Investigational Medications for Treatment of Patients With Alzheimer Disease

Pamela E. Potter

Abstract

Development of effective treatments for patients with Alzheimer disease has been challenging. Currently approved treatments include acetylcholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine hydrochloride. To investigate treatments in development for patients with Alzheimer disease, the author conducted a review of the literature. New approaches for treatment or prevention focus on several general areas, including cholinergic receptor agonists, drugs to decrease β-amyloid and tau levels, antiinflammatory agents, drugs to increase nitric oxide and cyclic guanosine monophosphate levels, and substances to reduce cell death or promote cellular regeneration. The author focuses on medications currently in clinical trials. Cholinergic agents include orthostatic and allosteric muscarinic M1 agonists and nicotinic receptor agonists. Investigational agents that target β-amyloid include vaccines, antibodies, and inhibitors of β-amyloid production. Anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs, the natural product curcumin, and the tumor necrosis factor α inhibitor etanercept, have also been studied. Some drugs currently approved for other uses may also show promise for treatment of patients with Alzheimer disease. Results of clinical trials with many of these investigational drugs have been disappointing, perhaps because of their use with patients in advanced stages of Alzheimer disease. Effective treatment may need to begin earlier—before neurodegeneration becomes severe enough for symptoms to appear.

Although more than 30 years have passed since the discovery of neurochemical alterations in individuals with Alzheimer disease, development of effective treatments remains challenging. Alzheimer disease is characterized by a progressive decrease in cognitive function and loss of short-term memory. Pathologic changes include accumulation of the neurotoxic peptide β-amyloid in plaques and of neurofibrillary tangles containing the protein tau, as well as massive cholinergic degeneration, which correlates closely with decline in cognitive function.^1-2 Thus, initial attempts to treat patients focused on augmenting cholinergic function,³ and the first successful treatments used acetylcholinesterase inhibitors.^4-6 In 2003, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine hydrochloride became available.^7-9 Although, in many cases, acetylcholinesterase inhibitors and memantine—alone or in combination—have produced improvements in symptoms and in tests of cognition, their effectiveness wanes as Alzheimer disease progresses.

A number of new medications are under investigation for treating patients with Alzheimer disease. The present review focuses on new approaches for Alzheimer disease treatment that are currently being tested in clinical trials or in animal studies. These investigational medications are categorized by therapeutic target or by mechanism of action. Among the drugs discussed are those that interact with cholinergic receptors, those that target β-amyloid, and those that are currently approved for other purposes (Figure).

Drugs That Stimulate Cholinergic Receptors

Muscarinic Agonists

The acetylcholinesterase inhibitors were developed in response to the observation that a severe loss of cholinergic pathways is a consistent finding in patients with Alzheimer disease. These agents are effective in many patients, particularly those in early stages of Alzheimer disease. However, because they rely on intact cholinergic nerve terminals, which continue to degenerate as the disease progresses, acetylcholinesterase inhibitors become less effective over time. In addition, acetylcholinesterase inhibitors are incapable of providing receptor selectivity—an inability that is problematic because research has shown that stimulation of M1 receptors, but not M2 receptors, is beneficial in decreasing levels of β-amyloid.^10-11

Direct-acting muscarinic agonists exert their effects postsynaptically, requiring no cholinergic terminals. Thus, these agonists should be effective much longer than acetylcholinesterase inhibitors. Muscarinic agonists may also slow the progression of Alzheimer disease by decreasing β-amyloid accumulation.

Figure.

Investigational medications for Alzheimer disease in clinical trials or animal studies. *The semagecestat clinical trials (ie, IDENTITY and IDENTITY-2) were stopped in August 2010 because cognitive function appeared to decline more rapidly in treated patients than in control groups. ⁸⁰

View Original | Slide (.ppt)

The M1 muscarinic receptor subtype represents an important therapeutic target, because it is abundant in the hippocampus and cerebral cortex, the brain regions where the cholinergic deficit is most pronounced in Alzheimer disease. This receptor subtype is involved in short-term memory.¹² Furthermore, stimulation of M1 muscarinic receptors decreases production of β-amyloid by activation of α-secretase.^13-15

The muscarinic agonist AF267B (NGX267; Torrey Pines Pharmaceutical Inc, Del Mar, California) decreased levels of β-amyloid and prevented its accumulation following lesion of cholinergic neurons in rabbits. It also decreased β-amyloid levels in a mouse model of Alzheimer disease.^16-18 Long-term treatment with the selective M1 agonists cevimeline hydrochloride (AF102B) and talsaclidine decreased β-amyloid levels in cerebral spinal fluid (CSF) of patients with Alzheimer disease.^13,19 Conversely, use of cholinergic antagonists in patients with Parkinson disease increased CSF levels of β-amyloid,²⁰ and M1 receptor knockout in amyloid precursor protein (APP)-transgenic mice also increased β-amyloid deposition.²¹ These results indicate that treatments that increase cholinergic function may slow progression of Alzheimer disease by decreasing β-amyloid accumulation.

The M1/M4 agonist xanomeline improved cognition and decreased behavioral disturbances in patients with Alzheimer disease, but adverse gastrointestinal effects limited its use.^22,23 Xanomeline is currently being tested for its usefulness in treating individuals with schizophrenia.²⁴ Unfortunately, stimulation of M4 receptors by xanomeline might mitigate the drug's beneficial effects on β-amyloid.¹¹ Nevertheless, a combination of xanomeline and tacrine hydrochloride (the first of the acetylcholinesterase inhibitors to be clincially used for Alzheimer disease) is now being tested.²⁵

The orthostatic agonist AF267B is more selective for M1 receptors than is xano-meline.^10,26 It was originally tested in patients with Alzheimer disease, but it caused excessive salivation. As a result, it has since gone through phase 1 and phase 2 clinical trials for treatment of patients with xerostomia.²⁷

▪ Allosteric M1 Agonists—Many G protein–coupled receptors contain allosteric binding sites that are separate from the orthostatic binding site for the neurotransmitter.²⁸ The orthostatic muscarinic binding site is highly conserved, making development of agonists with strong receptor selectivity difficult.^28,29 For this reason, a number of newer agents have been developed to target the allosteric sites associated with M1 receptors.^30,31

Allosteric sites might differ more between different receptor subtypes than do orthorstatic sites, allowing for the development of highly specific drugs. Stimulation of an allosteric site may enhance the binding of an agonist, or it may have distinct actions of its own to increase signal transduction. Issues that need to be clarified with allosteric M1 agonists include the degree to which they are orally available and the effect of their interaction with the allosteric receptor. Allosteric M1 agonists that have been developed and tested in animal tests or clinical trials include AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine; Acadia Pharmaceuticals Inc, San Diego, California) and its analogue 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl) propyl]-3,4-dihydro-2(1H)-quinolone; GlaxoSmithKline, Brentford, England),³⁰ as well as AC-260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one; Acadia Pharmaceuticals Inc),³² TBPB (1-(1′2-meth ylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one; Merck & Co Inc, Whitehouse Station, New Jersey),^33,34 and BCQA (benzylquinoline carboxylic acid; Merck & Co Inc).³⁵

The allosteric agonists AC-42 and 77-LH-28-1 have similar activity in vitro, but 77-LH-28-1 has been shown to have better penetration into the CNS and to stimulate rat hippocampal activity.³³ Also, AC-260584 has been shown to increase cognitive performance in an animal model,³² but this compound has not yet been tested in humans.

The allosteric agonist TBPB is active in vivo, it is highly selective for M1 receptors,³⁴ and it does not appear to cause serious peripheral adverse effects, which are often mediated by M3 receptors.²⁷ This agent also induces NMDA-receptor–mediated receptor currents in the hippocampus, which is important for learning and memory.³⁴ In vitro studies also show that TBPB decreases the processing of APP into β-amyloid³⁴—an effect similar to that produced by previous M1 agonists. The allosteric agonist BCQA produces no direct agonist activity, but it shifts the dose-response for acetylcholine on M1 receptors. It is systemically active and reverses cognitive impairment induced by scopolamine.³⁵

The allosteric agonists may provide a highly selective means of activating M1 receptors. This area of research continues to be developed. Some of these drugs, if they directly activate G protein–mediated signal transduction, may overcome the problem of M1 receptor uncoupling, which has been shown to occur in Alzheimer disease and which may limit the effectiveness of orthostatic muscarinic agonists.^36-39

Nicotinic Receptor Agonists

The early findings of cholinergic loss suggested that nicotinic receptors might be a viable therapeutic target in patients with Alzheimer disease. Indeed, nicotine was shown to produce some improvement in attention and learning in such patients.^40,41 One subtype of nicotinic receptor, the α4β2 receptor, was targeted with a nicotinic receptor agonist called ABT-089 (2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride; Abbott Laboratories, Abbott Park, Illinois), which has been shown to reverse scopolamine memory loss, targets the α4β2 nicotinic receptor subtype.⁴² However, ABT-089 produced no statistically significant improvement in patients with Alzheimer disease in clinical trials.⁴³

More recently, attention has focused on the α7 subtype of nicotinic receptor, because it is predominant in brain areas showing cholinergic degeneration in Alzheimer disease. β-amyloid binds to this receptor, and its stimulation may improve cognitive function.^44-46 Stimulation of the α7 nicotinic receptor has also been shown to protect cells from β-amyloid–induced degeneration,⁴⁷ and chronic administration of nicotine decreases β-amyloid levels and prevents loss of short-term memory in rats receiving long-term β-amyloid infusions.⁴⁸ Thus, a number of new selective agonists for the α7 receptor have been developed.

One α7 nicotinic receptor agonist, A-582941 (2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole; Abbott Laboratories), decreased hyperphosphorylation of tau protein in Tg2576-transgenic mice that overproduced APP.⁴⁹ Another agonist, ABT-107 (5-(6-[(3R)-1-azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole; Abbott Laboratories), improved cognition in monkeys, rats, and mice, and it also improved short-term recognition memory when administered with the acetylcholinesterase inhibitor donepezil hydrochloride.⁵⁰ Continuous infusion of ABT-107 in tau/APP-double-transgenic mice also reduced spinal tau hyperphosphorylation, suggesting that this approach may be useful in treating patients with Alzheimer disease.⁴⁹ This drug has recently been tested in normal human controls, in whom it appeared to be well tolerated, with good pharmacokinetic findings and only mild adverse effects.⁵¹

Another α7 nicotinic receptor agonist, EVP-6124 (Elan Pharmaceuticals, Dublin, Ireland), has undergone one clinical trial,⁵² and a phase 2 trial of this drug is currently recruiting participants (ClinicalTrials.gov identifier No. NCT010 73228). In the initial trial, 48 participants with mild to moderate Alzheimer disease were treated for 1 month with EVP-6124, in addition to an acetylcholinesterase inhibitor that they had pre v iously been taking.⁵³ No serious adverse effects occurred in the study participants, and some improvement was observed in assessments of attention, verbal fluency, and executive function.^52,53 Thus, agonists of the nicotinic α7 receptor may have potential for treatment of patients with Alzheimer disease.

Agents That Target β-Amyloid

Vaccines

As previously noted, one of the pathologic hallmarks of Alzheimer disease is the presence of neuritic plaques containing the neurotoxic peptide β-amyloid. Thus, reducing levels of β-amyloid in the brain might slow the progression of Alzheimer disease. A vaccine developed against β-amyloid, AN1792, was found to be effective in mouse models in which β-amyloid was overproduced.⁵⁴ Transgenic mice with amyloid deposits that were given the vaccine showed a substantial decrease in β-amyloid levels in their brains, as well as improvement in cognitive function.^55,56

In a human trial with the AN1792 vaccine, levels of β-amyloid appeared to decrease. Unfortunately, meningoencephalitis developed in some patients, leading to termination of the trial.^57-59 Levels of β-amyloid and tau were found to be low in autopsies of 2 patients who had received the vaccine.^59-61 However, cognitive function was not significantly improved in the overall study population.⁶² These findings suggest that overproduction of β-amyloid occurs for many years before the onset of Alzheimer disease symptoms, and that—to be effective—vaccine administration would need to occur much earlier in patients deemed to be at high risk.

The CAD-106 vaccine, currently in clinical trials, was found to cause decreases in levels of β-amyloid in animals, and it did not cause CNS inflammation in early trials with humans.⁶³ Several other Alzheimer disease vaccines (eg, ACC-001, ACI-24, UB-311, V-950) have been developed and are in early stages of clinical trials.⁵² Short peptides that mimic parts of β-amyloid are also currently being tested.⁶⁴ A nonviral amyloid vaccine has shown promise in animals,⁶⁵ but it has not yet been tested in humans.

Humanized Monoclonal Antibodies

Another approach to decreasing levels of β-amyloid is passive immunization with antibodies targeting portions of the β-amyloid molecule. Bapineuzumab (AAB-001) is a humanized monoclonal antibody to the N-terminus of β-amyloid. Two phase 2 trials have been conducted with this drug. In one trial, cortical β-amyloid load was decreased.⁶⁶ In the other trial, no statistically significant difference in cognitive function was found between the treatment group and the placebo group.⁶⁷ Interestingly, bapineuzumab appeared to produce some beneficial cognitive effects in individuals who did not have the ϵ4 allelle of the apolipoprotein E (ApoE) gene, but those results were not statistically significant.⁶⁶

The most serious adverse effect in both bapineuzumab studies^66,67 was cerebral vasogenic edema, which occurred in almost 10% of study participants. This adverse effect seemed to correlate with higher doses of bapineuzumab and with presence of the ApoE ϵ4 allele. This finding is unfortunate, because the ApoE ϵ4 allele is a risk factor for Alzheimer disease.

Treatment with bapineuzumab has also been found to reduce tau levels in patients with Alzheimer disease in two clinical trials.⁶⁸ A phase 3 clinical trial is currently being conducted with bapineuzumab.⁶⁹

Solanezumab (LY2062430), a monoclonal antibody to a fragment of β-amyloid (β-amyloid 13-28), may recognize some variants of β-amyloid that are unrecognized by bapineuzumab.⁷⁰ In contrast to bapineuzumab, which targets plaques, solanezumab binds to soluble β-amyloid and should be able to increase clearance of β-amyloid from the body.⁷¹ Early studies suggest that solanezumab decreases the amount of β-amyloid in neuritic plaques.⁷²

A number of other monoclonal antibodies are in various stages of development and testing. Ponezumab (PF-04360365), an antibody targeted to the free carboxy terminus of β-amyloid 1-40,⁷³ has undergone preliminary human trials and has been shown to increase CSF β-amyloid.^74,75 Monoclonal antibodies in earlier stages of development include GSK-933776, Gantenerumab (R-1450), and MABT-5102A, as well as an immunoglobulin G2 antibody to β-amyloid.^52,69

As with the vaccine approach, it seems likely that drugs targeting β-amyloid would need to be given to patients early in the course of disease—before neurodegeneration becomes severe enough to impair cognitive function.

Secretase Inhibitors

Another area of drug development involves the targeting of γ-secretase, one of the enzymes required for production of β-amyloid from APP.^76,77 Developing specific drugs to inhibit this enzyme is complicated by the fact that γ-secretase has many functions in the body. For example, it interacts with several neuronal factors, as well as with the Notch receptor, which is involved in cell differentiation.⁷⁶ Thus, toxicity may be a problem with these drugs. Nevertheless, a number of γ-secretase inhibitors are being tested.

Semagecestat (LY-450139), a γ-secretase inhibitor that reduces β-amyloid levels in the CNS, was being studied in two clinical trials.^78,79 However, these trials (ie, IDENTITY and IDENTITY-2) were recently stopped because cognitive function appeared to decline more rapidly in the treated patients than in the control groups.⁸⁰ It is possible that the failure of this drug may also be a result of insufficient selectivity for γ-secretase as opposed to Notch.

Some types of γ-secretase inhibitors currently under development have less harmful effects on the Notch receptor than previously tested types. One of these γ-secretase inhibitors, begacestat (GSI-953), decreased plasma levels, but not CSF levels, of β-amyloid in humans.^81,82 Another γ-secretase inhibitor, BMS-708163, decreased CSF levels of β-amyloid in humans.⁸³ A third γ-secretase inhibitor, PF-3084014 ([(S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pe ntanamide]), decreased plasma and CSF levels of β-amyloid in animals, but only plasma levels in humans.⁸⁴

Stimulation of α-secretase leads to non-amyloidogenic processing of APP. Muscarinic agonists increase α-secretase activity, and a number of other drugs are being investigated for this potential.⁵² Etazolate (EHT-0202) is a γ-aminobutyric acid (GABA_A) receptor modulator that is in a phase 2 trial in patients with Alzheimer disease.^85,86

Inhibition of β-secretase (β-site APP-cleaving enzyme [BACE1]), which cleaves APP to produce β-amyloid, is another approach to treatment of patients with Alzheimer disease.⁵² As with γ-secretase, this enzyme has multiple functions, and selective drugs have not yet been developed. The type 2 diabetes mellitus drugs rosiglitazone maleate (Avandia; GlaxoSmithKline, Brentford, England) and pioglitazone hydrochloride (Actos; Takeda Pharmaceuticals North America, Deerfield, Illinois) inhibit β-secretase, but thus far beneficial effects have not been reported in clinical trials of these drugs for Alzheimer disease.^87,88

Anti-inflammatory Agents

Inflammation is considered to be an important component of Alzheimer disease, and epidemiologic studies have suggested a beneficial effect from nonsteroidal anti-inflammatory drugs (NSAIDs) in decreasing the risk of Alzheimer disease.^89-91 Some NSAIDs have been shown to decrease β-amyloid and tau levels in animal models⁹²—effects that may be the result of inhibition of APP-associated γ-secretase.^76,93 Clinical trials have been conducted with several of these NSAIDs.

The ADAPT study found no improvement from treatment with the NSAIDs naproxen or celecoxib on cognitive function in older adults, and the trial was stopped early because of cardiovascular adverse effects associated with naproxen.^94,95 A trial investigating ibuprofen for use against Alzheimer disease was also disappointing, showing no statistically significant decrease in cognitive decline, though that trial did detect a small, but not statistically significant, beneficial effect in patients who had the ApoE ϵ4 genotype.⁹⁶

Research results suggest that the neuroprotective effects of NSAIDs occur primarily in younger patients (ie, those younger than 65 years),⁸⁹ and that NSAIDs may actually increase neuronal damage in some patients with Alzheimer disease.⁹⁷

Interestingly, the incidence of Alzheimer disease is lower in India than in many developed countries.^98,99 Evidence shows that levels of β-amyloid and tau are lower in people who consume large amounts of curcumin,^100,101 a component of turmeric that inhibits γ-secretase.¹⁰² Evidence further shows that curcumin protects against β-amyloid toxicity,¹⁰³ and decreases β-amyloid in Tg2576 transgenic mice.¹⁰⁴ Thus far, however, clinical trials of curcumin have demonstrated no improvement in cognitive function in patients with Alzheimer disease.¹⁰⁵

These approaches to decreasing β-amyloid production may work best as preventive measures, before symptoms appear, because once the plaques and tangles have formed, neuronal damage is irreversible.

Drugs That Target Tau

Much of the discussion in the present article has focused on drugs that affect production of β-amyloid. However, the other hallmark of Alzheimer disease is the presence of neurofibrillary tangles containing the tau protein. Tau stabilizes microtubules in neurons and is normally phosphorylated. In Alzheimer disease, tau appears to become hyperphosphorylated, which may contribute to destabilization of microtubules.¹⁰⁶ The hyperphosphorylated tau may be incorporated into neurofibrillary tangles.

One approach used with transgenic mice has involved NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln; NAPVSIPQ), an octapeptide that prevents disruption of microtubules by binding to tubulin. Administration of this compound decreased hyperphosphorylation of tau and improved cognitive function in mice.^107,108 This drug has entered a clinical trial.¹⁰⁶

Another approach focuses on enzymes involved in phosphorylating tau. One kinase, glycogen synthase kinase-3 (GSK-3), has been shown to cause hyperphosphorylation of tau when overexpressed in transgenic mice,^109,110 and inhibition of this enzyme decreases levels of β-amyloid.¹¹¹ Lithium chloride inhibits GSK-3, and chronic administration of this substance has been shown to decrease hyperphosphorylation of tau and improve cognition.^112,113 Lovastatin (Mevacor; Merck & Co Inc)¹¹⁴ and the thiadiazolidinones¹¹⁵ may also inhibit GSK-3.

Inhibition of tau aggregation is yet another approach. Immunotherapy with antibodies directed at tau decreased tangles in the Tg P301L mouse model.¹¹⁶ Methylene blue (Rember), which may prevent aggregation of tau, displayed promising results in a phase 2 clinical trial,¹¹⁷ and it decreased levels of β-amyloid and cognitive deficits in 3xTg-AD-transgenic mice.¹¹⁸ Other drugs are being investigated for their ability to inhibit tau aggregation, to target heat shock protein and increase clearance of tau, or to stabilize the microtubules.¹⁰⁶

Tau clearly presents a potential therapeutic target in Alzheimer disease. However, as with other medications, treatment would be most useful if initiated early in the course of disease, before the onset of massive neurodegeneration.

New Uses for Old Drugs

Latrepirdine

Latrepirdine (Dimebon; Medivation Inc, San Francisco, California; Pfizer Inc, New York, New York) is a nonselective antihistamine that was marketed in Russia for a number of years. Latrepirdine inhibits acetylcholinesterase and blocks NMDA receptors, and it has been shown to improve cognitive function in rats with cholinergic loss.¹¹⁹ Thus, some researchers thought that this drug might combine the beneficial effects of an acetylcholinesterase inhibitor with those of memantine.

Results of a clinical trial of 14 patients with Alzheimer disease in Russia suggested that latrepirdine produced substantial improvement in cognitive function.¹¹⁹ A subsequent clinical trial in Russia with 89 patients showed statistically significant improvement in cognition and activities of daily living with latrepirdine.¹²⁰ These findings led to the establishment of a similar, but larger (598 participants), clinical trial of latrepirdine for Alzheimer disease in the United States. In that US trial, no statistically significant difference was detected between the treatment and placebo groups.^120,121 Ongoing studies are attempting to determine reasons for the discrepancies between the Russian and US studies.

Etanercept

A number of studies have suggested that the inflammatory cytokine tumor necrosis factor α (TNF-α) may play a role in the pathogenesis of Alzheimer disease.¹²² TNF-α increases the production of β-amyloid,¹²³ and blockade of TNF-α decreases toxicity of β-amyloid.¹²⁴ Etanercept (Enbrel; Amgen Inc, Thousand Oaks, California), a TNF-α inhibitor, is currently approved by the US Food and Drug Administration for treatment of patients with rheumatoid arthritis. Two reports have found improvement in aphasia, verbal fluency, and cognition in patients with Alzheimer disease after perispinal administration of enteracept.^125-127 Another clinical trial on the use of enteracept for Alzheimer disease is scheduled but has not begun recruiting participants (ClinicalTrials.gov identifier No. NCT01068353).

Phosphodiesterase-5 Inhibitors

In a study of double transgenic (ie, human APP/presenilin 1) mice with pathologic characteristics of Alzheimer disease, treatment with sildenafil citrate (Viagra; Pfizer Inc, New York, New York), a drug that increases cyclic guanosine monophosphate (cGMP) levels by inhibiting phosphodiesterase-5, improved memory and decreased β-amyloid levels in the brain.¹²⁸ Cyclic guanosine monophosphate levels are also increased by drugs that increase nitric oxide levels. Nitric oxide synthase knockout mice that overexpressed APP showed increased β-amyloid pathologic characteristics.¹²⁹

Cyclic guanosine monophosphate increases phosphorylation of cyclic adenosine monophosphate (cAMP)-responsive element binding factor (CREB). By contrast, β-amyloid inhibits CREB phosphorylation, which may be one of the mechanisms involved in β-amyloid–mediated neuronal stress. The effect of β-amyloid on CREB phosphorylation can be prevented by analogues of cGMP or by medications that increase nitric oxide levels, suggesting that increasing nitric oxide might be another potential therapeutic approach.

Selective inhibitors of phosphodiesterase-5 are being developed for possible use in Alzheimer disease. Because phosphodiesterase-5 inhibitors are widely used in older men for erectile dysfunction, epidemiologic evidence may demonstrate whether the incidence of Alzheimer disease is decreased over time in this population.

Diabetes Mellitus Drugs

A postmortem analysis of patients who were treated with insulin and other medications for diabetes mellitus revealed that levels of neuritic plaques were substantially lower in individuals given a combination of insulin and oral agent than in other individuals.¹³⁰ Other research has suggested that patients with Alzheimer disease who take diabetes mellitus medications show less cognitive decline than other patients with Alzheimer disease.¹³¹ The diabetes mellitus drugs rosiglitazone and pioglitazone are known to inhibit the β-secretase that is involved in production of β-amyloid.⁸⁸ These findings have led to suggestions that insulinlike hormones might provide a new avenue for treatment of patients with Alzheimer disease.¹³² However, as previously indicated, clinical trials of these drugs have not shown any effectiveness for Alzheimer disease.¹³³

Statins

The presence of neuritic plaques is correlated with high cholesterol levels,¹³⁴ and elevated cholesterol may increase β-amyloid production.^135,136 Several clinical trials have been conducted to determine whether using statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) to decrease cholesterol levels will also reduce the incidence or decrease symptoms of Alzheimer disease. Unfortunately, results of these studies have not been encouraging, though it is likely that the studies initiated drug treatment too late in the course of the disease.^137,138 Perhaps aggressive management of high cholesterol levels, which now occurs commonly in clinical practice, may lead to an overall decline of Alzheimer disease over the next few decades.

Other Approaches

A number of other approaches to the treatment of patients with Alzheimer disease are being pursued. Some of these approaches include drugs to decrease aggregation of β-amyloid; new NMDA antagonists designed to reduce excitotoxicity; various antioxidants; and drugs or cytokines that may stimulate neuronal regeneration.^52,139,140

Summary

Many of the newer treatments discussed in the present article have not been effective in ameliorating the symptoms of Alzheimer disease. One conclusion that could be drawn is that these treatments do not address appropriate targets in Alzheimer disease. With the exception of the cholinergic receptor agonists, which target neuronal dysfunction, many treatments are designed to affect degenerative processes that probably begin many years before symptoms are seen.

Therefore, a number of approaches are under investigation to develop new treatments for patients with Alzheimer disease. The present review has focused primarily on medications that have entered clinical trials. A key consideration with the majority of approaches discussed in the present review is the importance of initiating treatment early, before clinical symptoms of Alzheimer disease appear. Prevention of the neuropathologic cascade is likely to be more successful than attempts to manage the disease after neurodegeneration is substantial enough to cause impairment of cognitive function.

For this reason, an early diagnostic tool that can reliably predict the likelihood of development of Alzheimer disease is crucial to the success of treatment. Recently, a method was reported that holds great promise for early diagnosis. By analyzing a mixture of β-amyloid 1-42, phosphorylated tau, and total tau in CSF, De Meyer and colleagues¹⁴¹ were able to classify patients with Alzheimer disease or with mild cognitive impairment that eventually developed into Alzheimer disease. Nevertheless, until such diagnostic markers are widely available, it is imperative that patients begin treatment early—as soon as they begin to manifest symptoms of cognitive impairment.

Financial Disclosures: None reported.

This supplement is supported by an independent educational grant from the Alzheimer's Association.

1

Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J.. (1978). ;2 (6150):1457-1459.

2

Dournaud P, Delaere P, Hauw JJ, Epelbaum J. Differential correlation between neurochemical deficits, neuropathology, and cognitive status in Alzheimer's disease. Neurobiol Aging.. (1995). ;16 (5): 817-823.

3

Winblad B, Engedal K, Soininen H, et al; Donepezil Nordic Study Group. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology.. (2001). ;57(3):489-495.

4

Birks J. Cholinesterase inhibitors for Alzheimer's disease [review]. Cochrane Database Syst Rev.. January 25 , 2006;(1):CD005593 .

5

Takeda A, Loveman E, Clegg A, et al. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease [review]. Int J Geriatr Psychiatry. 2006;21(1):17-28.

6

Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis [review]. Clin Interv Aging. 2008;3(2):211-225.

7

McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia [review]. Cochrane Database Syst Rev. April 19 , 2006;(2):CD003154 .

8

Winblad B, Jones RW, Wirth Y, Stoffler A, Mobius HJ. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials [published online ahead of print May 10, 2007]. Dement Geriatr Cogn Disord. 2007;24(1):20-27.

9

Wilkinson D, Andersen HF. Analysis of the effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer's disease [published online ahead of print July 4, 2007]. Dement Geriatr Cogn Disord. 2007;24(2):138-145.

10

Fisher A. Cholinergic treatments with emphasis on m1 muscarinic agonists as potential diseasemodifying agents for Alzheimer's disease. Neurotherapeutics.. (2008). ;5(3):433-442.

11

Fisher A. M1 muscarinic agonists target major hallmarks of Alzheimer's disease—an update [review]. Curr Alzheimer Res. 2007;4(5):577-580.

12

Levey AI. Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc Natl Acad Sci USA. 1996;93(24):13541-13546.

13

Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. 2000;48(6):913-918.

14

Wolf BA, Wertkin AM, Jolly YC, et al. Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. J Biol Chem. 1995;270(9):4916-4922.

15

Haring R, Fisher A, Marciano D, et al. Mitogenactivated protein kinase-dependent and protein kinase C-dependent pathways link the m1 muscarinic receptor to beta-amyloid precursor protein secretion. J Neurochem. 1998;71(5):2094-2103.

16

Beach TG, Walker D, Sue L, et al. Immunotoxin lesion of the cholinergic nucleus baslis causes Aβ deposition: towards a physiologic animal model of Alzheimer's disease. Curr Med Chem. 2003;3:233-243.

17

Beach TG, Walker DG, Potter PE, Sue LI, Fisher A. Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Res.. (2001). ;905(1-2):220-223.

18

Caccamo A, Oddo S, Billings LM, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron.. (2006). ;49(5):671-682.

19

Hock C, Maddalena A, Raschig A, et al. Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease. Amyloid.. (2003). ;10(1):1-6.

20

Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH. Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Ann Neurol. 2003;54(2):235-238.

21

Davis AA, Fritz JJ, Wess J, Lah JJ, Levey AI. Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. J Neurosci. 2010;30(12):4190-4196.

22

Bodick NC, Offen WW, Levey AI, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in alzheimer disease. Arch Neurol.. (1997). ;54(4):465-473.

23

Eglen RM. Muscarinic receptors and gastrointestinal tract smooth muscle function. Life Sci.. (2001). ;68(22-23):2573-2578.

24

Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033-1039.

25

Fang L, Jumpertz S, Zhang Y, et al. Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors. J Med Chem. 2010;53(5):2094-2103.

26

Fisher A, Brandeis R, Bar-Ner RH, et al. AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease. J Mol Neurosci.. (2002). ;19(1-2):145-153.

27

Heinrich JN, Butera JA, Carrick T, et al. Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists. Eur J Pharmacol.. (2009). ;605(1-3):53-56.

28

Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009;8(1):41-54.

29

Davis CN, Bradley SR, Schiffer HH, et al. Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands. BMC Pharmacol. 2009;9:14 .

30

Thomas RL, Mistry R, Langmead CJ, Wood MD, Challiss RA. G protein coupling and signaling pathway activation by m1 muscarinic acetylcholine receptor orthosteric and allosteric agonists. J Pharmacol Exp Ther. 2008;327(2):365-374.

31

Avlani VA, Langmead CJ, Guida E, et al. Orthosteric and allosteric modes of interaction of novel selective agonists of the M1 muscarinic acetylcholine receptor. Mol Pharmacol. 2010;78(1):94-104.

32

Bradley SR, Lameh J, Ohrmund L, et al. AC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal model [published online ahead of print October 14, 2009]. Neuropharmacology. 2010;58(2):365-373.

33

Langmead CJ, Austin NE, Branch CL, et al. Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1. Br J Pharmacol. 2008;154(5):1104-1115.

34

Jones CK, Brady AE, Davis AA, et al. Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J Neurosci. 2008;28(41):10422-10433.

35

Wittmann M, Guangping X, Michelle P, et al. In vivo pharmacodynamic effects of BQCA, a novel selective allosteric M1 receptor modulator. Alzheimer Dement. 2008;4(suppl 1):T770 .

36

Ferrari-DiLeo G, Mash DC, Flynn DD. Attenuation of muscarinic receptor-G-protein interaction in Alzheimer disease. Mol Chem Neuropathol. 1995;24(1):69-91.

37

Flynn DD, Weinstein DA, Mash DC. Loss of highaffinity agonist binding to M1 muscarinic receptors in Alzheimer's disease: implications for the failure of cholinergic replacement therapies. Ann Neurol.. (1991). ;29(3):256-262.

38

Flynn DD, Ferrari-DiLeo G, Levey AI, Mash DC. Differential alterations in muscarinic receptor subtypes in Alzheimer's disease: implications for cholinergic-based therapies. Life Sci.. (1995). ;56(11-12):869-876.

39

Tsang SW, Lai MK, Kirvell S, et al. Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease. Neurobiol Aging.. (2006). ;27(9):1216-1223.

40

Newhouse PA, Sunderland T, Tariot PN, et al. The effects of acute scopolamine in geriatric depression. Arch Gen Psychiatry.. (1988). ;45(10):906-912.

41

Sahakian B, Jones G, Levy R, Gray J, Warburton D. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br J Psychiatry. 1989;154:797-800.

42

Baker JD, Lenz RA, Locke C, et al. ABT-089, a neuronal nicotinic receptor partial agonist, reverses scopolamine-induced cognitive deficits in healthy normal subjects. Alzheimer Dement.. (2009). ;5(4 suppl 1):P325-P325.

43

Lenz RA, Berry SM, Pritchett YI, et al. Novel investigation of a neuronal nicotinic receptor partial agonist in the treatment of Alzheimer's disease. Paper presented at: 11th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy; March 24-27 , 2010; Geneva, Switzerland.P100 .

44

Bitner RS, Bunnelle WH, Anderson DJ, et al. Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. J Neurosci.. (2007). ;27(39):10578-10587.

45

Mudo G, Belluardo N, Fuxe K. Nicotinic receptor agonists as neuroprotective/neurotrophic drugs. Progress in molecular mechanisms. J Neural Transm.. (2007). ;114(1):135-147.

46

Leiser SC, Bowlby MR, Comery TA, Dunlop J. A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol Ther.. (2009). ;122(3):302-311.

47

D'Andrea MR, Nagele RG. Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons. Curr Pharm Des.. (2006). ;12(6):677-684.

48

Srivareerat M, Tran TT, Salim S, Aleisa AM, Alkadhi KA. Chronic nicotine restores normal Abeta levels and prevents short-term memory and E-LTP impairment in Abeta rat model of Alzheimer's disease [published online ahead of print May 20 , 2009]. Neurobiol Aging..

49

Bitner RS, Nikkel AL, Markosyan S, Otte S, Puttfarcken P, Gopalakrishnan M. Selective alpha7 nicotinic acetylcholine receptor activation regulates glycogen synthase kinase3beta and decreases tau phosphorylation in vivo. Brain Res.. (2009). ;1265:65-74.

50

Bitner RS, Bunnelle WH, Decker MW, et al. In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer's Disease [published online ahead of print May 26 2010]. J Pharmacol Exp Ther. 2010;334(3):875-886.

51

Othman AA, Lenz RA, Zhang J, Li J, Awni WM, Dutta S. Single- and multiple-dose pharmacokinetics, safety and tolerability of the selective alpha7 neuronal nicotinic receptor agonist, ABT-107, in healthy human volunteers [published online ahead of print June 14 ,2010 ]. J Clin Pharmacol..

52

Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol.. (2010). ;9(7):702-716.

53

Hilt D, Safirstein B, Hassman D, et al. EVP-6124-Safety, tolerability, and cognitive effects of a novel a7 nicotinic receptor agonist in Alzheimer's disease patients on stable donepezil or rivastigmine therapy. EnVivo Pharmaceuticals Web site; 2009. http://www.envivopharma.com/library/user_files/Hilt_etal_A7_ICAD2009.pdf. Accessed September 17, 2010.

54

Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature.. (1999). ;400(6740):173-177.

55

Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000;408(6815):979-982.

56

Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature.. (2000). ;408(6815):982-985.

57

Hock C, Konietzko U, Papassotiropoulos A, et al. Generation of antibodies specific for [beta]-amyloid by vaccination of patients with Alzheimer disease. Nat Med.. (2002). ;8(11):1270-1275.

58

Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology.. (2003). ;61(1):46-54.

59

Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol.. (2004). ;14(1):11-20.

60

Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9(4):448-452.

61

Bouche D, Donald J, Love S, Neal JW, Holmes C, Nicoll J. Aβ42 immunization reduces both tau and Aβ deposits in Alzheimer's disease. Alzheimer Dement.. (2010). ;6(4 suppl 1):S144-S144.

62

Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64(9):1553-1562.

63

Winblad BG, Minthon L, Floesser A, et al. Results of the first-in-man study with the active Abeta immunotherapy CAD106 in Alzheimer patients. Alzheimer Dement.. (2009). ;5(4 suppl 1):P113-P114.

64

Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W. Development of AFFI-TOPE vaccines for Alzheimer's disease (AD)-from concept to clinical testing. J Nutr Health Aging. 2009;13(3):264-267.

65

Okura Y, Miyakoshi A, Kohyama K, Park IK, Staufenbiel M, Matsumoto Y. Nonviral Abeta DNA vaccine therapy against Alzheimer's disease: long-term effects and safety. Proc Natl Acad Sci USA.. (2006). ;103(25):9619-9624.

66

Rinne JO, Brooks DJ, Rossor MN, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9(4):363-372.

67

Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73(24):2061-2070.

68

Blennow K, Zetterberg H, Wei J, Liu E, Black R, Grundman M. Immunotherapy with bapineuzumab lowers CSF tau protein levels in patients with Alzheimer's disease. Alzheimer Dement. 2010;6(4 suppl 1):S134-S135.

69

Kerchner GA, Boxer AL. Bapineuzumab. Expert Opin Biol Ther. 2010;10(7):1121-1130.

70

DeMattos RB, Racke MM, Gelfanova V, et al. Identification, characterization, and comparison of amino-terminally truncated Aβ42 peptides in Alzheimer's disease brain tissue and in plasma from Alzheimer's patients receiving solanezumab immunotherapy treatment. Alzheimer Dement. 2009;5(4 suppl 1): P156-P157.

71

Seubert P, Barbour R, Khan K, et al. Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse. Neurodegener Dis. 2008;5(2):65-71.

72

Siemers ER, Friedrich S, Dean RA, et al. Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol.. (2010). ;33(2):67-73.

73

Nicholas T, Knebel W, Gastonguay MR, et al. Preliminary population pharmacokinetic modeling of PF-04360365, a humanized anti-amyloid monoclonal antibody, in patients with mild-to-moderate Alzheimer's disease. Alzheimer Dement.. (2009). ;5(4 suppl 1):P253-P253.

74

Zhao Q, Landen J, Burstein AH, et al. Pharmacokinetics and pharmacodynamics of ponezumab (PF-04360365) following a single-dose intravenous infusion in patients with mild to moderate Alzheimer's disease. Alzheimer Dement.. (2010). ;6(4 suppl 1):S143-S143.

75

Wood KM, McCush F, Conboy JJ, et al. IP/MS analysis of human CSF Abeta following a single dose of the C-terminal anti-Abeta antibody ponezumab (PF-04360365) to Alzheimer patients. Alzheimer Dement. 2010;6(4 suppl 1):S311-S311.

76

Tomita T. Secretase inhibitors and modulators for Alzheimer's disease treatment. Expert Rev Neurother. 2009;9(5):661-679.

77

Tomita T, Iwatsubo T. gamma-secretase as a therapeutic target for treatment of Alzheimer's disease. Curr Pharm Des.. (2006). ;12(6):661-670.

78

Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease. Expert Opin Pharmacother. 2009;10(10):1657-1664.

79

Bateman RJ, Siemers ER, Mawuenyega KG, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol.. (2009). ;66(1):48-54.

80

Lilly halts development of semagacestat for Alzheimer's disease based on preliminary results of Phase III clinical trials [press release]. Indianapolis, IN: Eli Lilly and Co; August 17, 2010. http://newsroom.lilly.com/releasedetail.cfm?releaseid=499794. Accessed September 18, 2010.

81

Jacobsen S, Comery T, Kreft A, et al. GSI-953 is a potent APP-selective gamma-secretase inhibitor for the treatment of Alzheimer's disease. Alzheimer Dement.. (2009). ;5(4 suppl 1):P139-P139.

82

Martone RL, Zhou H, Atchison K, et al. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther.. (2009). ;331(2):598-608.

83

Ereshefsky L, Jhee SS, Yen M, Moran SV. The role for CSF dynabridging studies in developing new therapies for Alzheimer's disease. Alzheimer Dement.. (2009). ;5(4 suppl 1):P414-P415.

84

Soares H, Raha N, Sikpi M, et al. Abeta variability and effect of gamma secretase inhibition on cerebrospinal fluid levels of Abeta in healthy volunteers. Alzheimer Dement.. (2009). ;5(4 suppl 1):P252-P253.

85

Marcade M, Bourdin J, Loiseau N, et al. Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J Neurochem. 2008;106(1):392-404.

86

Desire L, Marcade M, Peillon H, Drouin D, Sol O. Clinical trials of EHT 0202, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. Alzheimer Dement. 2009;5(4 suppl 1): P255.

87

Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled Phase III study. Dement Geriatr Cogn Disord.. (2010). ;30(2):131-146.

88

Landreth G, Jiang Q, Mandrekar S, Heneka M. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics.. (2008). ;5(3):481-489.

89

Hayden KM, Zandi PP, Khachaturian AS, et al. Does NSAID use modify cognitive trajectories in the elderly? The Cache County Study. Neurology.. (2007). ;69(3):275-282.

90

Rozzini R, Ferrucci L, Losonczy K, Havlik RJ, Guralnik JM. Protective effect of chronic NSAID use on cognitive decline in older persons. J Am Geriatr Soc.. (1996). ;44(9):1025-1029.

91

Szekely CA, Thorne JE, Zandi PP, et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology. 2004;23(4):159-169.

92

Yoshiyama Y, Higuchi M, Zhang B, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron.. (2007). ;53(3):337-351.

93

Sastre M, Gentleman SM. NSAIDs: how they work and their prospects as therapeutics in Alzheimer's disease. Front Aging Neurosci. 2010;2:20 .

94

ADAPT Research Group. Cognitive function over time in the Alzheimer's disease anti-inflammatory prevention trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol.. (2008). ;65(7):896-905.

95

ADAPT Research Group. Alzheimer's Disease Anti-Inflammatory Prevention Trial: Design, methods, and baseline results. Alzheimer Dement.. (2009). ;5(2):93-104.

96

Pasqualetti P, Bonomini C, Dal Forno G, et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease. Aging Clin Exp Res. 2009;21(2):102-110.

97

Breitner JC, Haneuse SJ, Walker R, et al. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology. 2009;72(22):1899-1905.

98

Chandra V, Pandav R, Dodge HH, et al. Incidence of Alzheimer's disease in a rural community in India: the Indo-US study. Neurology.. (2001). ;57(6):985-989.

99

Shaji S, Bose S, Verghese A. Prevalence of dementia in an urban population in Kerala, India. Br J Psychiatry. 2005;186:136-140.

100

Subramanian S, Sandhyarani B, Shree AN, et al. Lower levels of cerebrospinal fluid amyloid β (Aβ) in non-demented Indian controls [published online ahead of print September 15, 2006]. Neurosci Lett.. (2006). ;407(2):121-123.

101

Kandimalla RJ, Prabhakar S, Binukumar BK, et al. Cerebrospinal fluid profile of amyloid beta42 (Abeta42), hTau and ubiquitin in North Indian Alzheimer's disease patients [published online ahead of print July 3 , 2010]. Neurosci Lett..

102

Zhang C, Browne A, Child D, Tanzi RE. Curcumin decreases amyloid beta-peptide levels by attenuating the maturation of amyloid-beta precursor protein [published online ahead of print July 9, 2010]. J Biol Chem. 2010;285(37):28472-28480.

103

Qin XY, Cheng Y, Yu LC. Potential protection of curcumin against intracellular amyloid beta-induced toxicity in cultured rat prefrontal cortical neurons. Neurosci Lett.. (2010). ;480(1):21-24.

104

Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci.. (2001). ;21(21):8370-8377.

105

Hamaguchi T, Ono K, Yamada M. Curcumin and Alzheimer's Disease [published online ahead of print April 12 ,2010 .] CNS Neurosci Ther.

106

Bachurin S, Bukatina E, Lermontova N, et al. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann NY Acad Sci. 2001;939:425-435.

107

Matsuoka Y, Gray AJ, Hirata-Fukae C, et al. Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage. J Mol Neurosci.. (2007). ;31(2):165-170.

108

Matsuoka Y, Jouroukhin Y, Gray AJ, et al. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease. J Pharmacol Exp Ther. 2008;325(1):146-153.

109

Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J.. (2001). ;20(1-2):27-39.

110

Hernandez F, Borrell J, Guaza C, Avila J, Lucas JJ. Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments. J Neurochem. 2002;83(6):1529-1533.

111

Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003;423 (6938): 435-439.

112

Nakashima H, Ishihara T, Yokota O, et al. Effects of alpha-tocopherol on an animal model of tauopathies. Free Radic Biol Med.. (2004). ;37(2):176-186.

113

Noble W, Planel E, Zehr C, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA.. (2005). ;102(19):6990-6995.

114

Salins P, Shawesh S, He Y, et al. Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling. Neurosci Lett.. (2007). ;412(3):211-216.

115

Luna-Medina R, Cortes-Canteli M, Sanchez-Galiano S, et al. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. J Neurosci.. (2007). ;27(21):5766-5776.

116

Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci.. (2007). ;27(34):9115-9129.

117

Staff RT, Ahearn TS, Murray AD, Bentham P, Seng KM, Wischik C. P4-347: tau aggregation inhibitor (TAI) therapy with rember(TM) arrests the trajectory of rCBF decline in brain regions affected by Tau pathology in mild and moderate Alzheimer's disease (AD). Alzheimer Dement. 2008;4(4 suppl 1): T775-T775.

118

Medina DX, Caccamo A, Oddo S. Methylene blue reduces Abeta levels and rescues early cognitive deficit by increasing proteasome activity [published online ahead of print July 27 ,2010 ]. Brain Pathol..

119

Bachurin S, Bukatina E, Lermontova N, et al. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann NY Acad Sci. 2001;939:425-435.

120

Doody RS, Gavrilova SI, Sano M, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet.. (2008). ;372(9634):207-215.

121

Miller G. Pharmacology. The puzzling rise and fall of a dark-horse Alzheimer's drug. Science.. (2010). ;327(5971):1309 .

122

Perry RT, Collins JS, Wiener H, Acton R, Go RCP. The role of TNF and its receptors in Alzheimer's disease. Neurobiol Aging.. (2001). ;22(6):873-883.

123

Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B. TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J.. (1999). ;13(1):63-68.

124

Medeiros R, Prediger RD, Passos GF, et al. Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein. J Neurosci. 2007;27(20):5394-5404.

125

Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006;8(2):25 .

126

Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease. BMC Neurol. 2008;8:27 .

127

Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2 .

128

Puzzo D, Staniszewski A, Deng SX, et al. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model. J Neurosci.. (2009). ;29(25):8075-8086.

129

Colton CA, Wilcock DM, Wink DA, Davis J, Van Nostrand WE, Vitek MP. The effects of NOS2 gene deletion on mice expressing mutated human AβPP. J Alzheimer Dis. 2008;15(4):571-587.

130

Beeri MS, Schmeidler J, Silverman JM, et al. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology.. (2008). ;71(10):750-757.

131

Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol.. (2003). ;13(5):369-376.

132

Holscher C, Li L. New roles for insulin-like hormones in neuronal signalling and protection: New hopes for novel treatments of Alzheimer's disease? Neurobiol Aging. 2010;31(9):1495-1502.

133

Gold M, Alderton C, Zvartau-Hind M, et al. Effects of rosiglitazone as monotherapy in APOE4-stratified subjects with mild-to-moderate Alzheimer's disease. Alzheimer Dement.. (2009). ;5(4):P86 .

134

Sparks DL, Hunsaker JC III, Scheff SW, Kryscio RJ, Henson JL, Markesbery WR. Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease. Neurobiol Aging.. (1990). ;11(6):601-607.

135

Brian MA, Emma RF, Huw D. Cholesterol upregulates production of Aβ 1-40 and 1-42 in transfected cells. Neurobiol Aging. 2000;21:254 .

136

Austen BM, Sidera C, Liu C, Frears E. The role of intracellular cholesterol on the processing of the beta-amyloid precursor protein. J Nutr Health Aging. 2003;7(1):31-36.

137

Feldman HH, Doody RS, Kivipelto M, et al; LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe [published online ahead of print March 3, 2010]. Neurology.. (2010). ;74(12):956-964.

138

Sparks DL, Kryscio RJ, Connor DJ, 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. 2010;7(1-3):183-186.

139

Robles A. Pharmacological treatment of Alzheimer's disease: is it progressing adequately? Open Neurol J. 2009;3:27-44.

140

Chong ZZ, Li F, Maiese K. Employing new cellular therapeutic targets for Alzheimer's disease: a change for the better? Curr Neurovasc Res. 2005;2(1):55-72.

141

De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol.. (2010). ;67(8):949-956.

Figure.

Investigational medications for Alzheimer disease in clinical trials or animal studies. *The semagecestat clinical trials (ie, IDENTITY and IDENTITY-2) were stopped in August 2010 because cognitive function appeared to decline more rapidly in treated patients than in control groups. ⁸⁰

View Original | Slide (.ppt)

Investigational Medications for Treatment of Patients With Alzheimer Disease

Related content

Related Topics