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Statins and Dementia
In the article by Wolozin and colleagues,1
use of "statin" cholesterol-lowering drugs is observationally associated with
lower rates of Alzheimer disease (AD). Haley and Dietschy,2
in the accompanying editorial, make the vitally important point that causality
cannot be affirmed with certainty due to indication bias.
But an even stronger point can be made: These data are consistent with
and indeed can be taken to support the contrary conclusion—that high
cholesterol protects against dementia. Lipid-lowering drugs are used in the
context of—and may serve statistically as a marker for—elevated
cholesterol. Just as higher stroke risk occurs in those on antihypertensives,
and increased diabetic complications in those taking hypoglycemic medications,
so statin use may appear to be linked to improved cognition precisely because
high cholesterol confers protection, and those on statins may (before treatment
and often despite treatment) have higher cholesterol levels on average.
Three pieces of evidence fuel this perspective. First, Wolozin et al1 show a higher rate of transient ischemic attack
(TIA) in statin users. However, statins protect against cerebrovascular events
in randomized trials,3 a result consistent
with the possibility that statin use may have been associated with higher,
rather than lower, cholesterol. (Similarly, in the data of Wolozin et al,1 antihyperintensive agents were linked to increased
TIAs; do we propose that these agents are causing the excess TIAs, or should
we acknowledge that they may serve as a marker for hypertension?) Second,
as Haley and Dietschy observe, simvastatin was less associated with protection
than pravastatin or lovastatin, yet simvastatin is a substantially more potent
cholesterol-lowering agent than these,4
with higher lipophilicity and greater central nervous system penetration.5 Studies show that patients on more potent statins
are more likely to have adequate cholesterol control.6
Thus, dose-response considerations, too, are compatible with the contrary
proposal, ie, that lower cholesterol is associated with worse cognitive function.
Third, existing randomized trial data—which offer the strongest quality
of evidence for causal inference—show significant (if modest) average
reductions in cognitive function with statins.7
Clinically important cognitive loss with statins has been reported anecdotally,8 and our statin study group has received dozens
of written reports from statin users who cite marked cognitive loss with statins,
prompting family concern, loss of job function, and medical workups for AD.
Such cognitive loss reportedly8 resolves
with cessation of statins and recurs with statin resumption. If lower cholesterol
is linked to cognitive decline from any cause, the diagnosis of AD may be
hastened.
It is premature to tender a firm conclusion regarding the effect of
cholesterol or statins on cognitive function, and a bidirectional effect cannot
be excluded (eg, higher low-density lipoprotein levels may conduce to stroke-associated
vascular dementia risk over the long term).9
Anticipating the call for additional randomized controlled trial data, trials
are reportedly under way,10 and we are currently
conducting a randomized controlled trial (funded by the National Institutes
of Health) on the effects of statins on cognitive and other central nervous
system outcomes, including agents at the extremes of the hydrophilicity/lipophilicity
spectrum.
On another note, high cholesterol may be a noncausal concomitant of
genotypes that predispose to AD,11, 12
potentially contributing to existing conflict within the observational literature.
Beatrice Alexandra Golomb, MD, PhD
University of California, San Diego, Statin Study
Department of Medicine 0995
9500 Gilman Dr
La Jolla, CA 92093-0995
Beth Jaworski, MS
La Jolla
1. Wolozin B, Kellman W, Ruosseau P, Celesia
GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439-1443.
ABSTRACT/FULL TEXT
2. Haley RW, Dietschy JM. Is there a connection between the concentration of cholesterol circulating
in plasma and the rate of neuritic plaque formation in Alzheimer disease? Arch Neurol. 2000;57:1410-1412.
FULL TEXT
3. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality:
an overview of randomized trials [review]. JAMA. 1997;278:313-321.
ABSTRACT
4. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol. 1997;80:106-107.
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5. Koga T, Fukuda T, Shimada Y, Fukami
M, Koike H, Tsujita Y. Tissue selectivity of pravastatin sodium, lovastatin
and simvastatin: the relationship between inhibition of de novo sterol synthesis
and active drug concentrations in the liver, spleen and testes in rat. Eur J Biochem. 1992;109:315-319.
6. Hunninghake D, Bakker-Arkema RG, Wigand JP, et al. Treating to meet NCEP-recommended LDL cholesterol concentrations with
atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk
factors for coronary heart disease. J Fam Pract. 1998;47:349-356.
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7. Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 2000;108:538-546.
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8. Graedon J, Graedon T. The people's pharmacy. Los Angeles Times. May 22, 2000; health section:S2, S6.
9. Moroney JT, Tang MX, Berglund L, et al. Low-density lipoprotein cholesterol and the risk of dementia with stroke. JAMA. 1999;282:254-260.
ABSTRACT/FULL TEXT
10. Sparks DL, Martin TA, Gross DR, Hunsaker III JC. Link between heart disease, cholesterol, and Alzheimer's disease: a
review. Microsc Res Tech. 2000;50:287-290.
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11. Prince M, Lovestone S, Cervilla J, et al. The association between APOE and dementia does not seem to be mediated
by vascular factors. Neurology. 2000;54:397-402.
ABSTRACT/FULL TEXT
12. Wehr H, Parnowski T, Puzynski S, et al. Apolipoprotein E genotype and lipid and lipoprotein levels in dementia. Dement Geriatr Cogn Disord. 2000;11:70-73.
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In reply
While the proposal that high cholesterol levels protect against dementia
could be consistent with the data presented in our article, we feel that it
is not supported by the preponderance of data in the field and that it requires
a logical leap that extends well beyond the data presented in our article.
The current literature supports either of 2 competing hypotheses: (1) Elevated
cholesterol levels are associated with AD (2) Serum cholesterol levels are
unrelated to AD (perhaps because a different pool of cholesterol, such as
that in the brain or in neurons, is linked to AD). The observation that the
incidence of AD is elevated in patients with apolipoprotein E type 4 (ApoE4)
or heart disease, both of which are associated with elevated cholesterol levels,
provides an indirect link between cholesterol and AD. Alternatively, 3 different
articles have evaluated serum cholesterol levels without observing a link
to AD. Prince et al1 and Wehr et al2 both failed to observe a clear link between cholesterol
and AD, although they did confirm the linkage between ApoE4, which is associated
with elevated cholesterol, and AD. (Because of the connection between ApoE4
and AD, our article incorrectly characterized these 2 articles as supporting
an association between cholesterol and AD; we apologize for this error.) More
recently, Jick and colleagues3 also failed
to document a connection between elevated cholesterol and AD. While the relationship
between cholesterol and AD remains ambiguous, it is quite clear that none
of these articles provides any suggestion that elevated cholesterol levels
protect against AD.
The significance of the distinction between simvastatin and pravastatin/lovastatin
is unclear. The data from Jick and colleagues do show a beneficial effect
of simvastatin use. Our negative observations related to simvastatin use might
have been the result of its slow adoption by the Veterans Affairs hospital
system. Therefore, we encourage readers not to overinterpret the absence of
a protective effect of simvastatin in our study. Based on these considerations,
we doubt that the hypothesis that cholesterol protects against AD represents
a useful way of viewing the data.
Benjamin Wolozin, MD, PhD
Department of Pharmacology
Loyola University Medical Center
Bldg 102, Room 3634
2160 S First Ave
Maywood, IL 60153
(e-mail: bwolozi@luc.edu)
George Siegel, MD
Maywood
1. Prince M, Lovestone S, Cervilla J, et al. The association between APOE and dementia does not seem to be mediated
by vascular factors. Neurology. 2000;54:397-402.
ABSTRACT/FULL TEXT
2. Wehr H, Ryglewicz D, Rodo M, et al. In vitro oxidation of low density lipoproteins in patients after ischemic
stroke [in Polish]. Neurol Neurochir Pol. 2000;34:447-456.
MEDLINE
3. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356:1627-1631.
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Arch Neurol. 2001;58:1169-1170.
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Guidelines for Diagnosis and Treatment of High Cholesterol
Feeman et al.
JAMA 2001;286:2400-2402.
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