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Primary Psychiatry. 2007;14(8):39-54
Dr. Grossberg is the Samuel W. Fordyce Professor in the Department of Neurology & Psychiatry at the St. Louis University School of Medicine in Missouri. Dr. Pejovic is senior account executive and Dr. Miller is senior account manager at Prescott Medical Communications Group in Chicago, Illinois.
Disclosures: Dr. Grossberg is a consultant to Abbott, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, Novartis, Sepracor, and Takeda; and receives research support from Abbott, Forest, Myriad, the National Institute of Mental Health, the National Institute on Aging, Novartis, ONO, and Pfizer. Drs. Pejovic and Miller are consultants to Forest. Dr. Miller holds stocks in Eli Lilly, Medivation, and Pfizer. Funding for the development of this manuscript was provided by an unrestricted educational grant from Forest.
Acknowledgments: The authors wish to thank Jason T. Olin, PhD for his advisory and editorial support; and Carol Wilmot of Prescott Medical Communications Group for her graphic design support.
Please direct all correspondence to: George T. Grossberg, MD, St. Louis University School of Medicine, Department of Neurology & Psychiatry, 1221 S. Grand Blvd, St. Louis, MO 63104; Tel:314-577-8721; Fax: 314-268-5490; E-mail: grossbgt@slu.edu.
Focus Points
• Many new agents are being developed for the treatment of Alzheimer’s disease.
• Several strategies focus on prevention of Alzheimer’s disease.
• Drugs to treat Alzheimer’s disease target many molecular pathways.
Abstract
The need to develop effective and well-tolerated pharmacotherapies for the treatment and prevention of Alzheimer’s disease is becoming increasingly important as the worldwide incidence and prevalence of Alzheimer’s disease rapidly rise. Recent advances in our understanding of the numerous biochemical pathways contributing to Alzheimer’s disease pathology have resulted in targeted development of potential treatments and preventive strategies. The complexity of Alzheimer’s disease offers many possibilities for pharmacologic intervention and the potential to improve upon current treatment paradigms. Ongoing research and drug development have produced a variety of novel approaches, including normalization of neurotransmitter function, targeting of the β-amyloid cascade, and strategies aimed at delaying the onset of this debilitating disease. This article discusses compounds that are currently approved or are in late-stage (Phase III) development for the treatment or prevention of Alzheimer’s disease. The proposed mechanism(s) of action and biochemical rationale are provided for each therapeutic agent, along with an update of its clinical progress. Some additional early-stage compounds that purportedly act through unique mechanisms are also discussed.
Introduction
The deficits observed in patients with Alzheimer’s disease are the result of a complex interaction of aberrant biochemical pathways that ultimately lead to neuronal degeneration. In patients with Alzheimer’s disease, alterations have been found in the cholinergic and glutamatergic neurotransmitter systems; the β-amyloid (Aβ) pathway; and oxidative, inflammatory, and hormonal processes. Each of these offers a potential target for Alzheimer’s disease therapy.
Clinical and scientific developments in the Alzheimer’s disease field occur rapidly, as evidenced by a large number of reviews on the subject in recent years.1-5 The primary purpose of this article is to provide an update on approved and potential compounds for the treatment of Alzheimer’s disease (Table 1), together with the underlying rationale for their use (Figure 1).
In addition, an overview of substances investigated for their potential to delay the onset of the disease (Table 2) are provided. For the purpose of this article, such agents have been classified as “preventive,” although many of them are also being investigated as treatment options for patients already diagnosed with Alzheimer’s disease. This article focuses on approved therapies and those in a late stage (Phase III) of clinical development; however, some early-stage compounds that purportedly act through unique mechanisms are also discussed, along with some alternative hypotheses regarding Alzheimer’s disease pathogenesis that have been gaining momentum in recent years.
Treatment Strategies
Normalizing Neurotransmitter Systems
Several abnormalities in neurotransmitter systems are apparent in patients with Alzheimer’s disease. Two important systems that have been shown to be damaged in Alzheimer’s disease—the cholinergic and glutamatergic systems—are well-characterized for their importance in learning and memory.6,7
Cholinergic System
The cholinergic hypothesis of Alzheimer’s disease is rooted in observations that the Alzheimer’s disease brain undergoes a widespread loss of cholinergic neurons and decreased levels of the neurotransmitter acetylcholine (ACh), both of which are associated with impaired memory and cognition.8,9 Treatment strategies utilizing cholinergic agents are based upon the assumption that enhancing cholinergic neurotransmission in the Alzheimer’s disease brain will result in maintenance or improvement of cognitive function. Approaches designed to increase cholinergic neurotransmission include the use of agonists specific for nicotinic10-12 and muscarinic13,14 ACh receptors, administration of ACh precursors,15,16 and the inhibition of acetylcholinesterase and butyrylcholinesterase (the enzymes responsible for degradation of ACh in the synaptic cleft).17 Trials using cholinergic agonists and ACh precursors have been relatively disappointing, and thus far no compound of either class has reached Phase III of clinical development. However, cholinesterase inhibitors (ChEIs) have consistently produced significant beneficial effects in patients with mild-to-moderate Alzheimer’s disease and were the first class of compounds to earn an approval by the United States Food and Drug Administration for the treatment of Alzheimer’s disease.
Double-blind, placebo-controlled studies with ChEIs have demonstrated modest benefits on cognitive, global, functional, and behavioral outcomes relative to placebo in patients with Alzheimer’s disease.17 Open-label extension trials suggest that the beneficial effects of ChEIs persist for up to 5 years of treatment,18-22 although no study has definitely demonstrated that ChEIs can modify or slow disease progression over long periods of time. The three currently prescribed ChEIs, donepezil, rivastigmine, and galantamine, have demonstrated comparable efficacy in clinical trials.
Donepezil
Donepezil is a highly selective ChEI with a relatively long half-life (70 hours), allowing for once-daily dosing of either 5 mg or 10 mg.23 A meta-analysis of 15 donepezil trials covering the entire severity spectrum of the disease showed that both 5-mg and 10-mg doses produce a significant improvement over placebo on measures of cognition, global state, activities of daily living, and behavior, but not on the quality-of-life score.24 The difference in efficacy between the two dosing regimens was not shown to be statistically significant, but there was a trend favoring the 10-mg/day regimen. Compared to the placebo group, significantly more patient withdrawals occurred in the group treated with 10 mg/day, but not with 5 mg/day.24 Significantly more adverse events were associated with donepezil treatment compared to placebo. The most prevalent adverse events were nausea, vomiting, diarrhea, muscle cramps, dizziness, fatigue, and anorexia in the 10 mg/day group, and anorexia, diarrhea, and muscle cramps in the 5 mg/day group.24 Another meta-analysis of donepezil trials in Alzheimer’s disease and vascular dementia reached similar conclusions.25 The most recent trials of donepezil have been performed in patients with severe Alzheimer’s disease, and a recent approval by the FDA extended the indication of donepezil to include the entire range of Alzheimer’s disease severity.26-28
Rivastigmine
Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase and has a very short half-life (1–2 hours in plasma and cerebrospinal fluid [CSF]),29,30 requiring twice-daily dosing.31 (Half-life at the synapse is 9 hours, due to a covalent mechanism of enzyme inhibition.29) Due to gastrointestinal side effects, rivastigmine requires slow dose escalation and should be taken with meals.31 A summary analysis of seven trials revealed that both therapeutic-dose (6–12 mg/day) and low-dose (1–4 mg/day) rivastigmine treatments were associated with better cognitive and global outcomes than placebo, whereas the effect on the severity of dementia and the activities of daily living was statistically significant for 6–12 mg dosages only.32 Compared to the placebo group, patients treated with 6–12 mg/day rivastigmine experienced significantly more adverse events of nausea, vomiting, diarrhea, anorexia, headache, syncope, abdominal pain, and dizziness. Adverse events were less common with lower doses of the drug.32 Similar assessments of efficacy and safety of rivastigmine were reported in other meta-analyses as well.33,34 Recently, a 24-week placebo-controlled study of a rivastigmine patch, the first transdermal treatment for Alzheimer’s disease, found significant benefits over placebo for cognitive, global, and functional measures, with similar efficacy but fewer gastrointestinal side effects compared to the capsules.35
Galantamine
Galantamine acts not only as an acetylcholinesterase inhibitor but also as a modulator of presynaptic nicotinic ACh receptors.36 It has a short half-life (5–7 hours), requiring twice-daily dosing.37 A meta-analysis of eight galantamine trials revealed a statistically significant benefit over placebo on cognition at all doses (8–32 mg/day), and on global status at all doses except 8 mg/day.38 Significant treatment benefits on the activities of daily living and behavior were shown in some individual trials.38 Similar to donepezil and rivastigmine, the most prominent adverse events associated with galantamine treatment were mainly gastrointestinal, and included nausea, vomiting, diarrhea, and anorexia.37,38
Additional ChEIs are in various stages of evaluation. A Phase III trial of phenserine was curtailed in 2005 due to a lack of clinical efficacy; bisnorcymserine is in an early development stage; and a Phase II trial of huperzine A, a ChEI derived from the Chinese herb Huperzia serrata, is underway, with an expected completion date of late 2007.39,40
Glutamatergic System
Glutamate is the most abundant excitatory neurotransmitter in the vertebrate central nervous system.41 Its effects, mediated through ionotropic and metabotropic receptors, include long-lasting neuronal changes that are believed to be a molecular foundation for learning and memory.42,43 However, excessive activation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, as seen under pathologic conditions such as stroke or neurodegenerative disease, can result in cell death through a process termed “excitotoxicity.”44,45
A growing body of evidence suggests that the pathology of Alzheimer’s disease includes an excitotoxic component. Glutamatergic pathways in the hippocampus and related regions undergo selective neurodegeneration in Alzheimer’s disease,46-48 and this loss has been correlated to declines in memory and cognition.44,49 Furthermore, such degeneration occurs early in Alzheimer’s disease, in brain regions corresponding to the distribution of amyloid plaques and neurofibrillary tangles, the major neuropathologic hallmarks of Alzheimer’s disease.47,50,51 Glutamate toxicity is augmented by Aβ peptides,52,53 and NMDA receptor activation enhances the production of the pathologic forms of both Aβ and phosphorylated tau protein, a major component of tangles.54-57 For these reasons, the glutamatergic system is a logical target for Alzheimer’s disease therapy, not only for cognitive enhancement, but also for protection from neurodegenerative processes. However, similar to ChEIs, glutamatergic agents have not yet been shown to modify or slow disease progression in humans.
Memantine
Memantine is a moderate-affinity, uncompetitive NMDA receptor antagonist that is believed to modulate excitotoxic activation of the NMDA receptor while allowing physiologic receptor activity to occur.58-60 It is the first available non-cholinergic Alzheimer’s disease therapy, approved for the treatment of moderate-to-severe Alzheimer’s disease in the US and Europe. A relatively long half-life (70 hours) of memantine in plasma theoretically allows for once-daily dosing, although twice-daily dosing (10 mg twice-daily) is recommended by the manufacturer.61
An analysis of three pooled trials in moderate-to-severe Alzheimer’s disease62-64 showed benefits of memantine treatment over placebo on measures of cognition, global status, activities of daily living, and behavior, and pooled data of three trials in mild-to-moderate Alzheimer’s disease showed statistically significant benefits on global status and cognition.65 Memantine is well tolerated, with a safety profile similar to that of placebo. In addition, post-hoc analyses show that memantine-treated patients are less likely to experience agitation compared to their placebo-treated counterparts, although these findings need to be confirmed in prospective trials.65-67
It is worth noting that a key memantine trial in patients with moderate-to-severe Alzheimer’s disease involved patients concurrently taking stable doses of donepezil. Patients receiving memantine and donepezil showed significant improvement on all efficacy measures over patients receiving donepezil alone, with no additional adverse consequences on safety and tolerability.63 Results of this trial suggest that memantine-donepezil combination therapy may confer larger clinical benefits than the administration of each drug type individually, which is consistent with the distinct mechanisms of action for the two drugs. Preliminary open-label trials of memantine in combination with other ChEIs also support this view.68-71
Neramexane
The pharmacologic properties of neramexane are similar to those of memantine,72 and a Phase III trial involving patients with moderate-to-severe Alzheimer’s disease was completed in 2004.73 According to the manufacturer’s press release,74 there were no significant differences in the safety or tolerability of neramexane compared to placebo, and patients in the neramexane group demonstrated significant improvement in performing activities of daily living compared to their placebo-treated counterparts. A significant improvement in cognition was seen at an intermediary time point, but not at endpoint. The details of this trial have not yet been reported.
In addition to NMDA-type receptors, another group of ionotropic glutamate receptors (AMPA) has been a target for anti-Alzheimer’s disease drug development.75 CX516 is a drug that enhances the activity of AMPA receptors,76 which may help compensate for a general loss of glutamatergic signaling as the disease progresses. CX516 has also been shown to increase the expression of brain-derived neurotrophic factor, which promotes neuronal survival.75 A Phase II trial was completed in November 2005, but results from the trial have not yet been made public.77
Other Neurotransmitter Systems
Receptors for both serotonin (5-HT) and γ-aminobutyric acid (GABA) have also been recognized as targets for anti-Alzheimer’s disease therapeutics. Lecozotan sustained release (SRA-333), an antagonist of 5-HT1A receptors that has been shown to increase the release of glutamate and acetylcholine in the hippocampus,78 is currently being tested in a Phase III trial involving patients suffering from mild-to-moderate Alzheimer’s disease.79 Xaliproden (SR57746A), another serotonergic agent in Phase III of clinical development,80,81 is a 5-HT1A receptor agonist that, in addition, mimics and enhances the effects of the nerve growth factor.82 AC-3933, a partial inverse agonist that acts at the benzodiazepine site of the GABAA receptor,83 is believed to enhance cholinergic function by decreasing inhibitory GABAergic input. Its safety and efficacy in patients with mild-to-moderate Alzheimer’s disease are being assessed in a Phase II trial.84
Targeting β-Amyloid Metabolism
The observed accumulation of extracellular plaques containing Aβ peptides, a defining hallmark of Alzheimer’s disease pathology,85,86 helped to establish the amyloid hypothesis of Alzheimer’s disease. This hypothesis purports that abnormal production or accumulation of Aβ in brain regions associated with memory and cognition leads to a cascade of neurotoxic events, culminating in neurodegeneration and the development of Alzheimer’s disease.87 Aβ is a proteolytic product of amyloid precursor protein (APP), a type-I membrane protein important for embryo development and cell differentiation.88 APP is cleaved by secretases β and γ to generate Aβ peptides that are 40–42 amino acid residues in length. The longer amyloid peptide, Aβ1-42, aggregates quickly and appears to play a critical role in the initial accumulation of plaques,89-91 whereas Aβ1-40 seems to inhibit amyloid deposition in vivo.92 Therefore, Aβ1-42/Aβ1-40 ratio may prove to be a critical parameter in the pathogenesis of Alzheimer’s disease.93,94 Mounting evidence indicates that modulating the production or clearance of Aβ may provide clinical benefit for patients with Alzheimer’s disease. For this reason, some current therapeutic strategies aim to inhibit APP processing into Aβ, decrease Aβ aggregation, or enhance Aβ clearance from the brain.
Secretase Inhibitors
Cleavage of APP by β-secretase, the rate-limiting step in the production of Aβ peptides,95 produces a fragment that is subsequently cleaved by γ-secretase to release Aβ. β-site APP-cleaving enzyme 1 (BACE-1) is considered the primary enzyme responsible for cleaving APP at the β-site, and reducing BACE-1 expression using antisense oligonucleotides results in decreased Aβ production.96,97 The subsequent enzyme, γ-secretase, which cleaves on the C-terminal side of Aβ, is composed of at least four different membrane proteins (presenilin, nicastrin, APh-1, and Pen-2).98 Human presenilin gene mutations, rodent presenilin gene knock-out models, and the use of γ-secretase inhibitors have all been associated with decreased Aβ production.99-102
Although inhibiting the production of Aβ peptides in theory provides for a relatively short list of drug targets, the development of drugs that inhibit the activity of β- or γ-secretase has been complicated by several issues. First, the enzyme BACE-2, which is homologous to BACE-1,103-105 effectively limits the production of Aβ by cleaving elsewhere within the Aβ domain.106,107 Because of this, drugs that target β-secretase would need to distinguish between BACE-1 and BACE-2 in order to optimize the inhibition of Aβ production. Second, while γ-secretase inhibitors are effective in inhibiting the production of Aβ in cells overexpressing APP, they also affect cleavage of Notch, a protein crucial for cell differentiation.108 Effective inhibitors of γ-secretase must be selective for APP processing without affecting other proteolytic functions of the enzyme. R-flurbiprofen (MPC-7869), a drug currently in the Phase III stage of development (Act-Earli-Alzheimer’s disease trial),109 modulates (rather than inhibits) γ-secretase activity and results in a reduction of Aβ42 levels without interfering with Notch processing.110,111 Results from a recently completed Phase II trial suggest that flurbiprofen may produce significant effects on global condition and activities of daily living in patients with mild, but not moderate, stages of Alzheimer’s disease.112
Anti-Aggregation Agents
Single Aβ peptides (particularly Aβ1-42 in the early stages of Alzheimer’s disease) have a propensity to aggregate into oligomers, polymers, and then fibrils, ultimately condensing into the amyloid deposits found in plaques. Aggregated forms of Aβ have been shown to induce neuronal apoptosis,113-115 interfere with synaptic function,116 and trigger microglia- and astrocyte-mediated inflammatory processes that lead to neurotoxic cascades.117 Recent data suggest that the soluble Aβ oligomers may be the primary pathogenic amyloid structure,118-121 and that specific impairment of memory may be caused by nonamer and dodecamer aggregates.121,122 Anti-aggregation compounds currently in development include small peptide- and non-peptide molecules that target various phases of amyloid aggregation and plaque formation.123,124
Tramiprosate (3APS, NC-531), an amyloid fibrillogenesis inhibitor in late-stage clinical development for Alzheimer’s disease,125,126 is a small, sulfonated molecule that binds to soluble Aβ peptides and interferes with Aβ glycosaminoglycan interactions.125 It has been shown to prevent Aβ polymerization in vitro and plaque deposition in animals.123 A double-blind, placebo-controlled Phase II study in patients with mild-to-moderate Alzheimer’s disease demonstrated tolerability, safety, and brain penetration of the drug,127 while the open-label extension trial suggested efficacy on cognitive and global measures, particularly in individuals with mild disease.128 A large north-American Phase III trial of tramiprosate in mild-to-moderate Alzheimer’s disease has been completed recently,126 and an additional Phase III study of tramiprosate as an add-on therapy to ChEIs is underway in Europe.125
Metal Chelators
Metal ions such as zinc (Zn2+) and copper (Cu2+), which are elevated in the neocortex and concentrated in amyloid plaques,129,130 potentiate Aβ formation and aggregation.131-135 This process can be reversed using metal chelators, organic compounds that make soluble complexes with metal ions. The Zn2+/Cu2+ chelator iodochlorhydroxyquin (clioquinol, PBT-1) has been shown to solubilize plaques in post mortem brain tissue of patients with Alzheimer’s disease,136 and to inhibit and possibly reverse Aβ accumulation in a transgenic mouse model of Alzheimer’s disease.137 Evidence from a Phase II trial in patients with moderately severe Alzheimer’s disease suggests that clioquinol slows the rate of cognitive decline.138 However, the development of this compound was discontinued in 2005 due to the presence of a toxic contaminant produced during the manufacturing process. Other metal chelators are currently being investigated and are in early stages of development.
Vaccines
AN-1792, the immunogenic compound in an Alzheimer’s disease vaccine under development, is a synthetic form of Aβ1-42. In theory, administration of AN-1792 leads to the creation of amyloid-specific antibodies, which may help clear amyloid deposits from the brain. Preclinical data demonstrated that AN-1792 not only accelerated the removal of amyloid plaques, but prevented their deposition in transgenic models of brain amyloidosis.139 Phase I studies of AN-1792 in humans indicated that the vaccine was well tolerated, and a portion of the patients developed amyloid antibodies. As a result of these findings, a multicenter Phase IIa study in patients with mild-to-moderate Alzheimer’s disease was initiated. This trial was suspended, however, when four patients developed meningoencephalitis after receiving multiple doses of AN-1792, and terminated when meningoencephalitis was diagnosed in 11 additional patients. Most of these patients have since recovered,140,141 and a follow-up report from one of the study sites (n=30) indicated that most of the patients vaccinated (20 of 24) produced antibodies specific to amyloid deposits that did not cross-react with soluble Aβ or other APP fragments.142 Furthermore, patients from this study site who generated antibodies showed significantly slower rates of cognitive decline compared to those who did not.143 This result was not validated by the final assessment of all patients from the study, however, as no significant differences were found between antibody responders (n=59) and placebo-treated patients (n=72) on individual cognitive tests.144
Although the initial immunotherapy trial was halted, the theory driving the strategy persists. Passive immunization, or the direct administration of antibodies to patients (rather than the administration of antigens to produce an immune response), can introduce immunity without eliciting inflammatory T-cell responses. Researchers have shown that in animal models passive immunization using antibodies to Aβ4-10, a truncated form of Aβ, produces similar effects to AN-1792 antibodies without eliciting inflammation.145 Antibody therapies using truncated forms of AN-1792 are in early stages of development, and are hoped to provide safe immunization while effectively reducing Alzheimer’s disease plaque levels. Whether such passive immunizations (or active immunizations using AN-1792 fragments) would be preventive or merely reduce disease progression remains to be determined.146
Another immunotherapy currently under investigation for the treatment of Alzheimer’s disease, intravenous immunoglobulin (IVIg), is an FDA-approved treatment for immunodeficiency disorders. IVIg, isolated from the plasma of healthy human donors, contains natural antibodies against a variety of antigens, including Aβ peptides.147,148 Initial results suggest that IVIg infusion may have long-term benefits for the treatment of cognitive decline in Alzheimer’s disease.149 A Phase II study is currently underway.150
Targeting the Tau Protein
The severity of cognitive impairment in Alzheimer’s disease is more closely correlated with the density of hippocampal neurofibrillary tangles (NFTs) than with Aβ plaque deposition.151,152 NFTs consist primarily of a hyperphosphorylated form of tau, a protein normally involved in the stabilization of microtubules in the neuronal cytoskeleton.153 Hyperphosphorylated tau is resistant to cellular degradation, readily polymerizes into filamentous structures, and causes depolymerization of microtubules, thereby inhibiting axonal transport and disrupting neuronal function.153,154 It has been hypothesized that the pathways leading to tau hyperphosphorylation could provide a suitable target for the development of anti-Alzheimer’s disease medication.155,156 In addition, a recent study demonstrated that brief exposures to soluble Aβ peptides can cause a rapid, tau-dependent disassembly of microtubules in cultured neuronal cells, suggesting the existence of links between amyloid and tau that do not involve Alzheimer’s disease-specific tau hyperphosphorylation.157
To date, the only compound targeting tau hyperphosphorylation that has reached a Phase III trial158 is the mood stabilizer sodium valproate, which inhibits a kinase likely involved in the abnormal phosphorylation of tau in Alzheimer’s disease, glycogen synthase kinase 3β.159-162 Valproate is being investigated for its effect on agitation, psychotic symptoms, and the progression of cognitive and functional symptoms in patients with mild-to-moderate Alzheimer’s disease (valproate in dementia study).158 Memantine treatment has also been shown to decrease levels of hyperphosphorylated tau in the CSF of patients with Alzheimer’s disease,163 suggesting a possible mechanistic link between memantine and tau.
Miscellaneous Therapeutic Agents
Rosiglitazone, a thiazolidinedione currently approved for the treatment of type-2 diabetes, acts as an agonist of the nucleus-located peroxisome proliferator-activated receptor γ (PPAR-γ).164 Rosiglitazone has been shown to reduce blood glucose levels,165 increase insulin sensitivity,166,167 improve the function of pancreatic β-cells,166 and have an anti-inflammatory effect.168 The rationale for using rosiglitazone as an anti-Alzheimer’s disease drug includes observations that diabetes and insulin resistance are risk factors for Alzheimer’s disease,169,170 that patients with Alzheimer’s disease have reduced glucose utilization and insulin clearance,170,171 and that hyperinsulinemia and impaired insulin signaling have been linked to tau hyperphosphorylation, Aβ production, neuroinflammation, and altered acetylcholine homeostasis.170-174 A Phase III clinical trial of rosiglitazone in patients with mild-to-moderate Alzheimer’s disease showed no significant difference between the drug and placebo groups on measures of cognition and global function, but post-hoc analyses suggested that there was a cognitive improvement in patients who did not carry an ε4 allele for apolipoprotein E (APOE ε4),175 an important genetic risk factor for late-onset Alzheimer’s disease.176 It is currently speculated that insulin resistance may be an important Alzheimer’s disease risk factor and catalyst of neuropathology in the subset of patients who do not carry the APOE ε4 gene.177 Based on these findings, three Phase III trials have been initiated (REFLECT-1 in 2007, and REFLECT-2 and REFLECT-3 in 2006),178-180 aimed at determining whether rosiglitazone confers cognitive benefits on patients with mild-to-moderate Alzheimer’s disease, either as monotherapy (REFLECT-1)180 or in combination with donepezil (REFLECT-2 and REFLECT-3).178,179 In all three trials, the genetic make-up of the participants will be taken into consideration.
Another method proposed for overcoming impaired insulin signaling and glucose metabolism in Alzheimer’s disease involves increasing the availability of ketone bodies, particularly acetoacetate and 3-hydroxybutyrate.181 Ketone bodies are a crisis energy supply created during fatty-acid breakdown under conditions of low glucose availability, such as starvation or diabetes.182 In the brain, they can be converted into molecules of acetyl–CoA that directly enter the Krebs cycle, largely circumventing the glycolysis pathway and, therefore, the direct need for glucose.182 Acetyl-CoA is also a key component of both acetylcholine and cholesterol biosynthesis, providing a potential link to cholinergic deficits, cholesterol homeostasis, and ApoE as well. AC-1202 is a compound that is metabolized into 3-hydroxybutyrate in the liver. Similar to rosiglitazone, a recent Phase IIb trial in patients with mild-to-moderate Alzheimer’s disease showed no overall advantage for AC-1202-treated patients after 90 days; however, in patients who lacked the APOE ε4 allele, treatment was associated with a significant cognitive (but not global) improvement compared to placebo.183,184 Phase III trials are expected to begin in 2008.
Dimebolin (dimebon, dimebone) is approved in Russia as an antihistamine, but its effects are multifarious: it also blocks calcium channels (including the NMDA receptor), inhibits cholinesterase, and prevents the opening of mitochondrial pores under pathologic conditions.185,186 Dimebolin has been shown to protect cultured neuronal cells against amyloid-mediated cell death, protect mice against NMDA-mediated neurotoxicity, and enhance cognition in rats treated with a neurotoxin.185 A Phase II trial of dimebolin recently completed in Russia demonstrated that the drug was significantly superior to placebo on measures of cognition, global impression, activities of daily living, and behavior, with an excellent safety and tolerability profile.187 Phase III studies are expected to begin in 2008.
Nerve growth factor (NGF) enhances neuronal survival and has the potential to counteract the degeneration of cholinergic neurons.188,189 In a Phase I gene therapy trial, eight patients with mild Alzheimer’s disease were subjected to forebrain implantation of autologous fibroblasts genetically modified to express human NGF.190 After 22 months, patients demonstrated a slower mean rate of cognitive decline compared to the rate of decline prior to treatment, and brain autopsy from one participant suggested a robust growth of cholinergic neurons.190 Another Phase I study of NGF gene therapy in six patients with mild-to-moderate Alzheimer’s disease utilized injections of a viral vector carrying the gene for human NGF.191 Preliminary results from this trial suggest similar results.192
Preventive Strategies
Pathologic changes observed in Alzheimer’s disease are believed to commence more than 10 years prior to the appearance of clinical symptoms.151,193-196 Therefore, much research has focused on compounds with a neuroprotective potential, ie, those that might delay or prevent the onset of Alzheimer’s disease (Table 2). Among these, antioxidants, anti-inflammatory agents, statins, and estrogens are the most thoroughly studied. Polyphenols from food sources and extracts made from the leaves of the tree Ginkgo biloba are also the subject of much recent attention in the Alzheimer’s disease field.
Antioxidants
Free radicals are common metabolic products of oxygen-consuming cells,197,198 which in excess can cause oxidative stress that leads to cellular damage. There is considerable evidence of oxidative stress in Alzheimer’s disease pathogenesis, possibly occurring prior to the appearance of symptoms and the formation of neuropathologic hallmarks.198-205 Data suggest that oxidative processes are involved in Αβ aggregation,206 microglial stimulation,207 deoxyribonucleic acid damage,208 and protein and lipid peroxidation.209,210 Additionally, recent research has shown that H2O2-induced oxidative stress can upregulate BACE-1 transcription.211 Markers of oxidative injury have been found in postmortem brains of patients who suffered from Alzheimer’s disease,212 and increased levels of free radical-catalyzed peroxidation products have been detected in the CSF of patients with Alzheimer’s disease.212,213 Antioxidants such as vitamin E, vitamin C, β-carotene, α-lipoic acid, coenzyme Q, selenium and others can potentially protect cells from free radical damage. Therefore, the prophylactic use of antioxidants has been hypothesized as a means to thwart either the onset of Alzheimer’s disease symptoms or the progression of the disease.
While some epidemiologic studies indicate that regular use of vitamins E and C can reduce the risk of Alzheimer’s disease,214,215 prospective studies of dietary and supplemental antioxidant vitamins in the prevention of Alzheimer’s disease have produced conflicting results.169 In addition, a meta-analysis encompassing 135,967 participants in 19 clinical trials revealed that high-dosage (≥400 IU/day) vitamin E may increase all-cause mortality, and should be avoided.216 Another prospective study suggested that vitamin E from food, but not from dietary supplements, may be associated with a reduced risk of Alzheimer’s disease in individuals lacking the APOE ε4 allele.217 A large Phase III trial (PREADVISE) is currently underway, with an aim of examining the role of vitamin E and selenium (a co-factor of selenium-dependent glutathione peroxidases, a family of enzymes that neutralize some free radicals) in the prevention of Alzheimer’s disease. The study is expected to enroll a total of 10,400 patients, and to be completed in 2013.218
Anti-Inflammatory Drugs
Numerous studies of amyloid plaques and NFTs have demonstrated the presence of inflammatory markers, including activated microglia, proteins involved in the acute-phase response, and components of the complement cascade.219-221 The inflammatory response can damage neurons and may contribute to the gradual loss of synaptic function in the hippocampus and cortex in Alzheimer’s disease.219,222,223 A large body of epidemiologic evidence has demonstrated an inverse correlation between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and Alzheimer’s disease incidence.224-227 However, this effect was observed only in patients taking NSAIDs for >2 years during the latent period of the disease, prior to the emergence of cognitive symptoms.224,225,227 A large-scale preventive Phase III trial (ADAPT) was initiated, enrolling approximately 2,500 participants randomized to receive naproxen, celecoxib, or placebo for up to 3 years, but the trial was suspended in December 2005 due to safety concerns in a related trial.228
While NSAIDs may demonstrate a protective effect in lowering the risk of developing Alzheimer’s disease, a recent epidemiologic meta-analysis indicates that the appropriate dosage, duration of use, and risk-benefit ratios are yet to be determined.229
NSAIDs have also been investigated in therapeutic trials, and an early trial of indomethacin 100–150 mg/day in patients with mild-to-moderate Alzheimer’s disease showed modest benefit over placebo in a battery of cognitive tests.230 However, subsequent trials with celecoxib, rofecoxib, nimesulide, diclofenac, and naproxen have failed to demonstrate significant benefit in patients with mild-to-moderate Alzheimer’s disease.231-235
Statins
The APOE ε4 gene, a major risk factor for late-onset Alzheimer’s disease, encodes for the E4 isoform of apolipoprotein E, a molecule involved in cholesterol transport.176 Preclinical studies have linked altered cholesterol metabolism to several aspects of Alzheimer’s disease, including hyperphosphorylation of the tau protein and the production or aggregation of Aβ.236-239 A large epidemiologic study involving >1,000 elderly participants showed an association between increasing levels of cholesterol and the risk of Alzheimer’s disease in individuals who do not carry the APO ε4 allele.240
Other epidemiologic studies and pilot trials suggest that hypercholesterolemia may be associated with an increased risk of Alzheimer’s disease,240,241 and that the use of HMG-CoA reductase inhibitors, or statins, to lower serum cholesterol levels may reduce the risk of Alzheimer’s disease and stabilize cognitive performance in mildly impaired patients with Alzheimer’s disease.239,242-244 The mechanism by which statins may prevent Alzheimer’s disease is unclear since little is known about their effects in the brain; however, current hypotheses include the sensitivity of γ-secretase to lipid cholesterol content, decreased availability of bioactive isoprenoid precursors of cholesterol (and, consequently, reduced isoprenylation of several intracellular signaling proteins), and altered inflammation or microglial activation in response to statin treatment.245-247 A novel hypothesis suggests that angiogenesis is involved in the mechanism of Alzheimer’s disease, and that statins, NSAIDs, histamine H2-receptor blockers, and calcium channel blockers may prevent Alzheimer’s disease through anti-angiogenic mechanisms.248
Despite the potential for statins to inhibit Alzheimer’s disease pathogenesis through a variety of mechanisms, a case-control study of lipid-lowering agents and dementia revealed a reduced risk of Alzheimer’s disease only in individuals <80 years of age.249 Further, a recent prospective, randomized, dose-finding, 36-week trial of statins in patients with hypercholesterolemia failed to show a reduction in Aβ levels.250 A Phase III trial of simvastatin (CLASP),251 designed to investigate the safety and efficacy of this compound in slowing the progression of disease in patients with mild-to-moderate Alzheimer’s disease, was completed in December of 2005, but the results have not yet been reported. A Phase III trial designed to assess efficacy and safety of atorvastatin as an adjunctive therapy to ChEIs is currently being conducted.252
Omega-3 Unsaturated Fatty Acids
Several epidemiologic studies have suggested that dietary intake of omega-3 unsaturated fatty acids (usually found in fish) is associated with a lower risk of developing Alzheimer’s disease.253-255 However, a recent Phase III trial conducted in Sweden (OmegAD) failed to show that daily consumption of docosahexaenoic and eicosapentaenoic acid for 6 months delays cognitive decline in patients with mild-to-moderate Alzheimer’s disease, compared to patients taking placebo.256 A significant positive effect was observed only in a subgroup of patients with very mild Alzheimer’s disease.256 These findings suggest that the intake of ω-3 unsaturated fatty acids may be effective as a prevention strategy, but has little influence on progression of the disease.
Polyphenolic Compounds
Polyphenols are a broad class of naturally occurring and potent antioxidants found in fruits, vegetables, and other plants. A growing body of evidence suggests that dietary sources of polyphenols, such as red wine,257 fruit and vegetable juices,258 green tea,259 coffee,260,261 and curry262,263 may provide protective or therapeutic effects against a variety of diseases, including Alzheimer’s disease.264 A decreased prevalence of Alzheimer’s disease has been correlated with regular consumption of fruit juices258 and red wine,261,265 which contain polyphenols such as quercetin, catechin, and resveratrol. Resveratrol has also been shown to decrease inflammation, protect against apoptotic cell death, and diminish levels of secreted and intracellular Aβ peptides in cultured cells.264,266,267 The consumption of curcumin, a polyphenol found in curry, has been proposed to be partially responsible for the observation that incidence rates of Alzheimer’s disease in India are among the lowest in the world.268-270 In addition to possessing anti-inflammatory and antioxidant activities, curcumin has been shown to inhibit Aβ fibril formation, reduce levels of soluble and insoluble Aβ peptides, and decrease the amyloid plaque burden in animal models of Alzheimer’s disease.264,268 A Phase II study of curcumin in patients with mild-to-moderate Alzheimer’s disease is currently underway.271
Ginkgo Biloba
The standardized Ginkgo biloba extract, EGb 761, has been reported to produce biological effects ranging from vasodilation and antioxidant activity to modification of neurotransmitter systems and neuroprotection.272,273 Preclinical data indicate that EGb 761 inhibits the aggregation of Aβ fibrils, suggesting that ginkgo may offer neuroprotective effects.274 However, the purported cognition-enhancing effect of this substance in either cognitively intact adults or those with dementia remains controversial. While some studies in patients with mild-to-severe Alzheimer’s disease suggest that EGb 761 120 mg/day may confer modest cognitive benefits,275-277 another study in mild-to-moderate Alzheimer’s disease showed no effect of ginkgo (either 160 mg/day or 240 mg/day) compared to placebo on any outcome measure.278 In some studies EGb 761 has demonstrated comparable efficacy to donepezil, rivastigmine, and metrifonate,273,279 but cognitive benefits associated with ginkgo may vary according to the daily dose.280
In a recent 22-week, double-blind, placebo-controlled trial involving patients with mild-to-moderate Alzheimer’s disease or vascular dementia with neuropsychiatric symptoms, the group treated with EGb 761 performed significantly better than the placebo-treated group on measures of cognition, behavior, activities of daily living, and depression.281 Collectively, the evidence from preclinical and clinical findings suggests that a more thorough evaluation of the efficacy of ginkgo in the prevention and stabilization of Alzheimer’s disease symptoms is warranted.282 Two large, preventive Phase III trials (with a duration of 5 and 8 years)283,284 are currently being conducted to determine whether 240 mg/day ginkgo extract can reduce the incidence of Alzheimer’s disease. The 8-year trial will also assess whether ginkgo treatment can slow cognitive decline and functional disability, reduce the incidence of cardiovascular disease, or decrease total mortality.283
Hormone Therapy
A protective role of estrogen in the prevention of Alzheimer’s disease has been suggested by numerous epidemiologic studies, including a recent report demonstrating that long-term estrogen replacement therapy (ERT) in postmenopausal women is associated with a reduction in the risk of developing Alzheimer’s disease.285 However, results from larger clinical trials determined that neither short-term nor long-term ERT improved global, cognitive, or functional outcomes in women with mild-to-moderate Alzheimer’s disease.286,287 Additionally, hormone replacement therapy (estrogen and progesterone) in patients with Alzheimer’s disease who were treated with ChEIs showed no added benefits in patients taking rivastigmine288 (although greater efficacy on functional measures has been reported in patients taking tacrine289). As HRT has been shown to increase the risk of ischemic stroke,290 stimulate breast cancer growth,291 and create a slightly increased risk for probable dementia and cognitive decline in healthy postmenopausal women,292,293 clinical testing of HRT as an adjunctive therapy for Alzheimer’s disease prevention in postmenopausal women has been discontinued. However, a Phase II/III study is under way, designed to assess the effectiveness of transdermal HRT in improving memory and the ability to live independently in postmenopausal women with Alzheimer’s disease and other dementias.294
Another hormonal system under investigation as a target for anti-Alzheimer’s disease therapy is the hypothalamic-pituitary-gonadal axis. Receptors for luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), and activins are present in neuronal cells, and the dysregulation of this system following menopause and andropause might promote changes in both the structure and function of neurons.295 Experimental and epidemiologic evidence has revealed that the levels of LH are elevated in both the serum and pyramidal neurons of patients with Alzheimer’s disease, and that the use of GnRH agonists, such as leuprolide (VP4896), in prostate cancer patients is associated with a reduction in neurodegenerative processes.295 In addition, leuprolide was shown to enhance cognitive performance and decrease amyloid deposition in a mouse model for Alzheimer’s disease.296 A Phase II trial involving women with mild-to-moderate Alzheimer’s disease already receiving stable ChEI treatment (ALADDIN I) showed an advantage of leuprolide (22.5-mg injection every 12 weeks) over placebo on measures of cognition and global status.297 In October 2006, a Phase III ALADDIN trial, designed to investigate the potential of leuprolide to stabilize cognitive function in men and women with Alzheimer’s disease, was suspended due to financial reasons.298,299
Alternative Hypotheses of Neurodegeneration
Most traditional hypotheses of Alzheimer’s disease etiology center on amyloid, tau, the cholinergic system, or glutamatergic dysfunction and excitotoxicity. However, alternative hypotheses have also been garnering recent attention. First, the cell cycle hypothesis suggests that neurodegeneration occurs when post-mitotic neurons are stimulated to re-enter the mitotic pathway.300,301 Second, according to the “two-hit” hypothesis, the combination of both mitotic signals and changes due to oxidative stress is necessary and sufficient to cause Alzheimer’s disease.302,303 Last, the axonal transport hypothesis purports that neurodegeneration may be the result of deficits in axonal transport, a phenomenon that may precede aberrant amyloid processing.304,305 Theories involving oxidative stress, mitochondrial dysfunction, altered glucose metabolism and insulin resistance, and cholesterol homeostasis have also been gaining renewed interest.171,174,177,247,306-310 In addition, the conventional wisdom regarding the role of Aβ and hyperphosphorylated tau in Alzheimer’s disease also has been challenged, suggesting that both may actually play a role in cellular self-protection against the oxidative damage.311-313 As basic research begins to turn away from the more traditional paradigms of neurodegeneration in Alzheimer’s disease, a vast array of other potential therapeutic possibilities will likely emerge.
Conclusion
The ultimate goal for Alzheimer’s disease pharmacotherapy is not merely to ameliorate symptoms, but to alter the onset or progression of the disease. There are four drugs (donepezil, galantamine, rivastigmine, and memantine) currently approved for the treatment of Alzheimer’s disease, but the numerous complex and interrelated biochemical pathways underlying neurodegeneration in Alzheimer’s disease provide numerous potential targets for therapeutic intervention. Several investigational compounds have demonstrated potential as therapeutic or preventive therapies and merit additional study. Gradual elucidation of the exact mechanisms of neurodegeneration will result in increasingly focused drug development efforts.
Additional information about the clinical trials mentioned in this article can be found at www.clinicaltrials.gov.314 PP
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