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Serum Lipoprotein Levels, Statin Use, and Cognitive Function in Older Women
Kristine Yaffe, MD;
Elizabeth Barrett-Connor, MD;
Feng Lin, MS;
Deborah Grady, MD
Arch Neurol. 2002;59:378-384.
ABSTRACT
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Background Few strategies are available for the prevention of cognitive impairment
in elderly persons. Serum lipoprotein levels may be important predictors of
cognitive function, and drugs that lower cholesterol may be effective for
the prevention of cognitive impairment.
Objective To determine whether serum lipoprotein levels, the 4-year change in
serum lipoprotein levels, and the use of statin drugs are associated with
cognition in older women without dementia.
Design, Setting, and Participants An observational study of 1037 postmenopausal women with coronary heart
disease enrolled in the Heart and Estrogen/progestin Replacement Study (participants
at 10 of 20 centers).
Main Outcome Measure The Modified Mini-Mental State Examination was administered at the end
of the study after 4 years of follow-up. Women whose score was less than 84
points (>1.5 SDs below the mean) were classified as having cognitive impairment.
Lipoprotein levels (total, high-density lipoprotein, and low-density lipoprotein
[LDL] cholesterol and triglycerides) were measured at baseline and at the
end of the study; statin use was documented at each visit.
Results Compared with women in the lower quartiles, women in the highest LDL
cholesterol quartile at cognitive testing had worse mean ± SD Modified
Mini-Mental State Examination scores (93.7 ± 6.0 vs 91.9 ± 7.6; P = .002) and an increased likelihood of cognitive impairment
(adjusted odds ratio, 1.76; 95% confidence interval, 1.04-2.97). A reduction
in the LDL cholesterol level during the 4 years tended to be associated with
a lower odds of impairment (adjusted odds ratio, 0.61; 95% confidence interval,
0.36-1.03) compared with women whose levels increased. Higher total and LDL
cholesterol levels, corrected for lipoprotein(a) levels, were also associated
with a worse Modified Mini-Mental State Examination score and a higher likelihood
of impairment, whereas high-density lipoprotein cholesterol and triglyceride
levels were not associated with cognition. Compared with nonusers, statin
users had higher mean ± SD Modified Mini-Mental State Examination scores
(92.7 ± 7.1 vs 93.7 ± 6.1; P = .02)
and a trend for a lower likelihood of cognitive impairment (odds ratio, 0.67;
95% confidence interval, 0.42-1.05), findings that seemed to be independent
of lipid levels.
Conclusions High LDL and total cholesterol levels are associated with cognitive
impairment, and lowering these lipoprotein levels may be a strategy for preventing
impairment. The association between statin use and better cognitive function
in women without dementia requires further study.
INTRODUCTION
ABOUT 10% of people older than 65 years have cognitive impairment, ranging
from mild deficits to dementia.1 However, few
modifiable risk factors for cognitive impairment have been identified. Serum
lipoprotein levels, especially among people with cardiovascular disease, may
be a common and potentially modifiable risk factor for cognitive disorders.
The findings of studies that have investigated the relationship between serum
lipoprotein levels and risk of cognitive impairment are conflicting. Some
cross-sectional studies2-3 suggest
that high total cholesterol levels are associated with an increased risk of
Alzheimer disease (AD), while others4 report
that low total cholesterol levels are associated with the risk of developing
AD. Cross-sectional studies of this question can be misleading because dementia
may cause changes in lipoprotein levels by altering diet or metabolism. However,
prospective studies have also had conflicting results. In one study5 of more than 1000 elderly persons, a higher baseline
low-density lipoprotein (LDL) cholesterol level was associated with an increased
risk of developing stroke-related dementia but not with a risk of developing
AD. Two other prospective studies6-7
found no association between lipoprotein levels and risk of dementia, and
a third study8 reported a statistically significant,
but of unclear clinical significance, association between lower total cholesterol
levels and higher rates of cognitive decline in older twins. To our knowledge,
no studies have explored whether changes in lipoprotein levels are associated
with cognitive function in elderly persons.
In an attempt to better understand the relationship between lipoprotein
levels, cognitive function, and risk of cognitive impairment, we asked whether
serum lipoprotein levels and the 4-year change in levels are associated with
cognitive impairment in a cohort of older women with known cardiovascular
disease. We also investigated whether the use of lipid-lowering drugs, such
as statins, is associated with cognitive function. Several small trials of
statins have included cognitive outcomes, initially out of concern for harmful
effects, and have yielded inconsistent results. Most of these trials9-13
were short-term and enrolled young adults who are not at risk for cognitive
impairment. Two recent observational studies, one case-control14
and one nested case-control,15 reported a 60%
to 70% lower odds of developing dementia among statin users. Serum lipoprotein
levels were not measured directly in either study and, therefore, it is uncertain
whether the protective effect of statin use was related to lipoprotein level
or whether the effect was due to an unknown selection bias. However, in their
study, Jick and colleagues15 found that the
medical record diagnosis of untreated hyperlipidemia was not associated with
a risk of developing dementia. Our goal was to determine if statin use is
associated with cognitive function and risk of cognitive impairment in older
women without dementia and, if so, if it is mediated by lipoprotein level.
SUBJECTS AND METHODS
SUBJECTS
Women were enrolled in the Heart Estrogen/progestin Replacement Study
trial. The design and main outcomes of the trial have been published previously.16 Subjects were postmenopausal women younger than 80
years with established coronary disease who had not undergone a hysterectomy.
None of the women had a history of dementia or were taking antidementia medications
at enrollment. Women were randomly assigned (stratified by clinical center)
to treatment with daily oral estrogens, conjugated, 0.625 mg, and medroxyprogesterone
acetate, 2.5 mg, or an identical placebo. Because treatment was not associated
with cognitive performance,17 we combined treatment
groups for this study.
MEASUREMENTS
At the end of the 4-year trial, women at 10 of the 20 clinical centers
underwent cognitive testing. Trained clinical staff administered the Modified
Mini-Mental State Examination (3MS),18 a brief
cognitive test with components for orientation, concentration, language, praxis,
and immediate and delayed memory. Scores range from 0 to 100, with higher
scores denoting better cognitive performance. We defined cognitive impairment
to be a 3MS score less than 84 points, which is greater than 1.5 SDs below
the mean.
At baseline and at cognitive testing (year 4), participants completed
questionnaires that included information on demographics, smoking, general
health, and medical conditions. All medications, including statins and other
lipid-lowering drugs, were recorded. We defined statin use to be present if
a woman had regularly taken statins within the past month. Height and weight
were measured, and the body mass index was calculated. Depression was measured
with the 15-item Geriatric Depression Scale.19
Incident stroke was defined as a rapid onset of a neurological deficit attributable
to a vascular territory that lasted longer than 24 hours or that was confirmed
by a lesion compatible with an acute stroke on a computed tomographic or magnetic
resonance imaging scan. All strokes were adjudicated by medical record review
by 2 blinded Heart and Estrogen/progestin Replacement Study physicians. Incident
nonfatal myocardial infarction cases were adjudicated by an independent subcommittee
blinded to treatment assignment; a history of coronary artery bypass graft
(CABG) surgery at cognitive testing was verified by surgical report.
Lipoprotein levels were measured at baseline and at the end of the study.
All subjects were instructed to fast for 12 hours before measurement. Total,
LDL, and high-density lipoprotein (HDL) cholesterol and triglyceride levels
were determined by the Lipoprotein Analytical Laboratory, The Johns Hopkins
University, Baltimore, Md, in compliance with the standards of the Centers
for Disease Control and Prevention location. Lipoprotein(a) levels were measured
immunochemically with a sandwich enzyme-linked immunosorbent assay (Strategic
Diagnostics Inc, Newark, Del). Low-density lipoprotein cholesterol levels
were corrected for lipoprotein(a) levels with the following formula: corrected
LDL cholesterol level = LDL cholesterol level - [0.3 x lipoprotein(a)
level].
For this study, the analytic cohort consisted of the 1037 women who
underwent cognitive testing at the end of the trial and serum lipoprotein
measurements at the beginning and end of the trial.
STATISTICAL ANALYSIS
Statistical analyses were performed using SAS statistical software,
version 6.12 (SAS Institute Inc, Cary, NC), and all significance levels reported
are 2-sided, with P<.05 considered statistically
significant. Because the distributions of serum lipoprotein levels were not
normal, we divided subjects into approximate quartiles. Subject characteristics
were compared by analysis of variance for continuous variables and the  2 test for dichotomous variables across quartile of total cholesterol
level. To determine whether serum lipoprotein level at cognitive testing was
associated with the 3MS score, we compared scores on the 3MS across lipid
quartiles using an analysis of variance. Linear trends across quartiles were
tested using linear contrasts. We adjusted the 3MS scores for variables that
differed among subjects in the lipoprotein quartiles with P .05 (aspirin use), variables known to be associated with cognition
(age and educational level), conditions that might affect cognitive function
(diabetes, self-reported health status, or CABG surgery), and hormone treatment
group. We also compared models with and without statin use. To determine if
change in lipoprotein level during the trial was associated with cognitive
performance, we calculated the approximate 4-year change in level (follow-up
level - baseline level). We compared mean unadjusted and multivariate-adjusted
3MS scores among the quartiles of change in lipoprotein level. We used logistic
regression to examine the odds of cognitive impairment (an a priori 3MS cutoff
score >1.5 SDs of the cohort mean) as a function of lipoprotein quartile and
change quartile using the lowest 3 quartiles as the reference group for total
and LDL cholesterol and triglyceride levels and the highest 3 quartiles as
the reference for HDL cholesterol level. To determine if any association between
level and cognitive function was primarily due to stroke, we repeated all
analyses after excluding subjects with incident stroke.
We compared mean 3MS scores by statin use at cognitive testing with
the t test. Multivariate models were conducted using
an analysis of covariance; we first adjusted the models for age and total
cholesterol level. We then adjusted the models for variables that were statistically
different between statin and nonstatin users (educational level, current smoking,
and CABG surgery), age, treatment group, and total cholesterol level. We used
logistic regression analyses to determine if statin use, and use of other
lipoprotein-lowering drugs, was associated with the odds of cognitive impairment.
RESULTS
Serum lipoprotein concentration and ranges in each quartile at cognitive
testing are shown in Table 1,
along with mean 4-year changes from the baseline level. During the 4 years,
most women (those in the lowest 3 quartiles of lipoprotein change) had reductions
or little change in their lipoprotein levels. The mean ± SD age of
the women was 71.1 ± 6.3 years. The characteristics of the participants
did not differ across total cholesterol quartile, except that women in the
lowest quartile were more likely to be taking statins and aspirin (Table 2). None of the women were taking
medications for AD, such as donepezil.
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Table 1. Serum Lipoprotein Levels in the 1037 Women Enrolled in the
HERS Trial*
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Table 2. Subject Characteristics by Total Cholesterol Quartile at Cognitive
Testing in the 1037 Women Enrolled in the HERS Trial*
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Women's scores on the 3MS ranged from 53 to 100, with a mean ±
SD score of 93.3 ± 6.6. Unadjusted and multivariate-adjusted 3MS scores
by lipoprotein quartile at cognitive testing are shown in Table 3. Compared with women in the lower quartiles, women in the
highest LDL cholesterol quartile had worse performance on the 3MS. Almost
identical results were obtained for total cholesterol quartiles and for LDL
cholesterol levels after correcting for lipoprotein(a) levels. There was no
association between HDL cholesterol or triglyceride quartile and 3MS score
(P>.10). The results of these analyses did not change
after adjusting cognitive test scores for age, educational level, treatment
group, diabetes status, health status, CABG surgery, and aspirin use (Table 3). Adjusting for statin use also
did not change the magnitude or statistical significance of the results.
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Table 3. 3MS Scores by Quartile of Lipoprotein at Cognitive Testing
in the 1037 Women Enrolled in the HERS Trial*
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Change in lipoprotein level during the 4 years was also associated with
the 3MS score. Women in the lower 3 quartiles of LDL cholesterol change (women
whose levels declined or stayed the same during the trial) had better cognitive
scores compared with those whose levels increased (women in the highest quartile)
during the 4 years (mean ± SD scores, 93.8 ± 6.0, 93.8 ±
6.0, and 93.4 ± 6.2 vs 92.3 ± 7.6; P
= .007). Similar results were observed for total and LDL cholesterol change,
corrected for lipoprotein(a) level. There was no association between change
in HDL cholesterol and triglyceride levels and cognitive performance. Multivariate
adjustment for age, educational level, treatment group, diabetes status, health
status, CABG surgery, and aspirin use produced similar results (Figure 1). Further adjustment for statin use did not change the
results.
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Adjusted Modified Mini-Mental State (3MS) Examination score by 4-year
lipoprotein change quartile (year 4 level - baseline level), adjusted
for age, educational level, treatment group, diabetes status, health status,
and aspirin use. Values of lipid change are presented in Table 1; the lowest quartile had a reduction in lipid level, whereas
the highest quartile had an increase in lipid level. The asterisk indicates P = .02 for trend; HDL, high-density lipoprotein; and LDL,
low-density lipoprotein.
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Of the 1037 women, 79 (8%) met the criteria for cognitive impairment.
Compared with women in the lower 3 quartiles, women in the highest total and
LDL cholesterol quartile had almost a 2-fold greater likelihood of having
cognitive impairment (Table 4).
The odds of impairment for LDL cholesterol level after correction for lipoprotein(a)
level were slightly higher (unadjusted odds ratio [OR], 1.98 [95% confidence
interval {CI}, 1.22-3.23]; and adjusted OR, 1.83 [95% CI, 1.09-3.08]) than
for the uncorrected LDL cholesterol level. Additional adjustment for statin
use did not change the magnitude or statistical significance of the results
for any of the analyses. There was no association with HDL cholesterol or
triglyceride level quartile and odds of cognitive impairment. Reduction or
no change in total and LDL cholesterol levels during the 4 years was associated
with a lower odds of impairment, comparing women in the lowest 3 quartiles
(those whose lipoprotein levels were reduced or stayed the same) with women
in the highest quartile (those whose lipoprotein levels increased) (total
cholesterol level: unadjusted OR, 0.55 [95% CI, 0.34-0.91]; and adjusted OR,
0.53 [95% CI, 0.31-0.89]; LDL cholesterol level: unadjusted OR, 0.64 [95%
CI, 0.39-1.05]; and adjusted OR, 0.61 [95% CI, 0.36-1.03]; LDL cholesterol
level corrected for lipoprotein[a] level: unadjusted OR, 0.56 [95% CI, 0.34-0.92];
and adjusted OR, 0.50 [95% CI, 0.30-0.85]). There was no association between
4-year change in HDL cholesterol or triglyceride level and odds of impairment.
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Table 4. Association Between Lipoprotein Quartile at Cognitive Testing
and the Odds of Cognitive Impairment: Results of the Unadjusted and Adjusted
Analyses*
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To determine if the association between cognitive scores and the odds
of cognitive impairment and lipoprotein levels was explained by stroke incidence,
we excluded the 32 women who developed stroke during the trial. The results
were nearly identical when these subjects were excluded.
At cognitive testing, 583 (56%) of the women were taking statins (simvastatin,
atorvastatin calcium, pravastatin sodium, lovastatin, or fluvastatin sodium).
Statin users tended to be more educated (12.9 vs 12.5 years; P = .02), tended to smoke less (10% vs 15%; P
= .01), and were more likely to have undergone CABG surgery (43% vs 37%; P = .05), but they did not differ from nonusers on other
characteristics. The mean ± SD 3MS score among statin users was 93.7
± 6.1 compared with 92.7 ± 7.1 among women not taking statins
(Table 5). Adjustment for age
or for total cholesterol quartile did not affect the results, while adjustment
for age, educational level, treatment group, smoking status, CABG surgery,
and total cholesterol quartile attenuated the magnitude of the effect slightly;
however, there was still a trend for better cognitive performance in the statin
use group. Of the women taking statins, 6% (n = 37) had cognitive impairment,
whereas 9% (n = 42) of the women not taking statins had cognitive impairment
(OR, 0.67; 95% CI, 0.42-1.05). Sixty-three of the women were taking nonstatin
lipoprotein-lowering agents, such as niacin (n = 41) and cholestyramine resin
(n = 17). Use of nonstatin lipoprotein-lowering drugs was not associated with
an adjusted odds of having cognitive impairment (OR, 0.97; 95% CI, 0.36-2.61).
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Table 5. 3MS Scores by Statin Use*
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COMMENT
Among elderly women with coronary heart disease, higher serum levels
of total and LDL cholesterol were associated with worse cognitive scores and
a greater likelihood of cognitive impairment. Reductions in total and LDL
cholesterol levels during 4 years were associated with better cognitive functioning
and approximately 50% less risk of having cognitive impairment. These findings
suggest that lowering total and LDL cholesterol levels may be a potential
strategy for preventing the development of cognitive impairment or dementia.
Furthermore, we found a positive association between statin use and cognitive
function that seems to be independent of total cholesterol level.
Our finding is supported by several,2-3
but not all,4 cross-sectional studies that
found an association between high total cholesterol levels and increased risk
of developing AD. One prospective study5 also
found that a high LDL cholesterol level was associated with an increased risk
of developing dementia from stroke. When we excluded women with stroke, there
was still an association between high total and LDL cholesterol levels and
worse cognition, suggesting that factors other than large-vessel ischemia
may be involved. High total and LDL cholesterol levels may influence the risk
of cognitive impairment by increasing subclinical vascular disease. Furthermore,
recent evidence20 suggests that traditional
"vascular" risk factors, such as carotid atherosclerosis, atrial fibrillation,
and increase in coagulation factor I, may be also involved in the pathogenesis
of AD. While we did not have a clinical assessment for cognitive impairment
and cannot determine its cause, it is likely that the women in our study would
have various neuropathologic features, including AD and vascular dementia.
Women with coronary heart disease have an increased risk of dementia of all
types.21 The 8% incidence of cognitive impairment
that we observed is consistent with a 1% to 2% annual dementia incidence for
women of this age,22 assuming that most participants
were free of cognitive impairment when they enrolled in the trial. Nevertheless,
our study does not specifically address the efficacy of statins for the prevention
of AD.
Our finding that statins were associated with cognitive performance
and protection against cognitive impairment is not supported by 5 small trials9-13
that did not find a consistent improvement on cognitive testing with statin
treatment. However, most of these trials lasted only a few weeks, and all
enrolled young or middle-aged adults who rarely develop cognitive deficits.
In the only trial23 of older adults in which
431 subjects were randomized to placebo or to lovastatin for 6 months, no
differences on performance on the Digit Symbol test were found. In that study,
subjects with low Mini-Mental State Examination scores were excluded and there
may have been limited ability to detect differences in cognitive scores. As
with coronary disease,24 1 to 2 years of statin
use may be necessary to demonstrate any benefit on cognition.
Two recent observational studies14-15
found a lower likelihood of developing AD or dementia associated with use
of statins. Our observation of better cognitive scores in statin users supports
the hypothesis that statins may be associated with less risk of dementia.
The mechanism for a positive association with cognitive function is not known,
but several hypotheses have been suggested. One is a direct effect of lipid
reductions. We doubt that this is the entire explanation because after adjusting
for total cholesterol level, we still found that statins were associated with
better cognitive performance. Furthermore, we, along with others,15 did not find an association between nonstatin lipid-lowering
drugs and risk of cognitive impairment. Some of the statin trials25 for reduction of risk of coronary events also suggest
that event reduction is not fully explained by lipid level lowering. Statins
block the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate,
a precursor for cholesterol and for nonsterol intermediates, some of which
are involved in signal transduction. Statins may prevent atherothrombotic
events via nonsterol effects on smooth muscle function, macrophages, and platelets.26 Statins may also have a neuroprotective effect via
enhancement of endothelial nitric oxide synthase and reduction of inflammatory
responses, such as C-reactive protein and cytokine responses.26
Furthermore, cholesterol reduction with statins inhibits the formation of ß-amyloid
in hippocampal neurons, a finding that could explain how statins could lower
the risk of cognitive impairment.27-28
Several limitations of our study deserve mention. Our subjects were
mostly white women, and it is unclear whether our results would apply to other
ethnic groups or to men. Furthermore, all of the women had known coronary
heart disease and this could limit the generalizability of our findings. Unfortunately,
apolipoprotein E genotyping was not performed. Some studies have found an
interaction between apolipoprotein E  4 and total cholesterol level on
risk of AD2 or on cognitive decline,29 and further studies might investigate whether statin
use differentially affects cognitive function by apolipoprotein E 4
status. It is unclear whether the observed differences in mean 3MS scores
between lipid groups are of clinical significance. However, we found the same
association between lipid level and change in lipid level and risk of cognitive
impairment. Finally, because statin use was not randomly assigned to women,
and although we statistically adjusted for those characteristics that were
different among statin and nonstatin users, it is possible that the differences
in cognitive function were due to unmeasured confounders. Randomized controlled
trials of statins are necessary to determine if they protect against cognitive
decline.
In this study of 1037 women with cardiovascular disease, we found that
lower serum levels of LDL and total cholesterol were associated with better
cognitive performance and less risk of impairment. Furthermore, 4-year reductions
in these lipoprotein levels and use of statins were independently associated
with better cognitive scores. Aggressive lipoprotein management and statin
use may be potential strategies for preventing cognitive decline in elderly
persons. More studies, especially trials, aimed at understanding whether statins
may lower the risk of cognitive impairment are needed.
AUTHOR INFORMATION
Accepted for publication September 26, 2001.
Author contributions: Study
concept and design (Drs Yaffe and Grady); acquisition
of data (Dr Barrett-Connor); analysis and interpretation
of data (Drs Yaffe, Barrett-Connor, and Grady and Ms Lin); drafting of the manuscript (Drs Yaffe and Grady);critical revision of the manuscript for important intellectual content
(Drs Yaffe, Barrett-Connor, and Grady and Ms Lin); statistical
expertise (Dr Yaffe and Ms Lin); obtained funding (Dr Grady); and study supervision (Drs Yaffe,
Barrett-Connor, and Grady).
This study was supported by a grant from Wyeth-Ayerst Laboratories,
Philadelphia, Pa; and by grant K23-AG00888 from the US Public Health Service.
Dr Yaffe is a Paul Beeson Faculty Scholar in Aging Research.
Corresponding author and reprints: Kristine Yaffe, MD, Departments
of Psychiatry and Neurology, University of California, San Francisco, 4150
Clement St, Campus Box 111G, San Francisco, CA 94121 (e-mail: kyaffe{at}itsa.ucsf.edu).
From the Departments of Psychiatry (Dr Yaffe), Neurology (Dr Yaffe),
Epidemiology and Biostatistics (Drs Yaffe and Grady and Ms Lin), and Medicine
(Dr Grady), University of California, San Francisco; the San Francisco VA
Medical Center, San Francisco (Drs Yaffe and Grady); and the Department of
Community and Family Medicine, University of California San Diego, La Jolla
(Dr Barrett-Connor).
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