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Use of Lipid-Lowering Agents, Indication Bias, and the Risk of Dementia in Community-Dwelling Elderly People
Kenneth Rockwood, MD, FRCPC;
Susan Kirkland, PhD;
David B. Hogan, MD, FRCPC;
Chris MacKnight, MD, MSc, FRCPC;
Heather Merry, MSc;
René Verreault, MD, PhD;
Christina Wolfson, PhD;
Ian McDowell, PhD
Arch Neurol. 2002;59:223-227.
ABSTRACT
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Background Recent reports suggest a possibly protective effect for statins in patients
with Alzheimer disease. This association could be due to indication bias,
ie, people who elect to take lipid-lowering agents (LLAs) may be healthier
than those who do not, so that it may be these other health factors that explain
their lower risk of dementia.
Objectives To examine the association between the use of LLAs and dementia, adjusting
for other markers of health, and to investigate factors associated with LLA
use.
Design A cohort study of LLA use and a case-control study of dementia in relation
to LLA use, in a secondary analysis of the Canadian Study of Health and Aging.
Setting A nationally representative population-based survey of Canadians 65
years and older.
Participants To examine features associated with statin use, we evaluated data on
2305 people for whom health information, drug use, and cognitive status were
known. To examine the relationship between LLA use and dementia, we selected
incident cases of dementia (n = 492, of whom 326 had Alzheimer disease) that
occurred between the first and second waves of the study. Control subjects
were 823 persons examined during the first and second phases of the Canadian
Study of Health and Aging who had no cognitive impairment.
Results Use of LLAs was significantly (P<.001) more
common in younger (65-79 years) than in older ( 80 years) people. It was
not associated with other factors indicating a healthy lifestyle, but was
associated with a history of smoking and hypertension. Use of statins and
other LLAs reduced the risk of Alzheimer disease in subjects younger than
80 years, an effect that persisted after adjustment for sex, educational level,
and self-rated health (odds ratio, 0.26; 95% confidence interval, 0.08-0.88).
There was no significant effect in subjects 80 years and older.
Conclusions While the possibility of indication bias in the original observations
cannot be excluded, it was not demonstrated in LLA use in this study. Lipid-lowering
agent use was associated with a lower risk of dementia, and specifically of
Alzheimer disease, in those younger than 80 years. Further research is warranted.
INTRODUCTION
RECENT STUDIES have raised the possibility that the use of statins,
but not other lipid-lowering agents (LLAs), may prevent dementia. In a cross-sectional
analysis1 of more than 57 000 patients,
the prevalence of probable Alzheimer disease (AD) in those 60 years and older
taking lovastatin or pravastatin sodium, but not simvastatin, was 3.8 per
1000. This was significantly different from the overall prevalence of 8.1
per 1000 in the total patient population, and also significantly different
from the prevalence of AD among patients using other cardiovascular and/or
antihypertensive drugs. Similarly, Jick et al2
reported, in a nested case-control study derived from a computerized database
of 368 general practitioners, that the relative risk of dementia for those
prescribed statins was 0.29 (95% confidence interval [CI], 0.13-0.63).
While these results suggest a protective effect of statins on dementia,
they are also subject to important limitations. The representativeness of
patients in these databases is unclear, and information on important potential
confounding factors, such as educational level, was not available. Cross-sectional
and case-control designs are susceptible to bias, particularly indication
bias (or "confounding by indication"), which occurs when a drug is prescribed
for a reason that itself is associated with the outcome of interest. As argued
in the editorial that accompanied the article by Wolozin et al,1
while the data were gathered (1996-1998), physicians were more likely to have
prescribed statins to patients who were "more highly educated, attentive,
inquisitive and concerned about their future health."3(p1411)
The Canadian Study of Health and Aging (CSHA) is a national, population-based,
representative cohort study4-5
of dementia in elderly people that can provide insight into the extent to
which indication bias is responsible for the association between statins and
dementia. We reviewed the data therein to investigate whether statin use is
associated with demographic and lifestyle factors, such as educational level
and self-reported health, and to quantify the relationship between the use
of LLAs and dementia.
PARTICIPANTS AND METHODS
MEASURES
The study design and data collection protocol of the CSHA are described
in detail elsewhere.4-5 Briefly,
in the first phase (CSHA-1: February 1991 to May 1992), subjects were recruited
from the community and institutions based on age-stratified (65-74, 75-84,
and 85 years) random samples in 36 urban and surrounding rural areas in
all 10 Canadian provinces. Subjects were 65 years and older as of October
1, 1990, and were fluent in English or French. In all, 9008 community residents
and 1255 residents of institutions were surveyed. Participants living in the
community were first screened for cognitive impairment by the Modified Mini-Mental
State Examination.6 Those screening positive
for cognitive impairment (Modified Mini-Mental State Examination score of
<78) were invited to a clinical examination (n = 1106) and were assessed
according to a detailed protocol7 that used
standard criteria to diagnose dementia8 and
its causes, chiefly AD9 and vascular dementia.10 This protocol was also followed for those unable
to complete the screening test (eg, because of deafness [n = 59]) and for
a random sample of subjects who were cognitively normal, according to the
results of the screening test (n = 494). All institutionalized participants
underwent the clinical assessment without first being screened.
This clinical examination included the determination of functional status,
health history, and medication use and an informant interview by a nurse;
a medical history and physical examination by a physician; and, for most subjects
(those scoring 50 on the Modified Mini-Mental State Examination [n = 1879]),
neuropsychological testing. In addition, subjects without dementia completed
the Self-assessed Risk Factor (SARF) questionnaire. The SARF questionnaire
contains information on several lifestyle factors, including alcohol and tobacco
use, exercise level, and vaccination status.11
Of the 2914 subjects participating in the clinical examination, 921
had no cognitive impairment, 861 had cognitive impairment but not dementia,
and the remainder were diagnosed as having dementia. Those who screened negative
and were not invited to the clinical examination were presumed to not have
dementia.
In 1996, a follow-up data collection (CSHA-2) was undertaken. Of the
original participants, 1846 had died and 1135 refused to participate or could
not participate. Community subjects presumed to not have dementia at CSHA-1
were screened and examined as previously described. The screening interview
also included information on self-reported health and level of education.
All those who underwent a clinical examination during CSHA-1 were also invited
to the CSHA-2 clinical assessment, which was similar to the one conducted
during CSHA-1. A total of 2305 subjects participated in the clinical examination.
The clinical interview included an inventory of all prescribed drugs, including
LLAs.
DESIGN AND COMPOSITION OF THE SAMPLE
To assess the possibility of indication bias, we used a cohort design,
with exposures (demographic and lifestyle factors) from CSHA-1 and the outcome
(LLA use) at CSHA-2. The 2305 subjects participating in the clinical examination
were included in this portion of the analysis. Self-assessed Risk Factor data
were only available for 1354 of these subjects, as neither the 350 with dementia
at CSHA-1 nor the 210 originally institutionalized were asked to complete
the SARF questionnaire. The remaining 391 subjects did not return the questionnaire.
To assess whether LLAs were associated with dementia, we used a case-control
design. Control subjects were those without cognitive impairment at the CSHA-2
clinical interview who were also (by screening interview or clinical examination)
not impaired at CSHA-1. Cases were defined as those with incident dementia,
ie, those who at baseline did not have dementia, based on either the clinical
examination results or a screening Modified Mini-Mental State Examination
score of 78 or higher, and at CSHA-2 were diagnosed as having dementia. The
decision to use only recent-onset dementia cases was made to minimize confounding
by indication, given the observation that those already diagnosed as having
dementia in CSHA-1 were less likely to have undergone aggressive treatment
of vascular risk factors.12
Of the 2305 individuals who underwent a clinical examination at CSHA-2,
350 were excluded because they had dementia at CSHA-1 and 640 were excluded
because they had cognitive impairment, but no dementia, at CSHA-2.13 Of the remainder, 823 were controls and 492 met the
case definition of incident dementia. Of these 492 subjects, 326 were diagnosed
as having AD.
ANALYSIS
Comparisons regarding demographic and lifestyle characteristics for
LLA users and nonusers were conducted using  2 tests for categorical
data and 2-sided t tests for continuous data. Similarly,
baseline characteristics of cases and controls were compared using t tests or 2 tests as appropriate. Bivariate analyses
to assess the impact of potential confounders were first conducted using the
Mantel-Haenszel approach. The association between statin use and dementia
was examined by calculating crude and adjusted odds ratios (ORs) using logistic
regression analysis (SAS statistical software, version 8.01; SAS Institute
Inc, Cary, NC). Odds ratios and 95% CIs for them were calculated. Because
LLA use was likely to be less controversial in younger patients, and thus
less susceptible to confounding by indication, the analysis was stratified
by age, dichotomized as younger than 80 years vs 80 years and older.
RESULTS
At CSHA-2, 57 people were taking statins and 15 were taking other LLAs.
The characteristics associated with LLA use at CSHA-2 are presented in Table 1. Lipid-lowering agent users were
significantly younger than nonusers and were more likely to live in the community,
to have hypertension, and to be a current or a former smoker. Educational
level, self-reported health, and sex were not significantly associated with
use of an LLA.
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Table 1. Characteristics Associated With Use of LLAs in CSHA-2 (1996-1997)*
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The characteristics of cases and controls used in the analysis of the
association of dementia with LLA use are outlined in Table 2. Cases were slightly older and had a higher prevalence of
"cognitive impairment, no dementia" than controls at baseline. The prevalence
of stroke was much higher in those with other dementias, reflecting the preponderance
of vascular dementia in this group.
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Table 2. Characteristics of Cases and Controls With AD and Other Dementias*
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The unadjusted analyses showed that use of statins was associated with
a lower odds of AD (OR, 0.26; 95% CI, 0.09-0.72) and all types of dementia
(OR, 0.21; 95% CI, 0.08-0.54). Similar ORs were estimated for the use of any
LLA and AD or dementia (OR, 0.25; 95% CI, 0.10-0.62).
When stratified by age, the protective effect of taking either a statin
or another LLA was observed only for all types of dementia in those younger
than 80 years (OR, 0.24; 95% CI, 0.07-0.80); for those 80 years and older,
the OR was 0.43 (95% CI, 0.11-1.58). After further adjustment for sex, educational
level, and self-rated health, the OR for those younger than 80 years was 0.26
(95% CI, 0.08-0.88); for those 80 years and older, the OR was 0.50 (95% CI,
0.13-1.88). While the effect remains protective in those 80 years and older,
the CI includes 1.0. (Similar trends are observed when the analysis is restricted
to AD only, statin use only, or other LLA use. The inclusion of institutionalized
subjects, who had a high prevalence of dementia but who were infrequently
taking statins, narrows the CIs to less than 1.0.)
COMMENT
These data suggest that LLAs may have a role in protecting against the
expression of dementia in elderly people. The data go against such an association
being explained simply by confounding by indication: not only was LLA use
not associated with other markers of a healthy lifestyle but it was associated
with other vascular risk factors, which increasingly are implicated in all
types of dementia.14-16
Confounding by indication is a consideration in observational studies,
and parallel scenarios in which protective effects are documented with other
agents and outcomes suggest that it must be addressed carefully. For example,
in a meta-analysis17 of 10 observational studies,
postmenopausal estrogen use decreased the risk of dementia by 29%, but randomized
controlled trials18-19 in women
with dementia have failed to replicate this finding. Similarly, estrogen use
was long held to be protective for ischemic heart disease in women based on
many, but not all, observational studies20-21
that reported such an effect. In contrast, randomized treatment trials,22-23 again, have not shown a protective
effect. Moreover, the ongoing Women's Health Initiative,24-25
a randomized clinical trial of 27 500 healthy women, recently issued
a press release to communicate an early finding of a small increase in heart
attacks, strokes, and blood clots in women taking hormones compared with nonusers.
Our data must be interpreted with caution. Although confounding by indication
was addressed by controlling for known risk factors and markers of healthy
behaviors, we cannot account for unknown and/or unmeasured factors. Because
this is a secondary analysis, and because it covers a period in which the
use of LLAs in elderly people was controversial,3
the numbers of LLA users are smaller than would be needed to draw more robust
conclusions. Similarly, we were unable to make full use of the cohort design
of the CSHA, because, at baseline, of the 2914 subjects for whom drug information
was available, only 17 were taking statins and only 14 were taking other LLAs.
(The unadjusted analyses suggest a protective effect: the relative risk was
0.74 [95% CI, 0.54-1.01]). On the other hand, the data come from a representative
population-based sample, cover a similar period as the original reports, and
allow confounding by indication at least to be addressed. Restricting the
adjusted analysis to community-dwelling respondents is a conservative strategy,
and the persistence of the protective effect enhances the possibility that
the observed association is not simply due to confounding.
We restricted our analysis to incident cases at CSHA-2, on the grounds
that prevalent cases would have been less likely to be prescribed a statin
in the period under consideration. Earlier analysis12
of the CSHA data set suggested that, at least among those with severe dementia,
treatment of vascular risk factors occurs less often than in those with mild
or moderate dementia. One possibility, however, is that statin use might also
have been less likely among those with cognitive impairment but no dementia
at CSHA-1, who are more likely to be incident dementia cases. When we repeated
the analysis performed between statin or other LLA use and incident dementia
in community-dwelling subjects (stratified by age), but restricted incident
cases to those with no cognitive impairment at baseline, the effect was still
protective (OR, 0.36) but, likely as a result of fewer subjects, the CI included
1.00 (95% CI, 0.11-1.23).
In addition, even though we used only incident cases, we are unable
to account for cessation bias, ie, the possibility that the apparently protective
effect of LLAs is overstated because those who were taking LLAs and developed
dementia had their statins discontinued. Again, the numbers are too small
to allow conclusions to be drawn; of the 2 patients who were taking LLAs at
CSHA-1, were alive, and developed dementia by CSHA-2, the LLA was discontinued
in 1, compared with 2 of the 10 who were taking LLAs at CSHA-1 and had not
developed dementia at CSHA-2.
Small numbers also prevent us from commenting specifically on the merits
of any one statin over another. Interestingly, whereas simvastatin was not
evidently protective in one of the earlier reports, a recent experimental
study26 found that simvastatin strongly reduces
the abnormal ß-amyloid proteins used in animal models. In contrast to
the General Practice Research Database study,2
we found that LLAs other than statins were associated with a protective effect,
but again the small numbers prevent us from being more definitive.
It would be preferable to be able to adjust the LLA-dementia relationship
for all the lifestyle factors recorded in the SARF questionnaire, but as the
questionnaire was completed by only 681 of the 823 cases and 255 of the 452
controls, this was not possible. Analysis of the SARF data for these groups,
however, shows an interesting trend: in general, AD cases were more likely
to have a less healthy lifestyle than controls, whereas those cases with dementia
other than AD were as likely to have a healthy risk factor profile as controls.
For example, 69% of controls exercised regularly, compared with 66% of those
with other dementias and 56% of those with AD. Similar trends were observed
for smoking and vaccination status. People with AD were less likely to have
used alcohol (nonusers, 70%) than those with other dementias (nonusers, 42%)
and controls (nonusers, 60%). Thus, the protective effect seems to exist in
groups with dementia regardless of risk factor profiles.
The CSHA data lend support to the observation of a protective association
between statins and dementia and suggest that it might be extended to other
LLAs. Although longitudinal studies27-29
investigating the link between hypercholesterolemia and AD give conflicting
results, the tantalizing possibility that LLAs might help to prevent dementia
requires further research.
AUTHOR INFORMATION
Accepted for publication September 17, 2001.
Author contributions: Study concept and design (Drs Rockwood, Kirkland, MacKnight, Wolfson, and McDowell, and
Ms Merry); acquisition of data (Drs Rockwood, Hogan,
MacKnight, Verreault, Wolfson, and McDowell, and Ms Merry); analysis
and interpretation of data (Drs Rockwood, Kirkland, Hogan,
MacKnight, Wolfson, and McDowell, and Ms Merry); drafting of the manuscript (Drs Rockwood and MacKnight); critical revision of the
manuscript for important intellectual content (Drs Rockwood,
Kirkland, Hogan, MacKnight, Verreault, Wolfson, and McDowell, and Ms Merry); statistical expertise (Drs Kirkland, MacKnight,
Verreault, and Wolfson, and Ms Merry); obtained funding (Drs Rockwood, Wolfson, and McDowell); administrative, technical, and
material support (Dr McDowell); study supervision (Drs Rockwood and McDowell); data collection (Drs Rockwood, Hogan, MacKnight, and Verreault); and clinical input (Drs Rockwood, Hogan, and MacKnight).
Corresponding author and reprints: Kenneth Rockwood, MD, FRCPC, Geriatric
Medicine Research Unit, Queen Elizabeth II Health Sciences Centre, 5955 Veterans'
Memorial Ln, Room 1421, Halifax, Nova Scotia, Canada B3H 2E1 (e-mail: rockwood{at}is.dal.ca).
From the Departments of Medicine (Drs Rockwood and MacKnight and Ms
Merry) and Community Health and Epidemiology (Dr Kirkland), Dalhousie University
and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; Department
of Medicine, University of Calgary, Calgary, Alberta (Dr Hogan); Department
of Social and Preventive Medicine, Université Laval, Sainte-Foy, Québec
(Dr Verreault); Division of Geriatric Medicine, Department of Epidemiology
and Biostatistics, McGill University, Montréal, Quebec (Dr Wolfson);
and Department of Epidemiology and Community Medicine, University of Ottawa,
Ottawa, Ontario (Dr McDowell).
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Association of active {gamma}-secretase complex with lipid rafts
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J. Lipid Res. 2005;46:904-912.
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Atorvastatin for the Treatment of Mild to Moderate Alzheimer Disease: Preliminary Results
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Arch Neurol 2005;62:753-757.
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Do Statins Reduce Risk of Incident Dementia and Alzheimer Disease?: The Cache County Study
Zandi et al.
Arch Gen Psychiatry 2005;62:217-224.
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Chronic Administration of Statins Alters Multiple Gene Expression Patterns in Mouse Cerebral Cortex
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J. Pharmacol. Exp. Ther. 2005;312:786-793.
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Midlife cardiovascular risk factors and risk of dementia in late life
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Neurology 2005;64:277-281.
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3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate {beta}-Amyloid-Induced Microglial Inflammatory Responses
Cordle and Landreth
J. Neurosci. 2005;25:299-307.
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Mixed Dementia: Emerging Concepts and Therapeutic Implications
Langa et al.
JAMA 2004;292:2901-2908.
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Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia
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Statin therapy and risk of dementia in the elderly: A community-based prospective cohort study
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Neurology 2004;63:1624-1628.
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Loss of Apolipoprotein E Receptor LR11 in Alzheimer Disease
Scherzer et al.
Arch Neurol 2004;61:1200-1205.
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Brain Cholesterol: Long Secret Life Behind a Barrier
Bjorkhem and Meaney
Arterioscler. Thromb. Vasc. Bio. 2004;24:806-815.
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Caffeine as a Neuroprotective Adenosine Receptor Antagonist
Dall'Igna et al.
The Annals of Pharmacotherapy 2004;38:717-718.
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Plasma Levels of {beta}-Amyloid(1-40), {beta}-Amyloid(1-42), and Total {beta}-Amyloid Remain Unaffected in Adult Patients With Hypercholesterolemia After Treatment With Statins
Hoglund et al.
Arch Neurol 2004;61:333-337.
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The Role of Cholesterol and Statins in Alzheimer's Disease
Miller and Chacko
The Annals of Pharmacotherapy 2004;38:91-98.
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Serum lipids and memory in a population based cohort of middle age women
Henderson et al.
J. Neurol. Neurosurg. Psychiatry 2003;74:1530-1535.
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Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease
Chauhan
J. Lipid Res. 2003;44:2019-2029.
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Reduction in Levels of 24S-Hydroxycholesterol by Statin Treatment in Patients With Alzheimer Disease
Vega et al.
Arch Neurol 2003;60:510-515.
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Diet and risk of dementia: Does fat matter?: The Rotterdam Study
Engelhart et al.
Neurology 2002;59:1915-1921.
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Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Abeta Levels
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J. Biol. Chem. 2002;277:48508-48513.
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A Cross-Sectional Study of Lipids and ApoC Levels in Alzheimer's Patients With and Without Cardiovascular Disease
Adunsky et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2002;57:M757-761.
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Reduced incidence of AD with NSAID but not H2 receptor antagonists: The Cache County Study
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Neurology 2002;59:880-886.
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