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9The American Journal of Medicine (2005) Vol 118 (12A), 1S–2S

Statin therapy in the treatment of Alzheimer disease:what is the rationale?

Steven T.DeKosky,MD

Department of Neurology and Alzheimer Disease Research Center,University of Pittsburgh Medical Center Health System,Pittsburgh,Pennsylvania,USA.Alzheimer disease (AD)is a chronic neurodegenerative disorder that is manifested by cognitive decline,neuropsychiatric symptoms,and diffuse structural abnormalities in the brain.Its prevalence is predicted to rise 4-fold in the next 50years.AD is characterized pathologically by deposition of extracellular ?-amyloid and accumulation of neuro?brillary tangles.Neuronal death and speci?c neurotransmitter de?cits also are part of the pathologic picture.Strategies to delay symptom progression have focused on addressing the neurotransmitter de?cits.Strategies to delay the onset or biologic progression of AD largely have targeted the plaques formed by the deposition of ?-amyloid.AD and cardiovascular disease share common risk factors,notably hypercholesterolemia,and occur together more often than expected by chance.Therapy with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors (statins)is the ?rst-line treatment option for hypercholesterolemia,and observational studies have suggested that the risk of AD is reduced in patients who receive statin therapy in midlife.This reduction in risk of AD observed with statin therapy may be due to statins reducing ?-amyloid formation and deposition or to their known anti-in?ammatory effects.Two randomized double-blind statin trials in patients with AD to assess the potential for statins to slow disease progression are currently under way.If successful,statin AD primary prevention trials may be developed.?2005Elsevier Inc.All rights reserved.

KEYWORDS:

Alzheimer disease;Amyloid precursor protein;?-amyloid;Dementia;Statins

Alzheimer disease (AD)is a chronic neurodegenerative disorder that is manifested by cognitive decline,neuropsy-chiatric symptoms,and diffuse structural abnormalities in the brain.Cognitive de?cits are apparent from the time of disease onset;and include memory loss;language distur-bances;visuospatial de?cits;and dysexecutive de?cits such as lack of judgment,motivation,and insight.Neuropsychi-atric symptoms occur in most patients during the course of AD,and include depression,anxiety,sleep disturbances,aggression,and psychosis.

AD is the most common form of dementia,accounting

for ?66%of all dementia cases;it occurs mainly in the elderly.1 Its prevalence increases with age, with the disease affecting 1in 10persons aged ?65years,rising to nearly 50% of all persons aged ?85 years.2 With the prevalence of AD predicted to grow 4-fold over the next 50 years,3 a number of future health problems are of concern,in partic-ular the burdens on healthcare systems and on patients’families.

AD is a highly speci?c system disease that is character-ized primarily by the deposition of ?-amyloid in the form of neuritic plaques 4 and by accumulation of intracellular neu-ro?brillary tangles (NFTs),which are insoluble depositions resulting from altered metabolism of the cytoskeletal ?pro-tein. Ultimately NFTs result in cell death.5 ?-amyloid is also cytotoxic;however,the link between the tangles and ?-amyloid plaques has yet to be established.Other impor-

Requests for reprints should be addressed to Steven T.DeKosky,MD,Department of Neurology and Alzheimer Disease Research Cen-ter,UPMC Health System,3471Fifth Avenue,Suite 811,Pittsburgh,Pennsylvania 15213-2582.

E-mail address:

The American Journal of Medicine (2005)Vol 118(12A),48S–53S

tant pathologic changes associated with AD include region-speci?c neuronal death and de?cits in neurotransmitters,such as acetylcholine,serotonin,norepinephrine,and gluta-mate.

Treatment strategies for Alzheimer disease

Current preventive strategies for AD focus on delaying the onset or progression of the disease.A strategy that would delay the onset of AD by 5years has been projected to reduce the prevalence in 50years by 50%.A delay in onset of 10years would virtually eradicate AD,because most people would not live long enough to develop the disease.6 If the progression of AD were delayed, the major-ity of patients with AD would remain in the mild-to-mod-erate stages of the disease.Fewer patients would progress to the moderate and severe stages,resulting in a higher quality of life for patients and their caregivers as well as a reduced healthcare burden for the state.The optimal treatment strat-egy would therefore delay both onset and progression of AD,with fewer people developing the disease and with those who do remaining in its earlier stages.3

Treatment strategies largely have targeted the neuro-transmitter de?cits.In particular,the well-reported cholin-ergic de?cit in patients with AD 7–10 has been a major therapeutic target for improving cognition or delaying symptom progression.Controlled clinical trials of acetyl-cholinesterase inhibitors in patients with AD have demon-strated statistically signi?cant bene?ts in cognitive and non-cognitive symptoms.11–14 As a result, acetylcholinesterase inhibitors have now become the most widely approved symptomatic therapies available for the treatment of pa-tients with mild-to-moderate AD.Most recently a glutamate receptor modi?er,memantine,has been approved in Europe,the United States,and other countries for treatment of moderate-to-severe AD.15,16

Treatment strategies for delaying the onset of AD have targeted the amyloid plaques.Plaques are observed in all patients with AD and are composed of altered metabolites

of the amyloid precursor protein (APP),especially the 40-and 42-amino acid ?-amyloid.Under normal conditions APP is cleaved by ?-secretase just above the surface of the neuronal membrane, releasing soluble APP.17 In patients with AD,the APP molecule is cleaved further distal from the membrane surface by ?-secretase and within the neuro-nal membrane by ?-secretase,releasing ?-amyloid that can become deposited in the center of the amyloid plaque (Fig-ure 1). Efforts to delay the onset of AD have therefore focused on developing ?-or ?-secretase inhibitors to prevent abnormal APP cleavage or else focused on de-veloping antibodies to facilitate the removal of ?-amy-loid,by either active or passive immunization.However,no therapeutic options targeting this mechanism are cur-rently available.

Commonalities between Alzheimer disease and cardiovascular disease

A number of cardiovascular risk factors,such as hyper-tension,hypercholesterolemia,in?ammatory states,and dia-betes mellitus,have been shown in observational and epide-miologic studies to be associated with AD and dementia.18,19Furthermore,cardiovascular disease (CVD)and AD occur together more often than would be expected by chance,20and neuritic plaques have been observed in patients with myocardial infarctions without diagnosed dementia.21Moreover,vascular injury may lower the threshold for cog-nitive manifestations of clinical dementia.22

These observations have led to the hypothesis that the 2diseases may share common or complementary biologic antecedents.23 For instance, ?-amyloid can cause vasocon-striction in the brain and reduce endothelium-dependent cerebrovascular dilation.24 Impaired vasodilation and con-striction also occur in CVD and lead to in?ammation and ultimately to plaque formation.In addition,cerebral isch-emia can upregulate local APP expression and increase production of ?-amyloid,25 thereby further enhancing the likelihood of impaired vasodilation.Therefore,removal

Figure 1Amyloid precursor protein (APP)metabolism.AD ?Alzheimer disease;sAPP ?soluble APP.

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DeKosky Rationale for Statin Therapy in the Treatment of Alzheimer Disease

?-amyloid under conditions of ischemia would also de-crease some of the vasoconstriction and reduce oxidative stress as well as primary AD pathology.

Hypercholesterolemia and Alzheimer disease Hypercholesterolemia is among the major modi?able risk factors for CVD.26,27Although mean cholesterol levels in patients with AD are not higher than in controls,data from large epidemiologic studies and prospective popula-tion studies suggest that an elevated cholesterol level in midlife may increase the risk of AD in older age.A survey of a random sample of1,449participants who were fol-lowed for an average of21years revealed that participants with elevated systolic blood pressure or elevated serum total cholesterol levels in midlife had a signi?cantly higher risk of AD in later life than those with normal systolic blood pressure(odds ratio[OR],2.3;95%con?dence interval [CI],1.0–5.5)or total cholesterol levels in midlife(OR,2.1; 95% CI, 1.0 – 4.4).28This observation held even after ad-justing for age,body mass index,education,vascular events,smoking status,and alcohol consumption.Similarly, a retrospective study of444Finnish men found that early elevated total cholesterol levels predicted later incidence of AD(OR,3.1;95%CI,1.2–8.5),even after controlling for age and the presence of the apolipoprotein E4 allele.29

A review of autopsy cases of patients aged?40years revealed that in the youngest patients(40to55years) hypercholesterolemia correlated with the presence of neu-ritic plaques.30The authors concluded that hypercholester-olemia may be an early risk factor for AD.If early elevated cholesterol levels are indeed associated with a risk of AD, then this represents a rationale for lipid-lowering treatments to confer a reduction in risk for AD.

Statins and their effects on dementia

Cholesterol-lowering therapy with3-hydroxy-3-methylglu-taryl coenzyme A(HMG-CoA)reductase inhibitors(statins) has been shown to reduce the risk of death or cardiovascular events in patients with31–33or without CVD34,35and is the therapy of choice for treating hypercholesterolemia.26,27 Data from a number of observational studies suggest that statins may have a protective effect against the risk of devel-oping AD.

Data from the Canadian Study of Health and Aging (CSHA)revealed a74%reduced risk of AD in statin users and in users of any lipid-lowering agent compared with those not using statins or any other lipid-lowering medica-tions.36However, the reduction in risk was observed only in patients?80years of age.A similar effect in favor of statins was revealed in a cross-sectional analysis of60,349patients aged?60years.In this study,a60%to73%reduction in risk of AD in statin users was observed compared with the total population or with patients receiving other medications typically used in the treatment of CVD.37

There is some evidence that statins in particular,rather than low cholesterol levels or lipid-lowering agents in general,are associated with the reduction in risk of AD.

A nested case-control study demonstrated a risk reduc-tion of?70%for dementia in statin users compared with persons without hypercholesterolemia or persons who used other lipid-lowering agents.38In an observational study in postmenopausal women with coronary heart dis-ease,statin users scored higher on the Modi?ed Mini-Mental State Examination(MMSE)than nonusers of statins,indepen-dent of lipid levels.39There was also a trend for statin users to have a reduced risk of cognitive impairment. These results have led researchers to posit potential mechanisms for the possible bene?ts of statins in reduc-ing the incidence of AD.

Potential mechanisms of statins in the treatment of AD

This section describes a number of physiologic mechanisms by which statin therapy may reduce patients’risk of AD. Endothelial nitric oxide synthase

Statins upregulate the production of endothelial nitric oxide synthase (eNOS)40; eNOS facilitates increasing blood ?ow. Interestingly,the upregulating effect of statins on eNOS (Figure 2) is independent of statins’ lipid-lowering ability and may re?ect the absence of a close association between cholesterol level and cognition.41,42

Vascular wall mechanisms

Decreased platelet adhesion is observed with the use of statins and may be associated with decreased risk of vessel wall disease.

Alterations in ?-amyloid production and removal There is some evidence to suggest that statins may inhibit the formation of ?-amyloid.43– 45For instance, in a study in hippocampal neurons in cell culture,formation of?-amy-loid was completely inhibited after reducing cholesterol levels by 70% with lovastatin.44Statins may also maintain low-density lipoprotein(LDL)receptor–related protein pro-duction.LDL receptors are diminished in the vessel walls of patients with AD,and these receptors may facilitate the removal of ?-amyloid from the brain.46

Suppression of in?ammation

In?ammation is common in the brains of patients with AD.

A number of studies have demonstrated that statins may

50S The American Journal of Medicine,Vol118(12A),December2005

exert anti-in?ammatory effects.47– 49 For instance, statins may upregulate eNOS RNA.40 The evidence from observa-tional studies,along with hypothesized mechanisms for a treatment bene?t with statins,has provoked interest in con-ducting trials to assess the safety and ef?cacy of statins in the treatment of AD.

Future perspectives

Opportunities for major public health gains exist in the development of AD prevention therapies.However,AD primary prevention trials are very expensive to conduct,with each study costing in excess of US$25million.Unlike cardiovascular research,prevention trials in patients with AD often require physicians to work with patients on an individual level to assess cognitive function over extended periods of time.Power calculations based on projections of AD incidence would necessitate the recruitment of ?3,000participants in most trials and would have to last for 5to 7years or longer.Due to the requirement for double-blind placebo-controlled trial designs,early trials have focused on safe and inexpensive compounds,such as estrogen or Ginkgo biloba ,to assess the potential for delaying the onset of dementia.50,51

Two major statin trials are currently under way to assess the effects of statins in delaying the progression of AD in patients with serum cholesterol levels that do not require therapeutic intervention.The Cholesterol Lowering Agent to Slow Progression of Alzheimer’s Disease (CLASP)study is a double-blind trial that randomized approximately 400patients with AD to either simvastatin 20mg/day or placebo for 6weeks.Patients then received either simvastatin

40mg/day or placebo for the remainder of the 18-month study.52 Patients continued to receive their acetylcholines-terase-inhibitor medications.This trial is expected to be completed in December 2005.The Lipitor’s Effect in Alzheimer’s Dementia (LEADe)study is a double-blind trial that randomized approximately 600patients with AD to either atorvastatin 80mg/day or placebo for a period of 72weeks.At 72weeks,patients continued their double-blind therapeutic regimen for a further 8weeks or had their treatment replaced by matching placebo for 8weeks.All patients received the acetylcholinesterase in-hibitor donepezil 10mg/day for the duration of the study.The study is due to be completed in 2006.If these trials demonstrate that statin therapy confers symptomatic ben-e?t in patients with AD,they will open up the possibility of AD prevention trials with statins.

Summary

AD is a fatal,incurable,and chronic disease,the inci-dence of which is predicted to rise dramatically over the next 50years with an increase in associated healthcare burden.Current treatment options focus on delaying the symptomatic progression of the disease.Data from obser-vational studies suggest that statin therapy may delay the onset of AD by a variety of proposed mechanisms,such as suppression of ?-amyloid metabolism,vascular effects,and anti-in?ammatory effects.Clinical trials are currently under way that will assess the effect of statins on cognitive func-tion in patients with AD.If successful,statin trials for the primary prevention of AD may be

developed.

Figure 2Inhibition of mevalonic acid formation by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors (statins)results in upregulation of endothelial nitric oxide synthase (eNOS).ICAM-1?intercellular adhesion molecule-1;mRNA ?messenger RNA; – PMN ? polymorphonuclear (myocardial) neutrophil. (Reprinted with permission from FASEB J.42)

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