Vitamin E Association) in the
prevention of cardiovascular disease and cancer
among US women. Most participants are white
(>95%). The study design has been described
previously.12 Briefly, women were eligible if they
were aged 45 or more; had no history of coronary
heart disease, cerebrovascular disease, cancer (except
for non-melanomaskin cancer), or other major chronic
illnesses; and did not actively use or have a history of
side effects from the study drugs.
Channing Laboratory, Brigham and
Women’s Hospital, Harvard
Medical School, Boston, MA 02115,
USA
2Department of Medicine, Division
of Preventive Medicine, Brigham
and Women’s Hospital
Correspondence to: J H Kang
nhjhk@channing.harvard.edu
doi: 10.1136/bmj.39166.597836.BE
BMJ | ONLINE FIRST | bmj.com page 1 of 8
Cite this article as: BMJ, doi:10.1136/bmj.39166.597836.BE (published 27 April 2007)
Copyright 2007 BMJ Publishing Group Ltd
To identify women who were likely to be highly
compliant, we enrolled eligible women in a three
month run-in period of placebo administration. A
total of 39 876 compliant women were randomised
(19 934 to aspirin and 19 942 to placebo) from 1992
to 1995. Randomised assignments were computer generated
in blocks of 16 within five year age strata by
study programmers, masked to study investigators
and enrolling staff. Participants provided written
informed consent.
Every 12 months, based on their random assignments,
participants were posted a year’s supply of
monthly calendar packs with identical white pills containing
aspirin or placebo. Women were asked to complete
annual postal questionnaires to update
information on compliance, side effects, health and
lifestyle characteristics, and the occurrence of clinical
end points. They were instructed not to use vitamin E
supplements and any prescribed or over the counter
aspirin or aspirin containing drugs or any other nonsteroidal
anti-inflammatory drugs during the trial. The
trial continued through to the scheduled end (31
March 2004), when overall follow-up on mortality
exceeded 99%; the main results of the trial have been
published and showed a benefit of aspirin in reducing
the risk of stroke but no benefit in reducing the risk of
myocardial infarction11 or cancer.13 Details of side
effects are described elsewhere;11 briefly, the aspirin
group had excesses of self reported gastrointestinal
bleeding, peptic ulcer, haematuria, easy bruising, and
epistaxis.
Cognitive cohort
Although the original purpose of the trial was to evaluate
cardiovascular and cancer outcomes, this large
scale, long term trial provided an opportunity to incorporate
cognitive outcomes to study the potential effect
of aspirin on delaying cognitive decline. In 1998 we
started a study of cognitive function among women
aged 65 or more. Eligible women were aged 65 or
more and were still active participants of the women’s
health study (n=7175). Most of the ineligibility (98.5%)
was due to the age restriction in the cognitive study
protocol; only 1.5% of deaths or losses to follow-up
had occurred by the start of the cognitive study, and
these women were distributed equally between the
aspirin and placebo groups (figure).
Of the 7175 women selected for the substudy of cognitive
function, 296 (4.1%) were unreachable by telephone
and 502 (6.9%) did not participate; thus 6377
(88.9%) women completed the initial cognitive assessment
by telephone (figure). The initial assessments
were carried out an average of 5.6 years after randomisation.
The participation rates in the initial interview
were virtually identical in the two groups. In addition,
no significant differences were found in important
baseline characteristics by treatment assignment.
After the initial cognitive assessment, participants
underwent two follow-up assessments, at about two
year intervals. High follow-up was maintained (figure):
5845 (91.7%) of those who completed the initial assessment
also completed at least one follow-up assessment,
and 5073 women (79.5%) completed all cognitive
assessments. Among the 8% of participants who did
not complete any follow-up assessments, 2% died, 1%
was unreachable, and 5% refused. Follow-up rates
were nearly identical in the two groups.
Although the sample size of the women’s health
study was not designed for the cognitive outcome, the
6377 women in this substudy provided sufficient
power to detect modest differences in cognitive decline
between the aspirin and placebo groups (3215 receiving
aspirin and 3162 receiving placebo). For example,
for the categorical outcome of substantial cognitive
decline we had at least 80% power to detect a modest
relative risk of 0.76 in the aspirin group compared with
the placebo group; moreover, power was considerably
greater for continuous analyses of mean cognitive
decline in the two groups.
We have previously published results of the vitamin
E treatment14; we found no relation between vitamin E
and cognitive function.
Cognitive function assessment
The telephone cognitive battery was administered by
trained nurses masked to participants’ treatment
group. The assessment included five tests measuring
general cognition, verbal memory, and category fluency.
To assess general cognition we administered
the telephone interview of cognitive status,15 an adaptation
of the mini-mental state examination for use by
telephone. To test verbal memory we administered the
immediate and delayed recalls of the east Boston memory
test,16 in which a short paragraph is read and 12 key
elements must be repeated immediately and again at
15 minutes. To further evaluate delayed verbal memory
we administered a delayed recall of the telephone
interview of cognitive status 10 word list. Finally, to
Women in the women’s health study randomised, 1992-6 (n=39 876)
Aspirin group (n=19 934) Placebo group (n=19 942)
Status as of 1 January 1998 for selection into
cognitive function substudy
Women aged ≥65 selected (n=3618)
Exclusions (n=16 316):
Aged <65 (n=16 073)
Died (n=116)
Lost to follow-up (n=127)
Status as of 1 January 1998 for selection into
cognitive function substudy
Women aged ≥65 selected (n=3557)
Exclusions (n=16 385):
Aged <65 (n=16 145)
Died (n=134)
Lost to follow-up (n=106)
Status at first cognitive assessment, 1998-2000
Completed first assessment (n=3215)
Unreachable by telephone (n=151)
Refused participation (n=252)
Status at first cognitive assessment, 1998-2000
Completed first assessment (n=3162)
Unreachable by telephone (n=145)
Refused participation (n=250)
Completed all three assessments (n=2563, 80%)
Completed two assessments (n=377, 12%)
Completed first assessment (n=275, 8%)
Completed all three assessments (n=2510, 79%)
Completed two assessments (n=395, 13%)
Completed first assessment (n=257, 8%)
Flow chart of participation in cognitive cohort of women’s health study
RESEARCH
page 2 of 8 BMJ | ONLINE FIRST | bmj.com
assess category fluency,17 women were asked to name
as many animals as possible in one minute.
Our primary, prespecified outcome was a global
composite score averaging performance across all
five cognitive tests, using z scores. Because verbal
memory is among the strongest predictors of eventual
risk of Alzheimer’s disease,1 our key, secondary outcome
was a composite score of verbal memory, averaging
performance on four tests (the immediate and
delayed recalls of both the east Boston memory test
and the 10 word list).
In a test-retest study of the telephone interview of
cognitive status among 35 high functioning, educated
older women, we found a correlation of 0.7 (P<0.001)
between two assessments administered 31 days apart.
In a validation study of our telephone instrument,
among 61 high functioning, educated older women,
the correlation was 0.81 comparing overall performance
on our telephone administered interview and
overall performance on an extensive in-person interview,
showing high validity. Cognitive impairment
determined from our telephone assessment strongly
predicted later dementia in educated women; among
88 older women followed over three years, lower
scores on both the telephone interview of cognitive
status and verbal memory were associated with significant
eightfold and 12-fold increased risks of dementia.
Statistical analysis
We first examined mean performance at each cognitive
assessment using repeated measures analysis of
means (which permits examination of each time
point, taking into account correlation between assessments).
Secondly, we examined mean change in cognitive
function over the three cognitive assessments.
We treated scores and change in scores at each assessment
as repeated continuous outcomes and we modelled
the treatment effect by a time by treatment
interaction. Because the trends for test scores over
time were non-linear, in all analyses we used general
linear models of response profiles, modelling time
nominally rather than linearly.18 This approach
imposes minimal structure on outcome trends and permits
valid estimation of effects in non-linear data. We
fitted all models by maximum likelihood, incorporating
the longitudinal correlation within participants,
using unstructured covariance structures; for statistical
testing, we used Wald tests.18 All linear models were
fitted using Proc Mixed in SAS (version 9).
In secondary analyses we examined effect modification
by key risk factors for cognitive decline (most measured
at baseline): age, baseline score, perceived
change in memory, education, cigarette smoking, alcohol
consumption, body mass index, physical activity,
hormone replacement therapy use, history of diabetes,
hypertension, hyperlipidaemia, depression (at four
years after randomisation), and cardiovascular disease
(all incident occurrences from randomisation to the
end of the study). Cardiovascular disease included all
medical record confirmed non-fatal myocardial infarction,
non-fatal stroke, cardiovascular related deaths, or
vascular disease as evidenced by either a coronary
artery bypass graft or percutaneous transluminal coronary
angioplasty or stenting.11Wecarried out all tests
of effect modification by evaluating the interaction
terms in the models of mean change.
To assess the effect of aspirin treatment on the risk of
“substantial cognitive decline,” we used logistic regression
models in which substantial cognitive decline was
defined as the worst 10% of the distribution of decline
from the initial to the final cognitive assessment of the
whole cohort. In all models we adjusted for the time
between the first and third assessments.
RESULTS
Characteristics at randomisation were similar among
women assigned to aspirin and those assigned to placebo
(table 1). At the first cognitive assessment the
Table 1 | Characteristics of participants in women’s health study cognitive cohort at
randomisation. Values are numbers (percentages) unless stated otherwise
Characteristics Aspirin group (n=3215)
Placebo group
(n=3162) P value
Mean (SD) age (years) at randomisation 66.2 (4.1) 66.3 (4.1) 0.21
Mean (SD) age (years) at initial cognitive
assessment
71.8 (4.1) 71.9 (4.1) 0.19
Self reported perceived change in memory
in past year*:
None or improved 83.0 82.8 0.84
Memory worse 17.0 17.2
Highest attained education:
LPVN, associates degree, registered
nurse
66.6 67.7 0.37
Bachelors degree, masters degree,
doctorate
33.4 32.3
Cigarette smoking:
Never 53.3 (1712) 51.6 (1629) 0.30
Former 37.1 (1192) 38.0 (1203)
Current 9.6 (307) 10.4 (328)
Alcohol consumption:
Less than weekly 59.4 (1909) 59.3 (1874) 0.95
Weekly 28.5 (916) 28.4 (896)
Daily 12.1 (389) 12.3 (389)
Body mass index:
<25 49.4 (1549) 50.9 (1574) 0.49
25-9 35.1 (1100) 34.2 (1058)
≥30 15.5 (486) 14.9 (460)
Physical exercise:
Less than once weekly 59.7 (1919) 59.3 (1873) 0.70
Once or more weekly 40.3 (1293) 40.7 (1287)
Hormone replacement therapy use:
Never 40.0 (1285) 40.0 (1261) 0.67
Past 19.1 (613) 19.9 (628)
Current 40.9 (1314) 40.1 (1266)
Medical history:
Diabetes mellitus 3.4 (110) 3.5 (111) 0.85
Hypertension 40.9 (1315) 39.2 (1240) 0.18
Hyperlipidaemia 42.5 (1365) 43.5 (1374) 0.42
Depression‡ 6.0 (191) 5.8 (181) 0.69
LPVN=licensed practical or vocational nurse.
*At run-in period.
‡Assessed four years after randomisation.
RESEARCH
BMJ | ONLINE FIRST | bmj.com page 3 of 8
average duration of aspirin or placebo treatment was 5.
6 years (range 4.4-6.8) and the mean time between the
first and the last assessment was 4.0 years (range 2.6-
5.7); thus the average total follow-up from randomisation
to final evaluation was 9.6 years (range 8.2-11.3).
Compliance was identical between the groups: at the
final assessment, 70.0% of women in both treatment
groups reported taking at least two thirds of the
assigned pills.
At the first assessment cognitive performance did
not differ by assigned group (table 2). When performance
was examined at each follow-up assessment,
no mean differences were observed between the
groups for global score (table 3). For example, the
mean difference between aspirin and placebo groups
at the final assessment, after a mean 9.6 years of treatment,
was 0.00 (95% confidence interval −0.04 to 0.04).
Similarly, for verbal memory no differences were
observed between the groups at any of the three assessments.
For example, at the final assessment the mean
difference for the aspirin group compared with placebo
group was −0.02 (−0.06 to 0.02). The aspirin
group also did not show better performance in the telephone
interview of cognitive status. The aspirin group
performed better for category fluency than the placebo
group at all three assessments, and this difference was
statistically significant at the final assessment (mean difference
0.37 points, 95% confidence interval 0.10 to
0.65). To help interpret this mean difference, the effects
of aspirin were compared with the effects of age in this
cohort; for each year of age a mean difference in score
on category fluency of 0.14 points was observed, thus
the effects of aspirin on category fluency seemed
equivalent to being 2.6 years younger.
No differences were observed in mean change in
cognitive performance by treatment assignment for
any of the cognitive outcomes (table 4). The mean
change over time between the aspirin and placebo
groups was 0.01 (95% confidence interval −0.02 to
0.04) for global score, 0.01 (−0.03 to 0.04) for verbal
memory score, 0.02 (−0.11 to 0.16) for the telephone
interview of cognitive status, and 0.11 (−0.12 to 0.34)
for category fluency.
The risk of substantial decline on the global score
from the first to final assessments for women in the
aspirin group was not lower thanwomenin the placebo
group; compared withwomenin the placebo group the
relative risk of substantial decline was 0.92 (0.77 to
1.10) for women assigned to aspirin. Only for the test
of category fluency did women assigned to aspirin
have a statistically significant 20% lower risk of substantial
decline than women assigned to placebo (relative
risk 0.80, 0.67 to 0.97; table 5).
Secondary analyses
Few interactions were found between aspirin use and
cognitive risk factors (table 6). A significant interaction
Table 2 | Cognitive test scores at initial assessment.* Values are means (ranges) unless stated
otherwise
Cognitive tests Aspirin group (n=3215)
Placebo group
(n=3162) P value
Telephone interview of cognitive status 34.2 (4-41) 34.3 (15-41) 0.44
East Boston memory test:
Immediate recall 9.6 (0-12) 9.6 (0-12) 0.50
Delayed recall 9.3 (0-12) 9.3 (0-12) 0.30
Delayed recall of 10 word list 3.0 (0-10) 3.0 (0-10) 0.68
Category fluency 17.6 (0-36) 17.5 (0-43) 0.31
*Initial testing carried out a mean 5.6 years after randomisation.
†Adjusted means.
Table 3 | Cognitive function at each cognitive assessment
Cognitive test (assessment)
Aspirin group Placebo group
Mean difference* (95%
CI)
No of
participants Adjusted mean (SE)
No of
participants Adjusted mean (SE)
Global score†:
First 3215 −0.01 (0.01) 3162 0.00 (0.01) −0.01 (−0.04 to 0.02)
Second 2873 0.07 (0.01) 2819 0.06 (0.01) 0.01 (−0.03 to 0.04)
Third 2630 0.02 (0.01) 2596 0.02 (0.01) 0.00 (−0.04 to 0.04)
Verbal memory score‡:
First 3215 −0.01 (0.01) 3162 0.01 (0.01) −0.02 (−0.05 to 0.02)
Second 2873 0.13 (0.01) 2819 0.13 (0.01) 0.00 (−0.04 to 0.04)
Third 2630 0.09 (0.02) 2596 0.11 (0.02) −0.02 (−0.06 to 0.02)
TICS test:
First 3208 34.18 (0.05) 3154 34.26 (0.05) −0.08 (−0.22 to 0.05)
Second 2871 34.07 (0.05) 2817 34.12 (0.05) −0.05 (−0.20 to 0.10)
Third 2630 34.09 (0.06) 2596 34.11 (0.06) −0.02 (−0.19 to 0.14)
Category fluency test:
First 3202 17.58 (0.09) 3151 17.46 (0.09) 0.12 (−0.13 to 0.36)
Second 2871 18.13 (0.10) 2817 18.02 (0.10) 0.12 (−0.15 to 0.39)
Third 2629 17.76 (0.10) 2596 17.38 (0.10) 0.37 (0.10 to 0.65)
TICS=telephone interview of cognitive status.
*From longitudinal linear models by treatment assignment of mean cognitive performance.
†Composite of five tests: TICS, immediate and delayed recalls of east Boston memory test, delayed recall of 10 word list, and category fluency.
‡Composite of four tests: immediate and delayed recalls of both 10 word list and east Boston memory test.
RESEARCH
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(P for interaction 0.03) was found between cigarette
smoking and aspirin use. Among current smokers,
the aspirin group experienced significantly less cognitive
decline than the placebo group: the difference in
mean decline over time between the aspirin and placebo
groups was 0.13 (95% confidence interval 0.03 to
0.22). In contrast, little difference was found in mean
change between the treatment groups among never
smokers or former smokers. Significant differences
were also observed in effects of aspirin in relation to
cholesterol levels, with aspirin providing cognitive
benefits among women with hyperlipidaemia (difference
in mean decline 0.05, 95% confidence interval
0.01 to 0.09) but not among those without (−0.02,
−0.06 to 0.02).
Cognitive benefits with aspirin did not differ substantially
between women who developed cardiovascular
disease (7.4% of participants; mean
difference in change in global score 0.08, −0.04 to
0.20) and those who did not (92.6%; 0.00, −0.03 to
0.03). Relatively fewwomendeveloped cardiovascular
disease and the interaction was not statistically significant
(P for interaction 0.24).
To evaluate the sensitivity of the results for those at
the worst end of the spectrum of cognitive function,
those who performed in the worst 10% of the distribution
of cognitive function were excluded. No substantial
differences were found from the primary findings.
Finally, to assess whether compliance may have
influenced the results, the primary analyses were
repeated after excluding participants who reported
taking less than two thirds of their assigned treatment
by the third assessment (30% of participants). The
results were robust: the difference in mean change in
global score between the aspirin and placebo groups
was −0.01 (95% confidence interval−0.05 to 0.02).
DISCUSSION
In a randomised, placebo controlled trial with nearly
10 years of treatment among over 6000 women, this
study of women aged 65 or more showed that those
assigned to low dose aspirin had similar overall cognitive
performance to those receiving placebo. Compared
with women receiving placebo, women who
took low dose aspirin did not differ in overall performance
at any of the three assessments of cognition,
ranging from the first assessment after 5.6 years of
treatment to the final assessment after a mean
9.6 years of treatment, and also did not differ in their
average cognitive decline during 3-6 years of
follow-up.
There was some suggestion that women in the
aspirin group performed better in the category fluency
test than women in the placebo group, particularly at
the final assessment; women assigned to aspirin were
20% less likely to develop substantial decline in performance
on category fluency. A specific association with
category fluency has also been reported in one small
trial of low dose aspirin over five years,19 as well as in a
large observational study of long term aspirin use.20
Because the category fluency test partially assesses
executive function—a cognitive system that is influenced
by vascular disease21—it is biologically plausible
that low dose aspirin may specifically help preserve
executive function. However, because category fluency
was the only test in our battery that measured
executive function, and because this was not a primary
outcome of our trial, this result should be interpreted
with caution and confirmed by future studies.
We observed apparent effect modification by high
cholesterol level and by smoking status. Among the
subset of women with a high cholesterol level, aspirin
treatment protected against cognitive decline; this is
consistent with the results from the primary trial of
cardiovascular events, where aspirin seemed more
protective against major cardiovascular events among
Table 4 | Mean difference in cognitive decline between aspirin and placebo groups during followup,
frominitial assessment
Cognitive test Mean difference (95% CI) P value
Global score*:
From first to second assessment 0.01 (−0.02 to 0.05) 0.45
From first to third assessment 0.01 (−0.03 to 0.04) 0.70
Average over follow-up 0.01 (−0.02 to 0.04) 0.50
Verbal memory score†:
From first to second assessment 0.02 (−0.02 to 0.06) 0.38
From first to third assessment −0.01 (−0.05 to 0.03) 0.73
Average over follow-up 0.01 (−0.03 to 0.04) 0.71
TICS test:
From first to second assessment 0.01 (−0.13 to 0.16) 0.87
From first to third assessment 0.04 (−0.12 to 0.20) 0.61
Average over follow-up 0.02 (−0.11 to 0.16) 0.71
Category fluency:
From first to second assessment −0.01 (−0.28 to 0.25) 0.91
From first to third assessment 0.25 (−0.02 to 0.52) 0.07
Average over follow-up 0.11 (−0.12 to 0.34) 0.34
TICS=telephone interview of cognitive status.
*Composite of five tests: TICS test, immediate and delayed recalls of east Boston memory test, delayed recall of
10 word list, and category fluency.
†Composite of four tests: immediate and delayed recalls of both 10 word list and east Boston memory test.
Table 5 | Relative risk of substantial cognitive decline*
Cognitive test No of women
Relative risk of substantial decline
(95% CI) P value
Global score†:
Placebo 270 1.00
Aspirin 253 0.92 (0.77 to 1.10) 0.36
Verbal memory score‡:
Placebo 260 1.00
Aspirin 263 1.00 (0.83 to 1.20) 0.99
TICS test:
Placebo 297 1.00
Aspirin 294 0.98 (0.82 to 1.16) 0.79
Category fluency:
Placebo 268 1.00
Aspirin 222 0.80 (0.67 to 0.97) 0.02
TICS=telephone interview of cognitive status.
*Worst 10% of distribution of decline from first to third assessment (global score −0.8 points, verbal memory
score −0.9 points, TICS −4 points, category fluency −7 points).
†Composite of five tests: TICS, immediate and delayed recalls of east Boston memory test, delayed recall of 10
word list, and category fluency.
‡Composite of four tests: immediate and delayed recalls of both 10 word list and east Boston memory test.
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BMJ | ONLINE FIRST | bmj.com page 5 of 8
women with hyperlipidaemia (relative risk 0.80, 95%
confidence interval 0.66 to 0.97) than those with normal
blood lipid levels (0.98, 0.84 to 1.16).11 Also,
women who were current smokers and assigned to
aspirin experienced less cognitive decline over time
than smokers who were taking placebo; in contrast,
aspirin had no effect on cognition among women
who never smoked or had quit smoking. These results
were the opposite of those found in the primary trial of
cardiovascular events,11 where aspirin seemed protective
against major cardiovascular events only among
women who never smoked or had quit smoking.
Given the numerous subgroup analyses carried out,
chance cannot be ruled out as an explanation for
these findings.
Limitations of the study
A limitation of our trial is that the study population
consisted of mainly healthy white “young-old” (mean
age 72) women; thus, whether the results are generalisable
to women of older ages or other races is
unknown. The age of the study population may have
contributed to the lack of major decline in cognitive
function over the follow-up period of 3-6 years,
although we have detected other risk factors for cognitive
decline in these women over a similar period.22 23
In addition, we started cognitive testing a mean
5.6 years after randomisation, thus we were unable to
measure change in cognitive performance from randomisation.
However, at randomisation numerous risk
factors for cognitive impairment were similarly distributed
across treatment groups, and it is highly likely in
this large trial that cognitive function was also comparable
between the groups at randomisation. Thus the
lack of a true baseline cognitive assessment should
not have a major influence on our ability to detect
effects of long term aspirin use on cognitive decline.
Although it is possible that there may have been
some transient, short term benefits of aspirin on cognition
just during the first 5.6 years, this possibility seems
biologically implausible given that cognitive changes
develop progressively over long periods. Finally, loss
to follow-up did not differ by treatment group; however,
greater losses to follow-up occurred among
those who developed cardiovascular disease (15%)
compared with the entire cohort (8%). Thus there
may have been some bias towards the null; however,
such bias would be minimal as the proportion of
women with cardiovascular events was low.
Although many observational studies have investigated
the use of non-steroidal anti-inflammatory drugs
in relation to cognitive decline,8 few studies20 24-26 have
specifically examined aspirin use. These studies have
generally shown inconsistent associations between
aspirin and cognitive decline, largely supporting our
null results. For example, one small study26 of 612 participants
aged 62-85 followed for three years reported
significant inverse associations between continued low
dose aspirin use and cognitive decline. Yet in a study
among 2087 people aged 65 or more followed for three
years, little association was found for low or medium
dose aspirin (relative risk 0.90, 95% confidence interval
0.48 to 1.69);24 similarly, a study25 of 2556 participants
aged 65 or more found that aspirin use was
related to a small, non-significant decrease in cognitive
decline over six years: for intermittent use of aspirin
(<1 aspirin daily) the relative risk for cognitive decline
was 0.84 (0.66 to 1.06), and for 1-2 aspirins daily the
Table 6 | Mean difference in cognitive decline in global score between aspirin comparedwith
placebo groups: effectmodification bymajor risk factors for cognitive decline*
Characteristics Mean difference (95% CI) P for interaction
Age (years) at first cognitive assessment:
<75 0.00 (−0.03 to 0.03) 0.16
≥75 0.06 (−0.02 to 0.13)
Cognitive performance at first assessment:
Below median 0.02 (−0.02 to 0.07) 0.49
Above median 0.00 (−0.03 to 0.04)
Self reported perceived change in memory†:
None or improved 0.00 (−0.03 to 0.03) 0.21
Worse 0.05 (−0.02 to 0.12)
Highest attained education:
LPVN, associates degree, or registered nurse 0.02 (−0.02 to 0.05) 0.56
Bachelors degree, masters degree, or doctorate 0.00 (−0.05 to 0.05)
Cigarette smoking:
Never −0.01 (−0.05 to 0.03) 0.03
Former 0.01 (−0.03 to 0.06)
Current 0.13 (0.03 to 0.22)
Alcohol consumption:
Less than weekly 0.01 (−0.02 to 0.05) 0.94
Weekly 0.01 (−0.05 to 0.06)
Daily 0.00 (−0.08 to 0.08)
Body mass index:
<30 0.01 (−0.02 to 0.04) 0.96
≥30 0.01 (−0.06 to 0.08)
Physical exercise:
Less than once weekly 0.03 (−0.01 to 0.07) 0.14
Once or more weekly −0.02 (−0.06 to 0.03)
Hormone replacement therapy use:
Never 0.00 (−0.04 to 0.05) 0.69
Ever (former plus current) 0.01 (−0.02 to 0.05)
Diabetes:
Yes 0.13 (−0.03 to 0.29) 0.15
No 0.01 (−0.02 to 0.04)
Hypertension:
Yes −0.02 (−0.06 to 0.03) 0.17
No 0.03 (−0.01 to 0.06)
Raised cholesterol level:
Yes 0.05 (0.01 to 0.09) 0.02
No −0.02 (−0.06 to 0.02)
Depression‡:
Yes 0.09 (−0.04 to 0.21) 0.20
No 0.00 (−0.03 to 0.03)
Cardiovascular disease during follow-up§:
Yes 0.08 (−0.04 to 0.20) 0.24
No 0.00 (−0.03 to 0.03)
LPVN=licensed practical or vocational nurse.
*Characteristics at randomisation, unless stated otherwise.
†Assessed at run-in phase.
‡Assessed four years after randomisation.
§Includes non-fatal myocardial infarction, non-fatal stroke, revascularisation surgery, or cardiovascular death.
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relative risk was 0.91 (0.68 to 1.22). The largest observational
study,20 including 13 255 women aged at least
70, found that long term use of low dose aspirin for
15 years or more had little association with substantial
decline in cognition over two years (relative risk 0.91,
95% confidence interval 0.70 to 1.19). This present
study contributes to the existing literature in that biases
related to the indication for aspirin treatment are minimised
owing to randomisation and the length of aspirin
treatment (almost 10 years), allowing for strong conclusions
about the specificity of the role of aspirin in cognitive
changes.
Biologically our null results should be interpreted in
light of the treatment dose and the drug selected.
Although the low prophylactic aspirin dose used in
this trial (100 mg on alternate days) has shown antiplatelet
activity, it confers limited anti-inflammatory
effects.27 In addition, unlike some non-steroidal antiinflammatory
drugs such as ibuprofen,28 aspirin lacks
the ability in vitro to modulate the processing of the
amyloid precursor protein, believed to be critical in
the pathogenesis of Alzheimer’s disease, the most common
cause of dementia.
The most likely mechanism by which low dose
aspirin might influence cognitive decline is that aspirin
reduces platelet aggregation, improves cerebral blood
flow, and prevents cardiovascular disease; although,
overall, aspirin did not reduce major cardiovascular
events in the primary trial of the women’s health
study,11 among the subset of women aged 65 or more,
treatment conferred a modest protective effect against
major cardiovascular events (relative risk 0.74, 95%
confidence interval 0.59 to 0.92). Although we found
no cognitive benefits of aspirin in this trial, it remains
possible that any benefits require many years to noticeably
affect cognitive decline; indeed it is widely
believed that brain ageing takes decades to develop.29
Several recent studies30-34 have reported adverse relations
between vascular risk factors in middle age and
development of cognitive impairment later in life,
implying that for prevention, early modification of
cardiovascular risk may be most important.
In conclusion, in this study within a large, randomised,
placebo controlled trial among over 6000
healthy women aged 65 or more, we observed no
apparent benefit of low dose aspirin in slowing cognitive
decline over four years. Other methods for preserving
cognitive function in older people need to be
investigated.
We thank the participants, staff, and investigators of the women’s health study.
Contributors: All authors conceived and designed the study. JHK and FG
carried out the study. JHK and NC analysed the data. JHK drafted the manuscript
and is guarantor. All authors critically reviewed the paper and approved the final
draft for publication.
Funding: The study was supported by grant AG15933 from the National
Institute of Aging, HL-43851 from the National Heart, Lung, and Blood Institute,
and CA-47988 from the National Cancer Institute. Aspirin and placebo were
provided by Bayer HealthCare.
Competing interests: None declared.
Ethical approval: The trial was approved by the institutional review board of
Brigham and Women’s Hospital.
1 Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L. The course
of cognitive impairment in preclinical Alzheimer disease: three- and
6-year follow-up of a population based sample. Arch Neurol
2000;57:839-44.
2 Amieva H, Jacqmin-Gadda H, Orgogozo J-M, Le Carret N, Helmer C,
Letenneur L, et al. The 9 year cognitive decline beforedementia of the
Alzheimer type: a prospective population-based study. Brain
2005;128:1093-101.
3 Rogers J, Kirby LC, Hempelman SR, BerryDL, McGeer PL,
Kaszniak AW, et al. Clinical trial of indomethacin in Alzheimer’s
disease. Neurology 1993;43:1609-11.
4 Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A doubleblind,
placebo-controlled trial of diclofenac/misoprostol in
Alzheimer’s disease. Neurology 1999;53:197-201.
5 AisenPS, DavisKL,Berg JD,Schafer K, Campbell K, Thomas RG, et al.
A randomized controlled trial of prednisone in Alzheimer’s disease.
Alzheimer’s disease cooperative study. Neurology 2000;54:588-93.
6 Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ. Effect of
hydroxychloroquine on progression of dementia in early Alzheimer’s
disease: an 18-month randomised, double-blind, placebocontrolled
study. Lancet 2001;358:455-60.
7 AisenPS, SchaferKA,GrundmanM, Pfeiffer E, SanoM,DavisKL, et al.
Effects of rofecoxib or naproxen vs placebo on Alzheimer disease
progression: a randomized controlled trial. JAMA
2003;289:2819-26.
8 De Craen AJ, Gussekloo J, Vrijsen B, Westendorp RG.Meta-analysis of
nonsteroidal antiinflammatory drug use and risk of dementia. Am J
Epidemiol 2005;161:114-20.
9 Couzin J. Halt of Celebrex study threatens drug’s future, other trials.
Science 2004;306:2170.
10 Steering Committee of the Physician’s Health Study Research Group.
Final report on the aspirin component of the ongoing physician’s
health study.N Engl J Med 1989;321:129-35.
11 Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM,Manson JE, et al.
A randomized trial of low-dose aspirin in the primary prevention of
cardiovascular disease in women.N Engl J Med
2005;352:1293-304.
12 Buring JE, Hennekens CH. The women’s health study: summary of the
design. J Myocardial Ischemia 1992;4:27-9.
13 CookNR, Lee IM, Gaziano JM, GordonD, Ridker PM,Manson JE, et al.
Low-dose aspirin in the primary prevention of cancer: the women’s
health study: a randomized controlled trial. JAMA 2005;294:47-55.
14 Kang JH, Cook NR, Manson JE, Buring JE, Grodstein F. A randomized
trial of vitamin E and cognitive function in women. Arch Intern Med
2006;166:2462-8.
15 Brandt J, Folstein MF. Telephone interview for cognitive status:
professional manual. Lutz, FL: Psychological Assessment Resources,
2003.
16 Scherr PA, Albert MS, Funkenstein HH, Cook NR, Hennekens CH,
Branch LG, et al. Correlates of cognitive function in an elderly
community population. Am J Epidemiol 1988;128:1084-101.
17 Morris JC, HeymanA,MohsRC, Hughes JP, vanBelleG, FillenbaumG,
et al. The Consortium to Establish a Registry for Alzheimer’s Disease
(CERAD). Part I. Clinical and neuropsychological assessment of
Alzheimer’s disease. Neurology 1989;39:1159-65.
18 Fitzmaurice GM, Laird NM, Ware JH. Modelling the mean: analyzing
response profiles. Applied longitudinal analysis. Hoboken, NJ: John
Wiley, 2004:103-39.
19 Richards M, Meade TW, Peart S, Brennan PJ, Mann AH. Is there any
evidence for a protective effect of antithrombotic medication on
cognitive function in men at risk of cardiovascular disease? Some
preliminary findings. J Neurol Neurosurg Psychiatry
1997;62:269-72.
20 Kang JH, Grodstein F. Regular use of non-steroidal anti-inflammatory
drugs and cognitive function in aging women. Neurology
2003;60:1591-7.
21 Roman GC, Royall DR. Executive control function: a rational basis for
the diagnosis of vascular dementia. Alzheimer Dis Assoc Disord
1999;13(Suppl 3):S69-80.
WHAT IS ALREADY KNOWN ON THIS TOPIC
Laboratory and epidemiological evidence suggests that aspirin and other anti-inflammatory
drugs may be protective against dementia
Data from randomised studies to date have been inconclusive
WHAT THIS STUDY ADDS
Low dose aspirin did not provide overall cognitive benefits in generally healthy ageing women
participating in a large, long term randomised trial
RESEARCH
BMJ | ONLINE FIRST | bmj.com page 7 of 8
22 Devore E, Buring JE, Grodstein F. Plasma cholesterol levels and
cognitive function in older women [abstract]. Neurobiol Aging
2004;25(Suppl 2):S52.
23 Lee S, Buring JE, Cook NR, Grodstein F. The relation of education and
income to cognitive function among professional women.
Neuroepidemiology 2006;26:93-101.
24 Saag KG, Rubenstein LM, Chrischilles EA, Wallace RB. Nonsteroidal
antiinflammatory drugs and cognitive decline in the elderly. J
Rheumatol 1995;22:2142-7.
25 Sturmer T, Glynn RJ, Field TS, Taylor JO,Hennekens CH. Aspirin use
and cognitive function in the elderly. Am J Epidemiol
1996;143:683-91.
26 Jonker C, Comijs HC, Smit JH. Does aspirin or otherNSAIDs reduce the
risk of cognitive decline in elderly persons? Results from a
population-based study. Neurobiol Aging 2003;24:583-8.
27 Ridker PM, Hennekens CH, Tofler GH, Lipinska I, Buring JE. Antiplatelet
effects of 100 mg alternate day oral aspirin: a randomized,
double-blind, placebo-controlled trial of regular and enteric coated
formulations in men and women. J Cardiovasc Risk 1996;3:209-12.
28 Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A
subset of NSAIDs lower amyloidogenic Ab42 independently of
cyclooxygenase activity. Nature 2001;414:212-6.
29 Braak E, Griffing K, Arai K, Bohl J, Bratzke H, Braak H. Neuropathology
of Alzheimer’s disease: what is new since A. Alzheimer? Eur Arch
Psychiatry Clin Neurosci 1999;249(Suppl 3):14-22.
30 Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, et al.
Association of midlife blood pressure to late-life cognitive decline
and brain morphology. Neurology 1998;51:986-93.
31 Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association
between midlife blood pressure levels and late-life cognitive
function. The Honolulu-Asia aging study. JAMA 1995;274:1846-51.
32 Elias PK, Elias MF, D’Agostino RB, Cupples LA, Wilson PW,
Silbershatz H, et al. NIDDM and blood pressure as risk factors for
poor cognitive performance. The Framingham study. Diabetes Care
1997;20:1388-95.
33 CarmelliD, SwanGE, ReedT,MillerB,Wolf PA, JarvikGP, et al.Midlife
cardiovascular risk factors, ApoE, and cognitive decline in elderly
persons. JAMA 1998;50:1580-5.
34 Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M,
Alhainen K, et al. Midlife vascular risk factors and Alzheimer’s
disease in later life: longitudinal, population based study. BMJ
2002;322:1447-51.
Accepted: 21 February 2007
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