Statins for the treatment of dementia

Article (PDF Available)inCochrane database of systematic reviews (Online) 4(8):CD007514 · July 2010with119 Reads
DOI: 10.1002/14651858.CD007514.pub2 · Source: PubMed
Abstract
Background High levels of cholesterol (a fatty substance known as a lipid) in the blood are thought to contribute to the cause of Alzheimer's disease and vascular dementia. The statin family of medications (lovastatin, pravastatin, simvastatin and others) are powerful cholesterol-lowering medications and are first-line treatments for reducing cholesterol in people with, or at risk of, cardiovascular disease. There has been much interest in the possible role of statins in the treatment of dementia. Study characteristics Two independent authors searched scientific databases for studies in which a statin or a placebo (a pretend treatment) was given for at least six months. We included people with a probable or possible diagnosis of Alzheimer's disease according to standard clinical criteria. The findings were current to January 2014. Key results We identified four studies involving 1154 participants (age range 50 to 90 years). The studies used standard tests to assess the severity of Alzheimer's disease. From these trials, including two large trials, we found no evidence that statins help in the treatment of cognitive decline in dementia. Quality of the evidence The quality of evidence is felt to be high as two large randomised controlled trials have been included along with two smaller ones.
Statins for the treatment of demen tia (Review)
McGuinness B, O ’Hare J, Craig D, Bullock R, Malouf R, Passmore P
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 8
http://www.thecochranelibrary.com
Statins for the treatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Cognitive Change From Baseline, Outcome 1 Change in ADAS-Cog from baseline. . . 31
Analysis 1.2. Comparison 1 Cognitive Change From Baseline, Outcome 2 Change in ADAS-Cog from baseline (using
random effect). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Analysis 1.3. Comparison 1 Cognitive Change From Baseline, Outcome 3 Change in ADAS-Cog, 24-26 week data. 32
Analysis 1.4. Comparison 1 Cognitive Change From Baseline, Outcome 4 Modified ADAS-Cog. . . . . . . . 33
Analysis 1.5. Comparison 1 Cognitive Change From Baseline, Outcome 5 ADAS-Cog change from baseline over 18
months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Analysis 1.6. Comparison 1 Cognitive Change From Baseline, Outcome 6 ADAS-Cog Change from baseline (0 to 18)
months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Analysis 1.7. Comparison 1 Cognitive Change From Baseline, Outcome 7 ADAS-Cog Change from baseline (0 to 18)
months LOCF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Analysis 2.1. Comparison 2 Change in MMSE from Baseline, Outcome 1 Change in MMSE, 52 week data ADCLT. 36
Analysis 2.2. Comparison 2 Change in MMSE from Baseline, O utcome 2 Change in MMSE 52 week data ADCLT ( using
random effects). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Analysis 2.3. Comparison 2 Change in MMSE from Baseline, Outcome 3 Change in MMSE, 24 week data ADCLT and
LEADe. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Analysis 2.4. Comparison 2 Change in MMSE from Baseline, Outcome 4 MMSE change from baseline in LEADe. . 38
Analysis 3.1. Comparison 3 Change in CGIC, Outcome 1 Change in CGIC. . . . . . . . . . . . . . . 39
Analysis 3.2. Comparison 3 Change in CGIC, Outcome 2 CGIC at 3 months. . . . . . . . . . . . . . 40
Analysis 3.3. Comparison 3 Change in CGIC, Outcome 3 CGIC at 6 months. . . . . . . . . . . . . . 40
Analysis 3.4. Comparison 3 Change in CGIC, Outcome 4 CGIC at 9 months. . . . . . . . . . . . . . 41
Analysis 3.5. Comparison 3 Change in CGIC, Outcome 5 CGIC at 12 months. . . . . . . . . . . . . . 41
Analysis 3.6. Comparison 3 Change in CGIC, Outcome 6 CGIC at 15 months. . . . . . . . . . . . . . 42
Analysis 3.7. Comparison 3 Change in CGIC, Outcome 7 CGIC at 18 months. . . . . . . . . . . . . . 42
Analysis 3.8. Comparison 3 Change in CGIC, Outcome 8 CGIC LOCF. . . . . . . . . . . . . . . . 43
Analysis 4.1. Comparison 4 NPI, Outcome 1 NPI change from baseline to 6 months. . . . . . . . . . . . 43
Analysis 4.2. Comparison 4 NPI, Outcome 2 NPI change from baseline to 1 year. . . . . . . . . . . . . 44
Analysis 4.3. Comparison 4 NPI, Outcome 3 NPI change from baseline to 1 year (using random effects). . . . . 44
Analysis 4.4. Comparison 4 NPI, Outcome 4 NPI change from baseline over 18 months. . . . . . . . . . . 45
Analysis 5.1. Comparison 5 ADFACS, Outcome 1 ADFACS change f r om baseline at 6 months. . . . . . . . 46
Analysis 5.2. Comparison 5 ADFACS, Outcome 2 ADFACS change f r om baseline at 12 months. . . . . . . . 47
Analysis 5.3. Comparison 5 ADFACS, Outcome 3 ADFACS change f r om baseline at 18 months. . . . . . . . 47
Analysis 5.4. Comparison 5 ADFACS, Outcome 4 ADFACS over all (0-18 ) months. . . . . . . . . . . . 48
Analysis 5.5. Comparison 5 ADFACS, Outcome 5 ADFACS LOCF. . . . . . . . . . . . . . . . . . 48
Analysis 6.1. Comparison 6 Incidence of adverse effects, Outcome 1 Treatment related adverse effects requiring
discontinuation of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
49HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iStatins for the treatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
49CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iiStatins for the treatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Statins for the treatment of demen tia
Bernadette McGuinness
1
, John O’Hare
1
, David Craig
1
, Roger Bullock
2
, Reem Malouf
3
, Peter Passmore
1
1
Department of Geriatric Medicine, Queens University Belfast, Belfast, UK.
2
Kingshill Research Centre, Victoria Hospital, Swindon,
UK.
3
Cochrane Dementia and Cognitive Improvement Group, Oxford, U K
Contact address: Bernadette McGuinness, Department of Geriatric Medicine, Queens University Belfast, Whitla Medical Building,
97 Lisburn Road, Belfast, BT9 7BL, UK.
b.mcguinness@qub.ac.uk.
Editorial group: Cochrane Dementia and Cognitive Improvement Group.
Publication status and date: New, published in Issue 8, 2010.
Review content assessed as up-to-date: 2 March 2009.
Citation: McGuinness B, O’Hare J, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment of dementia. Cochrane
Database of Systematic Reviews 2010, Issue 8. Art. No.: CD007514. DOI: 10.1002/14651858.CD007514.pub2.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
The use of statin therapy in established Alzheimer’s disease (AD) or vascular dementia (VaD) is a relatively unexplored area. In AD ß-
amyloid protein (Aß) is deposited in the form of extracellular plaques and previous studies have determined generation is cholesterol
dependent. Hypercholesterolaemia has also been implicated in the pathogenesis of VaD. Due to the role of statins in cholesterol
reduction it is biologically plausible they may be efficacious in the treatment of AD and dementia.
Objectives
To assess the clinical efficacy and tolerability of statins in the treatment of dementia.
Search strategy
We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE,
EMBASE, PsycINFO, CINAHL and LILACS, as well as many trials registries and grey literature sources (27 October 2008).
Selection criteria
Double-blind, randomized controlled trials of statins given for at least six months in people with a diagnosis of dementia.
Data coll ection and analysis
Two independent authors extracted and assessed data independently against the inclusion criteria. Data were pooled where appropriate
and entered into a meta-analysis.
Main results
Three studies were identified (748 participants, age range 50-90 years). All patients had a diagnosis of probable or possible AD according
to standard criter ia and most patients were established on a cholinesterase inhibitor. Treatment in
ADCLT 2005 consisted of 80mg
atorvastatin compared to placebo for 52 weeks, serum low density lipoprotein (LDL) cholesterol was reduced by 54% in the atorvastatin
group. Treatment in
Simons 2002 consisted of 40mg simvastatin compared to placebo for 26 weeks, serum LDL cholesterol was
reduced by 52% in the simvastatin group. Treatment in LEADe 2010 consisted of 80mg atorvastatin compared to placebo for 72
weeks, LDL cholesterol was reduced by 50.2% by month 3 and remained constant through month 18. Change in Alzh eimer’s Disease
Assessment Scale- cognitive subscale (ADAS-Cog) from baseline was a primary outcome in 3 studies; when data were pooled there was
considerable heterogeneity so the random effects model was used, statins did not provide any beneficial effect in this cognitive measure
1Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[mean difference -1.12, 95% CI -3.99, 1.75, p = 0.44]. All studies provided change in Mini Mental State Examination (MMSE) from
baseline; again random effects model was used due to considerable heterogeneity: there was no significant benefit from statins in this
cognitive measure when the data were pooled [mean difference -1.53, 95% CI -3.28, 0.21, p = 0.08]. There was some evidence that
patients on statins in
ADCLT 2005 maintained better cognitive f unction if serum cholesterol was high at baseline, MMSE was higher
at baseline or if they had an apolipoprotein E4 allele present. This would need to be confirmed in larger studies however. Treatment
related adverse effects were available from two studies,
LEADe 2010 and Simons 2002; when data were pooled there was no significant
difference between statins and placebo [odds ratio 2.45, 95% CI 0.69, 8.62, p = 0.16]. There was no significant difference in global
function, behaviour or activities of daily living in the statin and placebo groups. One large randomised controlle d trial (RCT) (
CLASP
2008
) has not yet published its results. There were no studies identified assessing role of statins in treatment of VaD. There was no
evidence that statins were detrimental to cognition.
Authors conclusions
There is insufficient evidence to recommend statins for the treatment of dementia. Analysis from the studies available, including one
large RCT, indicate statins have no benefit on the outcome measures ADAS-Cog or MMSE. We need to await full results from
CLASP
2008
before we can be certain. This Cochrane review will be updated as these results become available.
P L A I N L A N G U A G E S U M M A R Y
There is insufficient evidence to recommend statins for the treatment of Alzheimer’s disease or dementia.
High levels of serum cholesterol are thought to contribute to the pathology of Alzheimer’s disease and vascular dementia. The statin
family of me dications (lovastatin, pravastatin, simvastatin and others) are powerful cholesterol lowering medications and are first line
treatments for reducing cholesterol in patients with, or at risk of cardiovascular disease. There has been much interest in their possible
role in treatment of dementia and several trials have been carried out in order to assess this outcome. We identified three studies
involving 748 participants, age range 50-90 years. From these trials, including one large one, there is insufficient evidence that statins
help in the treatment of dementia. One large scale trial has yet to publish their results. When this study is reported we will have greater
evidence regarding role of statins in the treatment of dementia.
2Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Patients: Patients with dementia
Setting: Community
Intervention: Statin medication
Comparison: Placebo
Outcomes Absolute Difference in
Means
(95% CI)
Number of participants
(Studies)
Quality of Evidence Comments
Change in ADAS-Cog 0.18
(-0.69,1.05)
704
(3)
High
Change in MMSE -0.50
(-0.92,-0.08)
721
(3)
High
Change in CGIC -0.02
(-0.14, 0.10)
660
(2)
High
Change in NPI -0.94
(-2.07,0.19)
577
(2)
High
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B A C K G R O U N D
Alzheimer’s disease (AD) is the most common cause of dementia,
accounting for 50 to 60% of all cases. Cerebrovascular disease
is the second most common cause responsible for 25 to 30% of
cases and resulting in vascular dementia (VaD). AD and VaD also
frequently co-occur leading to mixed dementia. In total, dementia
is thought to affect approximately 7% of the population older than
65 years of age and 30% of people olde r than 80. Other studies
have quoted that 10% of people aged > 65 years are affected, rising
to nearly 50% of all persons aged > 85 years (
Evans 1989; von
Strauss 1999
). Dementia is already a major public health problem
and is set to become even more so due to the anticipated increase
in life expectancy. In 2001 more than 24 million people worldwide
had dementia, this is expected to double every 20 years up to 81
million in 2040 (
Ferri 2005).
There is accumulating evidence that cholesterol may be implicated
in the pathogenesis of dementia (AD and VaD) and this h as led
investigators to assess the possible role of lipid lowering agents in
treatment of dementia. Many questions remain unanswered, how-
ever. This review aims to collate best evidence available regarding
use of statins in the treatment of dementia.
Cholesterol and AD
A possible role for cholesterol in AD was based on observations
of AD neuropathology among relatively young individuals with
no history of dementia but with coronary heart disease (Sparks
1990
). A ce ntral event in the development of AD is thought to
be abnormal processing of the cell membrane-associated amyloid
precursor protein (APP) followed by deposition of toxic β-amy-
loid (Aβ) protein in the form of amyloid plaques in the extra-
cellular space of the neocortex (Selkoe 2001). APP is a protein
containing 770 amino acids. Aβ peptide is generated by the se-
quential cleavage of APP by beta and gamma secretase in the amy-
loidogenic pathway. Aβ genesis may be precluded if APP is in-
stead cleaved first by alpha secretase within the Aβ domain, and
then by gamma secretase, forming a non-amyloidogenic fragment
(
Cole 2007). The nonamyloidogenic pathway appears to be neu-
roprotective compared to the neurodegenerative, amyloidogenic
pathway (
Vetrivel 2006). Aβ occurs in two different forms, Aβ40
and Aβ42, varying in the length at the C terminus. It is the longer
Aβ42 that aggregates more avidly. Early work discovered elevated
cholesterol levels led to greatly reduced levels of nonamyloido-
genic APP alpha in vitro (Bodovitz 1996). Perhaps more impor-
tantly, subsequent studies suggested that cerebral Aβ generation
3Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
in vitro (Simons 1998; Mizuno 1999) and in vivo (Burns 2003;
Sparks 1994; Refolo 2000) is cholesterol dependent. Cel l biol-
ogy investigations indicated that specialised cell ul ar membrane
microdomains rich in chole ste r ol and sphingolipids, termed lipid
rafts, might be th e link between cholesterol and amyloidogenic
processing of APP. Both beta and gamma se cretases are active in
lipid rafts and it appears that APP processing within th ese lipid
rafts by secretases deter mines the levels of Aβ production (
Ehehalt
2003
; Vetrivel 2004).
The ApoE ǫ4 alle le is associated with sporadic AD. Meta-analysis
has shown that the ApoE ǫ4 al lele increases the risk of th e disease
by three times in heterozygotes and by 15 times in homozygotes
(
Farrer 1997). It acts mainly by modifying age of onset, with each
copy of the allele lowering the age at onset by almost 10 years
(
Corder 1993). This is significant in the context of cholesterol
metabolism as ApoE acts as a cholesterol transporter in the brain.
It has been shown to bind directly to the Aβ peptide and influence
its fibrillogenesis and clearance in vitro (
Strittmatter 1993) and in
vivo (Naslund 1995; Wisniewski 1995). ApoE has also been shown
to be critically important for the formation of fibrillar Aβ in brain
parenchyma in vivo (
Holtzman 2000). Two recent genome-wide
association studies reported a significant association of AD with
a locus within the clusterin (CLU) gene (
Harold 2009; Lamber t
2009). Functionally clusterin has similarities to APOE as both
are major brain apolipoproteins and act as cholesterol transporters
in the central nervous system. Both are also present in amyloid
plaques and interact with Aß, and regulating the conversion of
into insoluble forms, cooperating to suppress deposition
and modifying clearance at the blood brain barrier (BBB) (
van Es 2009). The amyloid cascade hypothe sis states that an
imbalance between production of and clearance of Aβ in the brain
is the initiating event in the pathogenesis of AD, ultimately leading
to neuronal degeneration and dementia (
Hardy 2002) and thus
theoretically links chole sterol metabolism to the development of
AD.
Central and peripheral cholesterol pools are separate, however,
and almost all cholesterol in the brain is synthesized locally and is
not transferred into plasma because of the BBB (
Dietschy 2001).
How serum cholesterol affects brain cholesterol has been a ma-
jor question to date. Brain cholesterol content does not seem to
be affected by high serum low density l ipoprotein (LDL) or low
serum high density lipoprotein (HDL) levels, perhaps as a result
of the stability of cholesterol in myelin but it has not been es-
tablished whether intramembranous lipid domains or intracellu-
lar cholesterol content are affected (
Lane 2005). Studies in ani-
mal models have shown that diet-induced hypercholesterolaemia
increases Aβ and ApoE concentrations in temporal and frontal
cortices, but not in the cerebellum, and that these regional in-
creases parallel the amyloid pathology observed in the AD brain
(Wu 2003). Side chain oxidised ch olesterol metabolites such as
hydroxy-cholesterols do cross the BBB. In the steady state in the
adult brain, cholesterol clearance is facilitated by the formation
and excretion of 24-hydroxycholesterol (
Lutjohann 2000). This is
the major pathway for efflux of brain cholesterol and is crucial for
maintenance of brain cholesterol homeostasis (
Reiss 2004). 27-
Hydroxycholesterol is also found in the brain and may also provide
a link between hypercholesterolaemia and AD (
Heverin 2005);
the contribution of the 27-hydroxylase pathway to AD is an area
in need of furth er exploration.
Several epidemiological studies have shown an association between
high serum cholesterol levels and an increased susceptibility to
AD (Jarvik 1995 ; Kivipelto 2002; Notkola 1998). The Notkola
study was a long-term prospective study that found elevated total
serum cholesterol level was a risk factor for AD, independent of
the ApoE ǫ4 allele; however, the association between AD and the
ApoE ǫ4 allele became weaker after adjustment for serum total
cholesterol. The authors concluded that some of the effect of the
ApoE ǫ4 allele on the risk of AD might be mediated through el-
evated levels of total se rum choleste r ol . The Kivipelto study was
again a prospective population-based study that showed elevated
midlife total cholesterol level was a risk factor for AD and was
independent from risk from the ApoE ǫ4 allele and high midlife
systolic blood pressure. The Jarvik study was a case-control study
which again showed a positive association between ser um choles-
terol and risk of AD.
There may also be converging pathogenic mechanisms between
cerebrovascular and Aβ plaque pathology - cerebrovascular pathol-
ogy with ischaemia resulting in upregulation of APP expression
followed by Aβ deposition (
Jendroska 1995). However, coexisting
pathology may occur independently of the disease process and in-
crease th e probability of exhibiting dementia in otherwise asymp-
tomatic patients (
Riekse 2004).
Cholesterol and VaD
VaD is the second most common form of dementia. It is charac-
terised by both large and small vessel lesions. Subcortical ischaemic
vascular disease caused by damage to tiny blood vessels that lie
deep in the brain is now thought to be more prevalent than multi-
infarct dementia caused by large vessel lesions and stroke (
Ballard
2000; Esiri 1997).
Sclerosis of small cerebral arteries and arterioles is considered to be
responsible for the diffuse periventricular white matter abnormal-
ities involved in the pathogenesis of subcortical VaD (
Ryglewicz
2002
). Risk f actors for VaD are similar to risk factors for all ty pes
of vascular disease, namely hypertension, diabetes, smoking and
hypercholesterolaemia (
Ott 1998; Posner 2002; Stewart 1999).
These factors are alsoimportant in the pathogenesis of AD(
Decarli
2004
); f urthermore th e effects of vascular and AD pathologies are
additive and in most population samples these disorders appear
together (
Snowdon 1997).
Plasma lipids could be associated with the risk of VaD th rough sev-
eral mechanisms. High levels of LDL cholesterol and low levels of
HDL cholesterol are established risk factors for coronary heart dis-
4Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ease (Moroney 1999) and carotid artery atherosclerosis (Sharrett
1994
). These may lead to cognitive impairment through cerebral
hypoperfusion or embolism (
Breteler 1994). LDL cholesterol may
interact with APOE to cause small vessel disease, and low levels of
antioxidants known to occur in brains of VaD patients may lead
to a higher susceptibility to oxidative stress and a h igher grade of
LDL chole sterol oxidation (
Dantoine 2002; Paragh 2002).
A previous cross-sectional analysis showed that the prevalence of
VaD decreased with higher levels of HDL cholesterol and increased
with higher levels of non-HDL cholesterol. Treatment with lipid
lowering agents was not associated with the risk of prevalent VaD,
however. Incidence of VaD was also calculated, again risk of VaD
rose with increasing non-HDL level but treatment with lipid low-
ering agents did not lower risk of incident VaD (
Reitz 2004).
Other studies have found an association of VaD with decreased
levels of HDL cholesterol (
Kuriyama 1994; Muckle 1985; Zuliani
2001
). The role of LDL cholesterol remains controversial, with
some studies finding an association between increased LDL choles-
terol and risk of VaD (
Klich-Raczka 2002; Moroney 1999; Paragh
2002
) and other studies reporting a negative association (van Exel
2002
; Yoshitake 1995).
Stroke is also a major risk factor for VaD. Debate continues as to
whether increased cholesterol levels are a risk factor for stroke. Re-
cent clinical trials indicate that statins significantly decrease stroke
risk in vascular patients including patients with stroke (
CTTC
2005
; SPARCL 2006). The meta-analysis carried out by the The
Cholesterol Treatment Tr ialists’ Collaborators including 90,056
patients found that the use of statins caused a significant 17% pro-
portional reduction in the incidence of first ever-stroke of any type
per 1 mmol/l LDL cholesterol reduction. In th e secondary preven-
tion of stroke, the Stroke Prevention by Aggressive Reduction in
Cholesterol Levels (SPARCL) study showed that treatment with
atorvastatin reduced the risk of recurrent cerebrovascular events
in patients with recent stroke or transient ischaemic attack but no
history of heart disease. By reducing the risk of stroke, statins may
also act to reduce the incidence of post-stroke dementia.
Statins
Statins are a class of drugs that inhibit 3-hydroxy-3-methylglu-
taryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase
is the rate-limiting enzyme in the cascade of cellular cholesterol
biosynthesis. Statins thereby reduce the formation and entry of
LDL cholesterol into the circulation and upregulate LDL receptor
activity, lowering LDL cholesterol and triglycerides and increas-
ing HDL cholesterol. Several studies in cell culture and animals
have demonstrated that treatment with cholesterol lowering drugs
reduces the production of Aβ (
Fassbender 2001; Refolo 2001;
Simons 1998). It was therefore hypothesised that reduction of Aβ
levels by statins may have neuroprotective effects in patients with
AD (
Simons 2001; Wolozin 2001). However, one study of trans-
genic mice found that levels of Aβ in the brains of simvastatin
treated mice did not diff er from those of untreated mice. Simvas-
tatin treatment did lead to the reversal of learning and memory
deficits and the authors hypothesized the benefit of simvastatin
may have been due to modulation of signaling pathways in mem-
ory formation (
Li 2006). Further work, however, th en demon-
strated an association between antecedent statin use and neurofib-
rillary tangle burden at autopsy with risk for typical AD pathology
reduced in statin users (
Li 2007). The effects of statins on AD
neuropathology are therefore not totally understood. Their possi-
ble role in the treatment of VaD includes secondary prevention of
stroke and other pleiotrophic effects as detailed below.
Statins are classified according to their solubility in lipids or water
(lipophilic and hydrophilic respectively). Lipophilic statins (lovas-
tatin, simvastatin, ce rvistatin) cross the BBB and penetrate cell
membranes more effectively and may be more efficient theoret-
ically in the treatment of dementia than the hydrophilic statins
(atorvastatin, pravastatin, fluvastatin). In contrast, however, reduc-
ing cholesterol synthesis bel ow a critical l evel can induce neuronal
death (
Michikawa 1998) and may paradoxically make treatment
with hydrophilic statins more appropriate (
Sparks 2006).
Statins also have pleiotrophic effects. They can improve the en-
dothelial function of atherosclerotic vessel s by decreasing e ndothe-
lial 1 and angiotensin II type 1 receptor and increasing nitric ox-
ide (
Wassmann 2001). Low nitric oxide levels lead to impaired
endothelial function, platelet aggregation and enhanced leucocyte
adhesion to the endothelium. Statins also have antithrombotic ef-
fects as they decrease plasminogen activator levels and have anti-
inflammatory effects as they decrease adhesion molecules (Reitz
2004
). They may also have the ability to reduce apoptosis and
cellular death (Ruocco 2002). Many of these cholesterol-indepen-
dent ef fects reflect statins ability to block the synthesis of impor-
tant isoprenoid intermediates, which serve as lipid attachments for
a variety of intracellular signalling molecules (
Liao 2002).
It is also possible that reduced cholesterol synthesis and concentra-
tion in the CNS caused by treatment with statins may cause neu-
rocognitive deficits. Several investigators have therefore questioned
the potential detrimental effects of lowering cholesterol on cogni-
tion (
King 2003; Muldoon 2000; Wagstaff 2003; Zhang 2004).
It has been shown that large doses of statins can produce substan-
tial neurotoxicity in dogs (
Berry 1988; Walsh 1996). Statins lower
circulating levels of vitamin E and ubiquinone (Coenzyme Q10)
and may affect the synthesis of polyunsaturated fatty acids that
are integral to neuronal membranes (
Palomaki 1997; Rise 1997).
Researchers have speculated that low concentrations of one or
more components of lipoprotein particles circulating in the blood-
stream may produce subtle but measurable impairments of men-
tal processes by influencing the supply of fat-soluble micronutri-
ents, specifically, vitamin E, β-carotene and vitamin A (Muldoon
1997
). On balance, however, potential benefits from statins ap-
pear to outweigh potential detrimental effects and adverse effects
from statins will be assessed in this review.
Statins are widely available and prescribed for treatment of dyslipi-
5Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
demia and secondary prevention of cardiovascular and cerebrovas-
cular disease. Their cost is relatively low and some have come off
patent so are prescribed generically.
Statin treatment in dementia
The use of statin therapy in established AD or VaD is a relatively
unexplored area. There have been a number of studies on the role
of statins in the prevention of dementia but these are the focus of
another Cochrane review (
McGuinness 2009). Furthe r trials have
followed patients with AD and dementia; these are the focus of
this review and are presented in the results section.
A post-hoc analysis on data pooled from three double-blind
placebo-controlled clinical trials of galantamine in AD sh owed no
significant change in cognitive status in association with the use
of statins (
Winblad 2007).
An observational study in patients with AD f ollowed for 34.8
months showed that patients treated with lipid lowering agents
had a slower decline on the MMSE than patients with untreated
dyslipaemia or normolipaemic patients. The study concluded that
lipid l owering agents (including fibrates and statins) may slow cog-
nitive decline in patients with AD and may have a neuroprotec-
tive effect but this finding needs to be confirmed by randomized
placebo-controlled trials (
Masse 2005).
Other lipid lowering agents (fibrates, niacin/nicotinic acid, anion-
exchange resins) (LLAs) have been assessed with statins in several
dementia studies. Fibrates are the main class in use other than
statins. Rockwood et al. published a population based survey from
the Canadian Study of Health and Aging (CSHA) demonstrating
use of statins and other LLAs on reduced risk of AD in subjects
younger than 80 years old (
Rockwood 2002). In contrast the UK
GP Research Database study showed that only statins reduced the
risk of dementia, other LLAs did not (
Jick 2000). In a further study
in patients with AD all LLAs including statins were associated
with a slower annual cognitive decline but there was no significant
difference between statins and other LLAs and there was lack of
statistical power to compare statins to fibrates (Masse 2005).
Fibrates do not inhibit cholesterol biosynthesis, they stimulate β-
oxidation of fatty acids and act mainly by decreasing serum triglyc-
erides. They are only used first line in those with hypertriglyceri-
daemia and can be used in combination with statins in those not
responding to single therapy. They also have anti-inflammatory ef-
fects as they inhibit the pr oduction of different pro-inflammatory
molecules (
Pahan 2006). In this review however we are primarily
interested in role of statins in the treatment of dementia.
This review aims to collate the best available evidence regarding
use of statins in AD and VaD.
Statins have been proven to significantly decrease coronary events
in the primary and secondary prevention of coronary heart disease .
The question is whether they have a significant therapeutic effect
in dementia. A ny intervention shown to slow the progression of
dementia would have huge worldwide economic benefit.
O B J E C T I V E S
Primary objecti ve
To evaluate the ef ficacy and safety of statins in the treatment of
AD and VaD.
Secondary objective
To evaluate if the efficacy of statins in the treatment of AD and
VaD depends on cholesterol level, APOE genotype or cognitive
level.
M E T H O D S
Criteria for considerin g studies for this review
Types of studies
Randomized double-blind placebo controlled trials in which a
statin was given for at least six months. Six months was ch osen
as this was felt to be the minimum length of time required to be
on treatment to allow a disease-modifying effect and before any
cognitive benefit could be attained.
Trials comparing two different statins without a placebo were ex-
cluded.
Types of participants
Patients with a diagnosis of probable or possible Alzheimer’s dis-
ease according to National Institute of Neurological and Commu-
nicative Disorders and Stroke-the Alzheimer’s Disease and Related
Disorders Association (NINCDS/ADRDA) criteria or acceptable
equivalent.
Patients with a diagnosis of probable or possible vascular de-
mentia according to National Institute of Neurological Disor-
ders and Stroke-Association International pour le Recherché at
l’Enseignement en Neurosciences (NINDS-AIREN) criteria or ac-
ceptable equivalent.
Trials with DSM 3, 3R or 4 dementia wil l be included but analysed
separately from those with causal diagnoses for dementia.
Types of interventions
Any type of statin (hydrophilic and lipophilic) given in appropriate
dose compared to placebo.
6Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of outcome measures
Primary outcomes
Change in MMSE, ADAS-cog or other accepted cognitive mea-
sure.
Secondary outcomes
Incidence and severity of adverse effects from RCTs
Change in cognitive status accounting for prior cholesterol
level, APOE genotype and cognitive level
Patient perceived quality of life
Change in Activities of Daily Living (ADLs)
Change in behaviour
Search methods for identification of studies
See
Cochrane Dementia and Cognitive Improvement Group
methods used in reviews.
On 27 October 2008, searches were run in the Dementia and Cog-
nitive Improvement Group Specialized Register, The Cochrane Li-
brary, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS
as well as in many trials databases and grey literature sources. The
following search terms were used in combination with terms used
for Alzheimer’s disease and dementia: statin* OR lipophilic OR
hydrophilic OR lovastatin OR simvastatin OR cervistatin OR
atorvastatin OR rosuvastatin OR provastatin OR fluvastatin OR
hydroxymethylglutaryl-CoA Reductase Inhibitors.
For the detailed se arch strategy, see
Table 1.
Table 1. Search strategy
Database/source Search strategy Notes
Specialized Register statin* OR l ipophilic OR hydrophilic
The Cochrane Library 1. statin*.tiabkw.
2. hydroxymethylglutaryl-CoA Reductase
Inhibitors/ (all subheadings)
3. 1 OR 2
4. Alzheimer-disease/ all subheadings
5.exp dementia-vascular/ all subheadings
6.creutzfeldt-jakob-syndrome/ all subheadings
7.kluver-bucy-syndrome/ all subheadings
8.lewy-body-disease/ al l subheadings
9.pick-disease-of-the-brain/ all subheadings
10.Huntington-disease/ all subheadings
11.delirium/ all subheading
12.wernicke-encephalopathy/ all subheadings
13.(dement$ OR Alzheimer$).tiab.
14.(lewy$ AND bod$).tiab.
15.((cognit$ OR memor$ OR mental) and (decline$
OR impair$ OR los$ OR deteriorate$)).tiab.
16.(chronic AND cerebrovascular).tiab.
17.((organic brain syndrome) OR (organic brain dis-
ease)).tiab.
18.((cerebr$ AND deteriorate$) OR (cerebr$ AND
insufficien$)).tiab.
19.((pick$ and disease) or (creutzfeldt or JCD or
CJD) or huntington$ or binswanger$ or korsako$)
.tiab.
20. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11
OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18
OR 19
21. 20 AND 4
7Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Search strategy (Continued)
22. limit 21 to (randomized controlled trial).pt.
Medline (Ovid SP) 1.(statin$ OR lipophilic OR hydrophilic).mp.
2.(lovastatin OR simvastatin OR cervistatin OR
atorvastatin OR rosuvastatin OR provastatin OR flu-
vastatin).mp.
3.Hydroxymethylglutaryl-CoA Reductase
Inhibitors/ all subheadings
4.Alzheimer-disease/ all subheadings
5.exp dementia-vascular/ all subheadings
6.creutzfeldt-jakob-syndrome/ all subheadings
7.kluver-bucy-syndrome/ all subheadings
8.lewy-body-disease/ al l subheadings
9.pick-disease-of-the-brain/ all subheadings
10.Huntington-disease/ all subheadings
11.delirium/ all subheading
12.wernicke-encephalopathy/ all subheadings
13.(dement$ OR Alzheimer$).mp.
14.(lewy$ AND bod$).mp.
15.((cognit$ OR memor$ OR mental) and (decline$
OR impair$ OR los$ OR deteriorate$)).mp.
16.(chronic AND cerebrovascular).mp.
17.((organic brain syndrome) OR (organic brain dis-
ease)).mp.
18.((cerebr$ AND deteriorate$) OR (cerebr$ AND
insufficien$)).mp.
19.((pick$ and disease) or (creutzfeldt or JCD or
CJD) or huntington$ or binswanger$ or korsako$)
.mp.
20.1 OR 2 OR 3
21.4 OR 5 OR 6 OR 7 OR 8 O R 9 OR 10 OR 11
OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18
OR 19
22.20 AND 21
23.randomized controlled trial.pt.
24.controlled clinical trial.pt.
25.randomized.ab.
26.placebo.ab.
27.drug therapy.fs.
28.randomly.ab.
29.trial.ab.
30.groups.ab.
31.23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29
OR 30
32.humans.sh.
33.31 AND 32
34.22 AND 33
8Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Search strategy (Continued)
Embase (Ovid SP) 1.(statin$ OR lipophilic OR hydrophilic).mp.
2.(lovastatin OR simvastatin OR cervistatin OR
atorvastatin OR rosuvastatin OR provastatin OR flu-
vastatin).mp.
3.Hydroxymethylglutaryl-CoA Reductase
Inhibitors/ all subheadings
4.Alzheimer-disease/ all subheadings
5.exp dementia-vascular/ all subheadings
6.creutzfeldt-jakob-syndrome/ all subheadings
7.kluver-bucy-syndrome/ all subheadings
8.lewy-body/ all subheadings
9.pick-presenile-dementia/ all subheadings
10.Huntington-chorea/ all subheadings
11.delirium/ all subheading
12.wernicke-encephalopathy/ all subheadings
13.(dement$ OR Alzheimer$).mp.
14.(lewy$ AND bod$).mp.
15.((cognit$ OR memor$ OR mental) and (decline$
OR impair$ OR los$ OR deteriorate$)).mp.
16.(chronic AND cerebrovascular).mp.
17.((organic brain syndrome) OR (organic brain dis-
ease)).mp.
18.((cerebr$ AND deteriorate$) OR (cerebr$ AND
insufficien$)).mp.
19.((pick$ and disease) or (creutzfeldt or JCD or
CJD) or huntington$ or binswanger$ or korsako$)
.mp.
20.1 OR 2 OR 3
21.4 OR 5 OR 6 OR 7 OR 8 O R 9 OR 10 OR 11
OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18
OR 19
22.20 AND 21
23.randomized controlled trial.pt.
24.controlled clinical trial.pt.
25.randomized.ab.
26.placebo.ab.
27.drug therapy.fs.
28.randomly.ab.
29.trial.ab.
30.groups.ab.
31.23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29
OR 30
32.humans.sh.
33.31 AND 32
34.22 AND 33
Cinahl (Ovid SP) 1.(statin$ OR lipophilic OR hydrophilic).mp.
2.(lovastatin OR simvastatin OR cervistatin OR
atorvastatin OR rosuvastatin OR provastatin OR flu-
9Statins for the t reatment of dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Search strategy (Continued)
vastatin).mp.
3.Hydroxymethylglutaryl-CoA Reductase
Inhibitors/ all subheadings
4.Alzheimer-disease/ all subheadings
5.exp dementia-vascular/ all subheadings
6.creutzfeldt-jakob-syndrome/ all subheadings
7.kluver-bucy-syndrome/ all subheadings
8.lewy-body-disease/ al l subheadings
9.pick-disease-of-the-brain/ all subheadings
10.Huntington-disease/ all subheadings
11.delirium/ all subheading
12.wernicke-encephalopathy/ all subheadings
13.(dement$ OR Alzheimer$).mp.
14.(lewy$ AND bod$).mp.
15.((cognit$ OR memor$ OR mental) and (decline$
OR impair$ OR los$ OR deteriorate$)).mp.
16.(chronic AND cerebrovascular).mp.
17.((organic brain syndrome) OR (organic brain dis-
ease)).mp.
18.((cerebr$ AND deteriorate$) OR (cerebr$ AND
insufficien$)).mp.
19.((pick$ and disease) or (creutzfeldt or JCD or
CJD) or huntington$ or binswanger$ or korsako$)
.mp.
20.1 OR 2 OR 3
21.4 OR 5 OR 6 OR 7 OR 8 O R 9 OR 10 OR 11
OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18
OR 19
22.20 AND 21
23.randomized controlled trial.pt.
24.controlled clinical trial.pt.
25.randomized.ab.
26.placebo.ab.
27.drug therapy.fs.
28.randomly.ab.
29.trial.ab.
30.groups.ab.
31.23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29
OR 30
32.humans.sh.
33.31 AND 32
34.22 AND 33
PsycINFO (Ovid SP) 1.(statin$ OR lipophilic OR hydrophilic).mp.
2.(lovastatin OR simvastatin OR cervistatin OR
atorvastatin OR rosuvastatin OR provastatin OR flu-
vastatin).mp.
3.Hydroxymethylglutaryl-CoA Reductase
Inhibitors/ all subheadings
4.Alzheimer-disease/ all subheadings
10Statins for the treatment o f dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Search strategy (Continued)
5.exp dementia-vascular/ all subheadings
6.creutzfeldt-jakob-syndrome/ all subheadings
7.kluver-bucy-syndrome/ all subheadings
8.lewy-body-disease/ al l subheadings
9.pick-disease-of-the-brain/ all subheadings
10.Huntington-disease/ all subheadings
11.delirium/ all subheading
12.wernicke-encephalopathy/ all subheadings
13.(dement$ OR Alzheimer$).mp.
14.(lewy$ AND bod$).mp.
15.((cognit$ OR memor$ OR mental) and (decline$
OR impair$ OR los$ OR deteriorate$)).mp.
16.(chronic AND cerebrovascular).mp.
17.((organic brain syndrome) OR (organic brain dis-
ease)).mp.
18.((cerebr$ AND deteriorate$) OR (cerebr$ AND
insufficien$)).mp.
19.((pick$ and disease) or (creutzfeldt or JCD or
CJD) or huntington$ or binswanger$ or korsako$)
.mp.
20.1 OR 2 OR 3
21.4 OR 5 OR 6 OR 7 OR 8 O R 9 OR 10 OR 11
OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18
OR 19
22.20 AND 21
23.randomized controlled trial.pt.
24.controlled clinical trial.pt.
25.randomized.ab.
26.placebo.ab.
27.drug therapy.fs.
28.randomly.ab.
29.trial.ab.
30.groups.ab.
31.23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29
OR 30
32.humans.sh.
33.31 AND 32
34.22 AND 33
LILACS (statin* OR lipophilic OR hydrophilic) AND
(alzheimer$ OR dementia)
Data c ollection and analysis
Selection of studies
The search and screening of publications was undertaken by two
authors (BMcG, supported by JOH). The MeSH terms and search
strategy were agreed upon and tested by both reviewers. The other
authors (PP, DC and RB) acted as adjudicators and reviewed the
process. Authors independently sel ected trials for relevance against
the defined inclusion criteria. Those trials that did not fulfil the
criteria were excluded from further analysis.
11Statins for the treatment o f dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Quality assessment
The methodological quality of the included trials was assessed with
particular emphasis on th e concealment of treatment allocation.
Trials were ranked using the Cochrane approach (
Higgins 2008):
Grade A: Adequate concealment
This is where the report describes allocation of treatment by:
(i) some f orm of centralised randomized scheme, such as having to
provide details of an enrolled participant to an office, or by phone
to receive the treatment group all ocation;
(ii) some form of randomisationscheme controlled by a pharmacy;
(iii) numbered or coded containers, such as in a pharmaceutical
trial in which capsules from identical-looking numbered bottles
are administered sequentially to enrolled participants;
(iv) an on-site or coded computer system, given that the al locations
are in a locked, unreadable file that can be accessed only after
inputting the characteristics of an enrolled participant; or
(v) if assignment envelopes were used, the report will at least specify
that they are sequentially numbered, sealed, opaque envelopes;
(vi) other combinations of described elements of the process that
provides assurance of adequate concealment.
Grade B: Uncertain
This is where the report describes allocation of treatment by:
(i) use of a list’ or table to allocate assignments;
(ii) use of ’envelopes or sealed envelopes’;
(iii) stating the study as randomized’ without further detail.
Grade C: Inadequate concealment
This is where the report describes allocation of treatment by:
(i) alter nation;
(ii) reference to case record numbers, dates of bir th, day of the
week, or any other approach;
(iii) any allocation procedure that is entirely transparent before as-
signment, such as an open list of random numbers or assignments.
Empirical research has shown that lack of adequate allocation con-
cealment is associated with bias. Trials with unclear concealment
measures have been shown to yield more pronounced estimates
of treatment effects than trials that have taken adequate measures
to conceal allocation schedules, but le ss pronounced than inade-
quately concealed trials (
Chalmers 1983; Schulz 1995). Thus, tri-
als were included if they conformed to category A and those falling
into categories B or C were excluded. Other aspects of trial quality
were not assessed by a scoring system al though details were noted
of blinding, whether intention-to treat analyses were extractable
from the published data, and th e number of patients lost to follow
up.
Inclusion criteria
Identified trials with the above quality assessment were included.
Any disagreement in the independent sele ction was resolved with
discussion.
Data extraction
Data were extracted from the published reports. The summary
statistics required for each trial and each outcome for continuous
data are the mean change from baseline, the standard error of
the mean change, and the number of patients for each treatment
group at each assessment. Where changes from baseline were not
reported, the mean, standard deviation and the number of patients
for each treatment group at each time point was e xtracted. We
also extracted available data on demographics of patients (age,
gender, diabetes, hypertension, current smoker, prior myocardial
infarction/cerebrovascular accident, lipid values at baseline), statin
regimen (type of statin, daily dosage, starting time, duration),
follow-up duration.
For binary data the numbers in each treatment group and the
numbers experiencing the outcome of interest were sought. The
baseline assessment is defined as the latest available assessment
prior to randomization, but no longer than two months prior. For
each outcome measure, data were sought on every patient assessed.
To al low an intention-to-treat analysis, the data were sought ir-
respective of compliance, whether or not the patient was subse-
quently dee med ineligible, or other wise excluded from treatment
or follow-up. If intention-to-treat data were not available in th e
publications, “on-treatment or the data of those who completed
the trial were sought and indicated as such. Data from titration
phases prior to the randomized phase were not used to assess safety
or efficacy because patients are usually not randomized, nor are
treatments concealed.
Publication bias is a potential problem when carrying out a re-
view. We will investigate whether this review is subject to pub-
lication bias by preparing a funnel plot and examining for signs
of asymmetry. If asymmetry is present likely reasons will be ex-
plored, these can include reasons other than publication bias and
these will also be considered: selection biases, poor methodological
quality of smaller studies, artefactual and chance. The trim and fill
method will be carried out in the event of asymmetry to estimate
the impact of possible publication bias.
Data analysis
Analysis: All types of statins (hydrophilic and lipophilic) used in
the treatment of dementia.
The outcomes measured in clinical trials of dementia and cogni-
tive impairment often arise from ordinal rating scales. Where the
rating scales used in the trials have a reasonably large number of
categories (more than 10), the data were treated as continuous out-
comes arising from a normal distribution. Summary statistics (n,
mean and standard deviation) were required for each rating scale
at each assessment time for each treatment group in each trial for
change from baseline. When change from baseline results was not
reported, the required summary statistics were calculated from the
baseline and assessment time treatment group means and standard
deviations. In this case a zero correlation between the measure-
12Statins for the treatment o f dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ments at baseline and assessment time was assumed. This method
overestimates the standard deviation of the change from baseline,
but this conservative approach is considered to be preferable in a
meta-analysis.
The meta-analysis requires the combination of data from trials
that may not have used the same rating scale to assess an outcome.
The measure of the treatment diff erence for any outcome is the
weighted mean difference where the pooled trials use the same
rating scale or test, and the standardised mean difference, which
is the absolute mean difference divided by the standard deviation,
where different rating scales or tests are used. The duration of
the trials varied from 24-72 weeks. A separate meta-analysis was
conducted for each period. Some trials may contribute data to
more than one time period if multiple assessments have been done.
For binary outcomes, such as dead or alive, progression of demen-
tia or not, mil d or moderate dementia, the odds ratio was used to
measure treatment effect. A weighted estimate of the treatment ef-
fect across trials was calculated. Overall estimates of the treatment
difference are presented. In all cases the overall estimate from a
fixed effect model is presented and a test for heterogeneity using
a standard chi-square statistic performed. If there was significant
heterogeneity a random effects model will be presented. Sensitivity
analyses were undertaken to assess the r obustness of the results to
fixed effect versus random effects models and on the inclusion or
exclusion of studies of poor quality. If the treatment effect in the
sensitivity analysis were of similar magnitude and precision as that
of the main analysis, a definite conclusion about the treatment
effectiveness could be made, otherwise no definite conclusion will
be made on the effectiveness of the treatment. The impact of het-
erogeneity on the meta-analysis was also assessed using I
2
as it is
considered appropriate for small sample sizes. This describes the
percentage of the variability in effect e stimates that is due to het-
erogeneity rather than sampling error (chance).
R E S U L T S
Description of studies
See:
Characteristics of includedstudies; Characteristics of excluded
studies
; Characteristics of studies awaiting classification.
Results of the search
152 references were retrieved by the electronic searches. 5 were
considered as potentially eligible after screening.
Included studies
3 randomized placebo-controlled trials were identified with 748
participants -
ADCLT 2005, LEADe 2010 and Simons 2002.
For full details se e Characteristics of included studies. Ages for
participation ranged from 50-90 years but mean ages in studies
were 68-78 years representing older adults with dementia.
ADCLT 2005 included 63 patients with a diagnosis of probable
or possible AD as outlined by NINCDS-ADRDA and DSM-IV
criteria; individuals 51 years or older with mild to moderate im-
pairment (MMSE score 12-28) were eligible. All but 6 individ-
uals were taking cholinesterase inhibitors, 3 in the atorvastatin
group and 3 in the placebo group. Mean age was 78.9±1.2 years
in placebo group and 78.15±1.3 years in atorvastatin group.
LEADe 2010 included 614 patients with a diagnosis of proba-
ble AD according to DSM IV and NINCDS-ADRDA criteria
and of mild to moderate severity, de fined as a MMSE score of
13-25 at screening. Subjects were 53% female age range 50 to
90 years, mean age 74±8 years. Patients were receiving donepezil
10mg for at least 3 months before randomization and LDL-C was
2.5-3.5mmol/l for inclusion.
Simons 2002 was primarily a study investigating whether statins
alter cholesterol metabolites and reduce Aβ levels in the CSF of
AD patients. Cognition was assessed as a secondary outcome. 44
patients with probable AD as defined by NINCDS-ADRDA cri-
teria and mild to moderate severity (MMSE scores 12-26) were
recruited. Patients were allowed to take donepezil or rivastigmine
if the dose had been unchanged for 3 months prior to study entry
and remained stable during the 26-week study period. Mean age
was 68.5±8 years in pl acebo group and 68.0±9 years in simvastatin
group.
Participants were recruited primarily from the community.
ADCLT 2005 provided data on change in ADAS-Cog at 3
monthly intervals up to 1 year. Data were also provided on change
in total cholesterol level, CGIC score, MMSE score, NPI total
score andGPS total score between placebo and atorvastatin groups.
LEADe 2010 provided data on change in ADAS-Cog and ADCS-
CGIC scores between atorvastatin and placebo groups. Following
randomization the se measures were performed at 3-month inter-
vals through month 18. Secondary outcome measures were change
in NPI, ADFACS, CDR-SB, MMSE and modified ADAS-Cog.
Change in total, LDL and HDL cholesterol and triglycerides was
provided.
Simons 2002 provided data on change in MMSE and ADAS-Cog
score between simvastatin and placebo groups at 26 weeks.
Treatment in
ADCLT 2005 consisted of atorvastatin 80mg daily
or matching placebo. 63 individuals were considered evaluable by
completing the three month visit, 32 individuals receiving ator-
vastatin and 31 individuals receiving placebo. 46 individuals com-
pleted the 1 year study, 25 receiving atorvastatin and 21 receiv-
ing placebo. Reasons for drop-out were not provided. Atorvas-
tatin treatment produced significant decreases in total cholesterol
(40%), LDL-C (54%), and VLDL-C (30%) relative to placebo.
ApoE genotyping was carried out on study participants. 60% of
the placebo group and 62.5% of the atorvastatin group had 1
E4 allele. Change in performance among subjects with screening
13Statins for the treatment o f dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
cholesterol levels 200mg/dL was compared with performance
change in subjects with l evels <200mg/dL. Mean change in ADAS-
Cog performance at 6 months was established for atorvastatin
and placebo treated individuals grouped according to their ApoE
genotype. Within and between group comparisons according to
presence of apolipoprotein E 4 allele were performed, followed by
comparisons based on dose of the apolipoprotein E4 allele.
Treatment in
LEADe 2010 consisted of 80mg of atorvastatin daily
or matching placebo for 72 weeks. 640 patients were randomized
with a modified intention to treat population of 297 in the atorvas-
tatin group and 317 in the placebo group. Mean prior donepezil
treatment was 409±407 days. Results concerning APOE genotype
were available for 511 patients, observed ApoE4 frequency was
60%. Atorvastatin treatment produced significant decreases in to-
tal cholesterol, LDL-C (50.2%) and triglycerides but no signifi-
cant change in HDL-C. Reasons for drop-outs were given.
In Simons 2002 treatment consisted of simvastatin 40mg daily for
4 weeks and 80mg daily for the foll owing 22 weeks. Disease dura-
tion was 2.8±1.3 years in the placebo group and 2.6±1.4 years in
the simvastatin group. Ser um LDL-C showed f ew changes in the
placebo group but was reduced by 52% on average in the simvas-
tatin group. Reasons for drop-outs were given. ApoE genotyping
was not carried out.
Total adverse events were reported by
LEADe 2010 and Simons
2002
.
Excluded studies
Two studies were excluded from the analysis (
Gutterman 2002,
Winblad 2007). For full details see Characteristics of excluded
studies.
Gutterman 2002 used data pooled from trials of patients
treated with galantamine 24mg/day or placebo for 5 to 6 months
in randomized, double-blind placebo controlled trials. This was
a post-hoc analysis and so did not fulfil criteria for inclusion nor
did it have adequate power to examine the effects of statins. Us-
ing last observation carried forward, me an ADAS-Cog change
from baseline was measured. Of 1,311 patients 8.8% were tak-
ing statins. In the placebo, galantamine, statin and galantamine +
statin groups there were 598, 598, 60 and 55 patients respectively.
While galantamine use was associated with a significant change in
mean ADAS-Cog from baseline (p<0.001), statin use (p=0.195)
or the interaction of galantamine with statins (p=0.372) were not.
The conclusion was the use of statins did not lead to significant im-
provement of cognitive function among AD patients either alone
or in combination with galantamine.
Winblad 2007 was also a post-hoc analysis conducted on data
pooled from three double-blind, placebo-controlled, clinical tri-
als of galantamine in patients with AD. There were 4 treatment
groups: statin plus galantamine (n=42), statin alone (n=50), galan-
tamine alone (n=614) and neither galantamine nor statin (n=619).
While galantamine was associated with a significant beneficial ef -
fect on cognitive status (p<0.001) there was no association seen
with use of statins (p=0.083). There was no significant effect on
cognition with use of statins and galantamine together (p=0.183).
Studies Awaiting Publication:
CLASP 2008 was identified by the
search strategy through the search of trial databases as a large ran-
domised controlled trial fulfilling the inclusion criteria. Results
from
CLASP 2008 have not been published. The study authors
were contacted but no response was received. Approximately 405
participants from 45 US sites were recruited. Primary outcomes
were change in ADAS-Cog and CGIC. When the results of this
study are known we will gain furthe r information regarding statin
therapy for the treatment of dementia and the Cochrane review
will be updated.
Risk of bias in included stud ies
For f ul l details see Risk of Bias tables
Allocation
In
ADCLT 2005 randomization was performed in blocks of 10
using the Excel spreadsheet random-number generator, this ap-
peared adequate. In
LEADe 2010 1:1 randomization was carried
out, the medication was assembled for each patient based on a ran-
domization code prepared by Clinical Data Operations of Pfizer
Inc.This appeared satisfactory. In
Simons 2002 a randomization
list was computer generated, two copies were prepared: one was
used by the packaging department of the study medication or
placebo and the other was kept in a locked location until the study
was comple ted. This appeared satisfactory.
Blinding
In
ADCLT 2005 all investigators were blinded to both treatment
group and cholesterol profiles after randomization as active treat-
ment was expected to reduce circulating cholesterol levels. Medi-
cations were supplied in bulk by the pharmaceutical company and
were coded at pharmacy. This appeared adequate.
In
LEADe 2010 it is stated in the published article there was
’blinding of both the investigator and the subject’ and in confer-
ence proceedings trial data remained blinded, and the authors,
steering committee, and the sponsor had no information relating
to study outcomes’. This appeared adequate.
In Simons 2002 adequate blinding appears to have been carried
out. ’All personnel directly involved in the conduct of the study
remained unaware of the treatment groups until all patients had
completed the trial and all data had been retrieved’. Blood results
were monitored by a ph ysician not involved in the study, this
guaranteed that all investigators were kept blinded.
14Statins for the treatment o f dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Incomplete outcome data
In
ADCLT 2005 flow of subjects through the year long study
was provided, from 63 evaluable subjects 46 attended for final
assessment. Reasons for not attending were not given.
In
LEADe 2010 incomplete data were addressed.
In
Simons 2002 incomplete data were addressed comprehensively.
Selective reporting
There was no evidence of this.
Other potential sources of bias
None identified
Effects of interventions
See:
Summary of findings for the main comparison Statins
Compared to Placebo for the Treatment of Dementia
Primary Outcomes:
The three studies assessed change in ADAS-Cog from baseline.
The mean change and standard deviation were calculated from the
available data and entered into a meta-analysis.
When the three studies were combined th ere was no significant dif-
ference in ADAS-Cog between the statin group and placebo group
[mean difference -0.18, 95% CI -0.69,1.05, p=0.68] (
Analysis
1.1). There was also considerable he terogeneity when the stud-
ies were combined (chi²=6.08, p=0.05, I²=67%). The random ef-
fects model, which usually gives more weight to small studies, was
therefore used to re-pool the data; the combined results were not
significant [mean difference -1.12, 95%CI -3.99, 1.75, p=0.44]
(
Analysis 1.2). As the Simons 2002 study ran for 26 weeks, data
from ADCLT 2005 at 24 weeks and from LEADe 2010 at 26
weeks were combined and again there was no significant differ-
ence in ADAS-Cog between the statin and placebo groups [mean
difference 0.02, 95% CI -1.05, 1.10] (
Analysis 1.3). Change in
ADAS-Cog and Modified ADAS-Cog (13-item, 85-point scale)
Mohs 1997) from LEADe 2010 has been provided in the tables
from the various time points. At no time was a beneficial effect on
ADAS-Cog or Modified ADAS-Cog seen with statin treatment.
Change in MMSE was available from the three studies also. When
data were combined in a meta-analysis the re was a significant but
small difference between the statin and placebo groups favouring
the statin group [mean difference -0.50, 95% CI -0.92,-0.08, p=
0.02] (
Analysis 2.1). There was significant heterogeneity when the
studies were combined (chi²=11.66, p<0.01, I²=83%) so again the
random effects model was used. There was no significant difference
between statins and placebo [mean diffe rence -1.53, 95% CI -
3.28, 0.21, p=0.08] (
Analysis 2.2). Data were also compared at 24
weeks for
ADCLT 2005 and LEADe 2010; there was no significant
difference between th e statin and placebo groups [mean difference
-0.37, 95% CI -0.80, 0.07, p=0.10] (
Analysis 2.3). Change in
MMSE at different time points has been provided from LEADe
2010
; at no time was a beneficial effect from statin therapy seen.
Change in ADCS-CGIC assessing clinical global impression of
change was given in two studies:
ADCLT 2005 and LEADe 2010.
When data from these two trials were combined in a meta-analysis
using generic inverse variance there was no significant difference
between the statin and placebo groups [mean difference -0.02,
95% CI -0.14,0.10, p=0.74] (
Analysis 3.1).
Secondary Outcomes:
Side Effects: These were elicited from blood tests and from speak-
ing to patients and caregivers.
LEADe 2010 stated incidence of
persistent elevated liver enzymes (3X upper limit of normal on 2
consecutive measures 4 to 10 days apart) in the atorvastatin group
was low at 2.6% and 0% in the placebo group. There were 60
(19.1%) atorvastatin-treated and 69 (21.2%) placebo-treated pa-
tients who experienced serious adverse events (SAEs), 6 of which
in the atorvastatin group and 1 in the placebo group considered
treatment related by the investigator or sponsor. The SAEs con-
sidered treatment related in the atorvastatin group were hepatitis,
acute renal failure/rhabdomyolysis/pancreatitis, abdominal pain/
nausea/chest discomfort, transaminases elevation, liver disorder
and gastrointestinal haemorrhage. In
Simons 2002 2 patients in
the simvastatin group experienced adverse events: 1 patient had
muscle pain without elevation of creatine kinase, 1 patient was
withdrawn because creatine kinase was elevated. No adverse ef-
fects were reported in the placebo group. Data from
LEADe 2010
and Simons 2002 were combined and no significant difference
between statin and placebo groups was seen (
Analysis 6.1).
Change in cognitive status accounting for prior cholesterol, ApoE
genotype and cognitive level : Data provided in
ADCLT 2005:
Among subjects treated with atorvastatin, those who had im-
proved on the ADAS-Cog at 6 months had baseline MMSE
scores 2 points higher th an those who continued to deteriorate
(21.93±0.85 compared to 19.83±1.10, p<0.06). Those who im-
proved on the ADAS-Cog also had higher baseline cholesterol lev-
els than those who deteriorated. [Mean change in ADAS-Cog -
2.14±1.20 atorvastatin + cholesterol >200mg/dl; 0.11±0.68 ator-
vastatin+ cholesterol <200mg/dl]. A significant difference was seen
in ADAS-Cog performance at 6 months between the atorvastatin
and placebo groups in individuals with an apolipoprotein E-4 al-
lele (p=0.012) but not between the groups comprised of subjects
without an apolipoprotein E4 allele (p=0.967). NB There were
very small numbers in all groups.
Quality of Life: In
LEADe 2010 there was no significant diff erence
between the atorvastatin and placebo groups in Caregiver Burden
Questionnaire and Patient Health Resources Utilization.
Behaviour:
ADCLT 2005 and LEADe 2010 provided data on
Neuropsychiatric Inventory Caregiver Distress Scale (NPI) (infor-
mation obtained from the caregiver). Data from these two stud-
ies were combined at 6 months (
Analysis 4.1) and 12 months
(
Analysis 4.2). There was no significant benefit from statins seen
[mean difference at 12 months -0.94, 95% CI -2.07,0.19, p=0.10;
15Statins for the treatment o f dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
mean difference at 6 months -0.72 95% CI -1.61, 0.16]. As there
was considerable heterogeneity data at 12 months were analysed
using a random effects model, no significant difference between
the groups was seen [mean difference -2.07, 95% CI -5.73, 1.59]
(Analysis 4.3). ADCLT 2005 provided change in Geriatric De-
pression Scale (GDS) (information obtained from the patient).
Atorvastatin provided significant benefit on the GDS (p<0.04);
there was deterioration in the placebo group and improvement in
the atorvastatin group.
Activities of Daily Living:In ADCLT 2005 differences in per-
formance on the caregiver rated Alzheimer’s Disease Coopera-
tive Study-Activities of Daily Living Inventory (ADCS-ADL) be-
tween the treatment and placebo groups did not reach signifi-
cance (p>0.23). In
LEADe 2010 there was no benefit from ator-
vastatin compared to placebo in the ADFACS, a measure of func-
tion (
Analysis 5.4).
D I S C U S S I O N
Summary of main results
Three studies were identified:
Simons 2002, ADCLT 2005 and
LEADe 2010. Mean change in ADAS-Cog from baseline was an
outcome in the three trials and there was no significant difference
between the statin and the placebo groups.
Change in MMSE from baseline was reported in all studies also.
There was no significant difference between the statin and placebo
groups when the random effects model was used due to hetero-
geneity.
Clinical Global Impression of Change did not differ between the
two groups in the two studies that recorded this measure,
ADCLT
2005
and LEADe 2010.
The statins were well tolerated and incidence of side effects was
low. The statin group did not h ave a significantly higher rate of
adverse effects requiring discontinuation of treatment when the
data were combined.
There was some evidence from
ADCLT 2005 that greater cog-
nitive effect from atorvastatin was seen in patients with higher
cholesterol at baseline, higher MMSE at baseline and those with
an apolipoprotein E4 allele present.
There was no difference in activities of daily living or quality of
life between the two treatment groups.There was no convincing
evidence that statins provided a benefit in behaviour.
The three trials included patients with AD only. There were no
trials identified that assessed e ffect of statins in the treatment of
VaD.
It was not possible to assess if lipophilic statins or hydrophilic
statins were more efficacious due to th e small number of studies.
There was no evidence that statins were detr imental to cognition.
Overall completeness and applicability of
evidence
The
LEADe 2010 study was th e largest with 640 patients in to-
tal so results from this are likely to be more robust. Cognition
was a primary outcome (ADAS -Cog) along with global func-
tion (ADCS-CGIC). Secondary outcomes included NPI, mod-
ified ADAS-Cog, MMSE, CDR-SB and ADFACS. E xpl oratory
measures included a Caregiver Questionnaire and a Patient Health
Resources Utilization questionnaire.
In
Simons 2002 the primary outcome was eff ect of statins on
cholesterol metabolites and Aβ levels in the CSF of 44 patients
with AD. Cognitive performance was a secondary outcome and
was assessed at the beginning and end of the 26 week study. Only
37 patients completed the study so the impact of this study is likely
to be small.
In
ADCLT 2005 primary outcomes were change in cognitive func-
tion (ADAS-Cog) and clinical efficacy (CGIC). Secondary out-
comes were change in MMSE, NPI, ADCS-ADL and GDS so re-
sults were applicable. The study was small also however with data
available from 63 subjects in total.
Quality of the evidence
All studies had adequate sequence generation and blinding. In
ADCLT 2005 there was unclear all ocation concealment and drop
out data.
Potential biases in the review process
Results from
CLASP 2008 have not been published yet. The study
authors were contacted but no response was received.
Agreements and disagreements with other
studies or reviews
A previous systematic review assessed prevention and treatment of
dementia or AD by statins
Zhou 2007. This was published before
the LEADe 2010 results were available. Two studies were identi-
fied
Simons 2002 and ADCLT 2005 as identified in this review
and there was no statistically significant difference in ADAS-Cog
between the statin and placebo groups when the trials were pooled.
This is in agreement with this review.
A U T H O R S C O N C L U S I O N S
Implications for practice
There is insufficient evidence to recommend statins for the treat-
ment of Alzheimer’s disease or dementia. In
LEADe 2010, the
16Statins for the treatment o f dementia (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
first large scale RCT evaluating statins as a treatment for mild to
moderate AD, the regimen of atorvastatin plus donepezil was not
associated with significant benefit on clinical outcome measures
over 72 weeks. When data from this trial were pooled with two
smaller scale studies (Simons 2002 and ADCLT 2005) there was
no benefit from statins seen with the primary outcome measure
ADAS-Cog or in MMSE.
From
ADCLT 2005 there was some evidence that atorvastatin
treatment was more beneficial at six months in AD patients with
higher MMSE at baseline, those with an apolipoprotein E4 allele
and higher cholesterol levels at baseline. This would need to be
confirmed in larger scale studies.
Implications for research
We await full results of the
CLASP 2008 study. As this is a fur-
ther large scale RCT it will pr ovide further evidence as to whether
statins are beneficial in the treatment of A D and dementia. Results
from
LEADe 2010 suggest statins have no clinical benefit in treat-
ment of AD over 72 weeks so it would not be advisable to embark
upon further l arge scale RCTs until ful l results are known. At this
stage this Cochrane review will be updated to al low inclusion of
results from CLA SP 2008.
If considering additional studies it would be beneficial to further
assess impact of treatment at an earlier stage of the disease process,
effect of Apolipoprotein E4 allele and effect of baseline cholesterol
level as results from
ADCLT 2005 suggest these factors may have
an impact on efficacy.
A C K N O W L E D G E M E N T S
This protocol has been peer reviewed by four peer reviewers. We
wish to acknowledge the consumer editors, Clare Jeffrey, Anne
Lyddiatt and Andrew Herxheimer.
R E F E R E N C E S
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Indicates the major publication for the study
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