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662 | DECEMBER 2011 | VOLUME 7 www.nature.com/nrneurol NEWS & VIEWS ALZHEIMER DISEASE Statins in the treatment of Alzheimer disease D. Larry Sparks A recent clinical trial showed no beneficial effects of statin treatment in patients with Alzheimer disease (AD) and normal cholesterol levels. Other studies show that the effects of statins can vary depending on cholesterol levels and stage of disease, so statins should not be ruled out as an AD therapy. Sparks, D. L. Nat. Rev. Neurol. 7, 662–663 (2011); published online 18 October 2011; doi:10.1038/nrneurol.2011.165 ‘‘ …statin treatment might be of benefit in AD, but only for those patients who have high cholesterol levels... ’’ ‘‘ …at least some patients with AD can garner clinically relevant benefits from statin therapy ’’ Evidence obtained from in vitro studies and some clinical trials has suggested that a reduction in cholesterol levels could be beneficial in patients with Alzheimer disease (AD). The Alzheimer’s Disease Cooperative Study has investigated the therapeutic effects of simvastatin—a cholesterol-lowering drug—in the treat- ment of mild to moderate AD. 1 As reported by Sano et al. in Neurology, no evidence was found of either benefit or harm to patients with AD who were treated with simva- statin for 18 months, compared with those who were administered placebo treatment. However, this study only assessed the effect of simvastatin among individuals within the normal range of cholesterol levels (as defined by the Adult Treatment Panel III final report 2 ). This patient selection is in sharp contrast to that of a previous study in which individuals with high cholesterol levels were allowed to participate, which found beneficial effects of atorvastatin treatment in patients with AD. 3 The first prolonged trial on statin treat- ment in AD—the Alzheimer’s Disease Cholesterol-Lowering Treatment (ADCLT) trial—was performed on the premise that elevated cholesterol levels might promote disease progression, but did not directly cause the disease. 3 Individuals participat- ing in the ADCLT trial were administered 80 mg of atorvastatin or placebo per day, for 1 year, without dose escalation. By compari- son, patients in the study by Sano et al. were treated with 20 mg per day of simvastatin for 6 weeks and then 40 mg per day for the following 16.5 months. 1 Mean cholesterol levels in patients at baseline were compa- rable in both studies. Patients who received atorvastatin in the ADCLT trial showed positive benefits on the Alzheimer’s Dis- ease Assessment Scale-cognitive subscale (ADAS-cog). 3 This benefit in cognition following atorvastatin treatment achieved statistical significance compared with placebo at 6 months, and patients treated with the statin showed a trend towards improvement at 1 year. By contrast, Sano et al. found no evidence of improvement in ADAS-cog scores: deterioration in ADAS- cog performance was comparable between the placebo population and the simvastatin treatment group over the entire 18-month period of the study. 1 The only other differ- ence that might explain the discrepancies in results between the two trials was in the magnitude of cholesterol reduction in the treatment populations. In the ADCLT trial, atorvastatin induced a 54% decrease in LDL cholesterol and a 40% reduction in total cholesterol, 3 whereas in the study by Sano et al. patients treated with simvastatin showed only 37% and 23% reduction in LDL and total cholesterol, respectively. 1 In the paper by Sano et al., the authors raise the possibility that statin therapy could be beneficial in individuals with mild cognitive impairment (MCI), or that the treatment might reduce the risk of AD in individuals who are asymptomatic when treatment is initiated. This reduced risk of AD in statin-treated asympto- matic indivi duals is a clear possibility: studies that were performed as part of the Alzheimer’s Disease Anti-Inflammatory Prevention Trial showed that, in cognitively normal individuals, elective statin use was associated with a reduced risk of AD. 4,5 Furthermore, re-evaluation of data from a study that primarily investigated the effects of ginkgo biloba on memory also identified a reduced risk of AD among statin users who were asymptomatic, but not in those who were already experiencing MCI. 6 It is reasonable to suppose that statin treatment might be of benefit in AD, but only for those patients who have high cholesterol levels, so the fact that simvastatin treatment exerted little effect on cognitive measures in AD patients with normal cholesterol levels 1 is not surprising. Of note, Sano et al. did not mention in their paper the results of a previously pub- lished large clinical trial—the Atorvastatin/ Donepezil in Alzheimer’s Disease (LEADe) study—that investigated atorvastatin treatment in patients with AD who were receiving background therapy with the cholinesterase inhibitor donepezil. 7 In the LEADe study—as in the ADCLT trial— patients were treated with 80 mg per day of atorvastatin without dose escalation, but the trial lasted for 18 months (as in the study by Sano et al.). Consistent with findings in the ADCLT trial, LDL cho- lesterol levels were decreased by over 50% in patients receiving atorvastatin treat- ment in the LEADe study. An improve- ment in ADAS-cog scores was evident in the atorvastatin group versus the placebo group after 6 months of treatment, but the difference between the two patient groups did not reach statistical significance. 7 Sano et al. say that beneficial effects of statin treatment in AD “seem unlikely”, despite previous reports to the contrary. 3,7 In the LEADe trial, the positive effects of statin treatment were confined to male partici- pants, 8 but this sex-related finding was possibly a statistical illusion. On the basis of preliminary observa- tions from the ADCLT trial, 9 part of the preplanned assessment of the data from the LEADe trial investigated the influence of apolipoprotein E (APOE) genotype and cholesterol levels on the cognitive benefit associated with atorvastatin treatment. 10 Not all individuals who participated in the LEADe study allowed the researchers to analyze their APOE genotype but, among those who did, a modest improvement in the baseline ADAS-cog score was observed © 2011 Macmillan Publishers Limited. All rights reserved

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Page 1: Alzheimer disease: Statins in the treatment of Alzheimer disease

662 | DECEMBER 2011 | VOLUME 7 www.nature.com/nrneurol

NEWS & VIEWS

ALZHEIMER DISEASE

Statins in the treatment of Alzheimer diseaseD. Larry Sparks

A recent clinical trial showed no beneficial effects of statin treatment in patients with Alzheimer disease (AD) and normal cholesterol levels. Other studies show that the effects of statins can vary depending on cholesterol levels and stage of disease, so statins should not be ruled out as an AD therapy.Sparks, D. L. Nat. Rev. Neurol. 7, 662–663 (2011); published online 18 October 2011; doi:10.1038/nrneurol.2011.165

‘‘…statin treatment might be of benefit in AD, but only for those patients who have high cholesterol levels...’’

‘‘…at least some patients with AD can garner clinically relevant benefits from statin therapy’’

Evidence obtained from in vitro studies and some clinical trials has suggested that a reduction in cholesterol levels could be bene ficial in patients with Alzheimer dis ease (AD). The Alzheimer’s Dis ease Cooperative Study has investigated the thera peutic effects of simvastatin—a cholesterol­lowering drug—in the treat­ment of mild to moderate AD.1 As reported by Sano et al. in Neurology, no evidence was found of either benefit or harm to patients with AD who were treated with simva­statin for 18 months, com pared with those who were administered placebo treatment. However, this study only assessed the effect of simvastatin among individuals within the normal range of cholesterol levels (as defined by the Adult Treatment Panel III final report2). This patient selection is in sharp contrast to that of a previous study in which individuals with high cholesterol levels were allowed to participate, which found bene ficial effects of atorvastatin treatment in patients with AD.3

The first prolonged trial on statin treat­ment in AD—the Alzheimer’s Disease Cholesterol­Lowering Treatment (ADCLT) trial—was performed on the premise that elevated cholesterol levels might promote disease progression, but did not directly cause the disease.3 Individuals participat­ing in the ADCLT trial were administered 80 mg of atorvastatin or placebo per day, for 1 year, without dose escalation. By compari­son, patients in the study by Sano et al. were treated with 20 mg per day of simva statin

for 6 weeks and then 40 mg per day for the following 16.5 months.1 Mean cholesterol levels in patients at baseline were compa­rable in both studies. Patients who received atorvastatin in the ADCLT trial showed positive benefits on the Alzheimer’s Dis­ease Assessment Scale­cognitive subscale (ADAS­cog).3 This benefit in cognition follow ing atorvastatin treatment achieved statistical significance compared with placebo at 6 months, and patients treated with the statin showed a trend towards improvement at 1 year. By contrast, Sano et al. found no evidence of improvement in ADAS­cog scores: deterioration in ADAS­cog performance was comparable between the placebo population and the simvastatin treatment group over the entire 18­month period of the study.1 The only other differ­ence that might explain the discrepancies in results between the two trials was in the mag nitude of cholesterol reduction in the treatment populations. In the ADCLT trial, atorvastatin induced a 54% decrease in LDL cholesterol and a 40% reduction in total cholesterol,3 whereas in the study by Sano et al. patients treated with simva statin showed only 37% and 23% reduction in LDL and total cholesterol, respectively.1

In the paper by Sano et al., the authors raise the possibility that statin therapy could be beneficial in individuals with mild cognitive impairment (MCI), or that the treatment might reduce the risk of AD in individuals who are asympto matic when treatment is initiated. This reduced risk of AD in statin­treated asympto­matic indivi duals is a clear possibility: studies that were performed as part of the Alzheimer’s Disease Anti­Inflammatory Prevention Trial showed that, in cognitively normal individuals, elective statin use was associated with a reduced risk of AD.4,5 Furthermore, re­evaluation of data from a

study that primarily investigated the effects of ginkgo biloba on memory also identified a reduced risk of AD among statin users who were asymptomatic, but not in those who were already experiencing MCI.6 It is reason able to suppose that statin treatment might be of benefit in AD, but only for those patients who have high cholesterol levels, so the fact that simvastatin treatment exerted little effect on cognitive measures in AD patients with normal cholesterol levels1 is not surprising.

Of note, Sano et al. did not mention in their paper the results of a previously pub­lished large clinical trial—the Atorvastatin/Donepezil in Alzheimer’s Disease (LEADe) study—that investigated atorvastatin treat ment in patients with AD who were receiv ing background therapy with the cho linesterase inhibitor donepezil.7 In the LEADe study—as in the ADCLT trial—patients were treated with 80 mg per day of atorva statin without dose escalation, but the trial lasted for 18 months (as in the study by Sano et al.). Consistent with findings in the ADCLT trial, LDL cho­lesterol levels were decreased by over 50% in patients receiving atorvastatin treat­ment in the LEADe study. An improve­ment in ADAS­cog scores was evident in the atorva statin group versus the placebo group after 6 months of treatment, but the difference between the two patient groups did not reach statistical significance.7 Sano et al. say that beneficial effects of statin treatment in AD “seem unlikely”, despite pre vious reports to the contrary.3,7 In the LEADe trial, the posi tive effects of statin treatment were confined to male partici­pants,8 but this sex­related finding was possib ly a statistical illusion.

On the basis of preliminary observa­tions from the ADCLT trial,9 part of the preplanned assessment of the data from the LEADe trial investigated the influence of apolipoprotein E (APOE) genotype and cholesterol levels on the cognitive benefit associ ated with atorva statin treatment.10 Not all individuals who participated in the LEADe study allowed the researchers to analyze their APOE geno type but, among those who did, a modest improvement in the baseline ADAS­cog score was observed

© 2011 Macmillan Publishers Limited. All rights reserved

Page 2: Alzheimer disease: Statins in the treatment of Alzheimer disease

NATURE REVIEWS | NEUROLOGY VOLUME 7 | DECEMBER 2011 | 663

NEWS & VIEWS

Figure 1 | Changes in ADAS-cog scores in the LEADe study. Patients with AD who were receiving background treatment with donepezil were randomly assigned to receive daily atorvastatin or placebo treatment. The primary analysis was performed on patients who were APOE-genotyped, randomly received at least one dose of study medication, and had both baseline and at least one follow-up study evaluation. Cognitive function was assessed using ADAS-cog scores on a 70-point scale. Mean change in ADCS-cog scores between baseline and follow-up values were determined. Abbreviations: AD, Alzheimer disease; ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; APOE, apolipoprotein E; LEADe, Atorvastatin/Donepezil in Alzheimer’s Disease; LOCF, last observation carried forward.

after 6 months of atorvostatin treatment10 (Figure 1)—a finding simi lar to that of the ADCLT trial.3 In the APOE­genotyped subpopulation of the LEADe participants, there was no apparent influ ence of APOE ε4 allele frequency, patient sex or the magnitude of elevated cholesterol levels on the benefi cial effect of atorvastatin on ADAS­cog performance.10

According to Sano et al.,1 whether or not statin therapy has a favorable impact on individuals with AD and elevated cho­lesterol levels is unknown, but they assert that patients with AD and high cholesterol levels should have been treated with a lipid­lowering medication for the purposes of heart health. This statement implies that such patients had not been receiving the best medical care possible; as a result, one would hope that a mechanism was in place such that participants who were excluded from the trial could obtain the medical care deemed necessary (that is, lipid­lowering medication), either directly from the study physician, or indirectly via the individual’s primary care physician.

The authors also suggest that recruit­ment of patients with high cholesterol levels would be unethical, as some patients would be treated with placebo, and their high cholesterol levels would, therefore,

go untreated. I find it curious that pro­viding placebo to an individual with high cholesterol levels in a trial to test a novel lipid­lowering medication for improved heart health may be deemed ethical, but providing placebo to a patient with elevated cholesterol levels as part of a trial to test the benefits of statin therapy on cogni­tive performance would be unethical. A patient who is an average of 73 years old and who has elevated cholesterol levels is likely to have had high lipid levels for quite some time. In this case, one would want to weigh the possible benefit that testing of a medication could bring to all patients with AD against the risk of administering a placebo to an individual for an additional 12–18 months, particularly if the individual with AD has normal HDL:LDL ratios.

The study by Sano et al.1 suggests that treatment with simvastatin is not benefi cial in patients with mild to moderate AD and nor mal cholesterol levels, and the indica­tions from the ADCLT and LEADe trials —namely that atorvastatin therapy may show benefit, but only in certain groups, such as males, patients with high cho­lesterol levels, or indivi duals with the APOE ε4 allele—were not confirmed in secon dary post­hoc analy sis of the LEADe data.10 Nevertheless, it seems clear that at

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P = 0.01

P = 0.04

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P = 0.17

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63 9

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Time of follow-up evaluation (months since baseline)

Atorvastatin 80 mg + donepezil 10 mg (n = 231)

Placebo + donepezil 10 mg (n = 258)

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least some patients with AD can garner clini cally relevant benefits from statin therapy. General practice physicians and neurologists have a responsibility to assess the benefit of statin therapy for each patient and to make the decision to treat (or not to treat) the individual, and with what medication.

Roberts Lab for Neurodegenerative Disease Research, Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. [email protected]

Competing interestsThe author declares no competing interests.

1. Sano, M. et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 77, 556–563 (2011).

2. Third report of the expert panel on detection, evaluation and treatment of high blood cholesterol in adults (ATP III final report). NIH National Heart Blood and Lung Institute [online], http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm (2002).

3. Sparks, D. L. et al. Atorvastatin for the treatment of mild-to-moderate Alzheimer’s disease: preliminary results. Arch. Neurol. 62, 753–757 (2005).

4. Sparks, D. L. et al. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr. Alzheimer Res. 5, 416–421 (2008).

5. Sparks, D. L. et al. Cholesterol and cognitive performance in normal controls and the influence of elective statin use after conversion to mild cognitive impairment: results in a clinical trial cohort. Neurodegener. Dis. 7, 183–186 (2010).

6. Bettermann, K. et al. Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. J. Stroke Cerebrovasc. Dis. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis. 2010.11.002.

7. Feldman, H. H. et al. Randomized controlled trial of atorvastatin in mild-to-moderate Alzheimer’s disease: LEADe. Neurology 74, 956–964 (2010).

8. Feldman, H. H. et al. The LEADe Study: a randomized controlled trial investigating the effect of atorvastatin on cognitive and global function in patients with mild to moderate AD receiving background therapy of donepezil [abstract LBS.005]. Neurology 71, 54 (2008).

9. Sparks, D. L. et al. Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in AD: results of the Alzheimer’s disease cholesterol-lowering treatment (ADCLT) trial. Acta. Neurol. Scand. 114, 3–7 (2006).

10. Sparks, D. L. et al. The atorvastatin/donepezil in Alzheimer’s disease (LEADe) study: effect of atorvastatin on Alzheimer’s disease progression by ApoE4 genotype. Presented at the International Conference on Alzheimer’s Disease (2008).

© 2011 Macmillan Publishers Limited. All rights reserved