8
Drug Discovery for Alzheimer’s Disease The End of the Beginning Lorenzo M. Refolo* ,1 and Howard M. Fillit 1 1 The Institute for the Study of Aging, New York, NY Journal of Molecular Neuroscience Copyright © 2004 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/04/24:1–8/$25.00 Journal of Molecular Neuroscience 1 Volume 24, 2004 Early in 1943, one of the great statesmen of the twentieth century, Winston Churchill, took the occa- sion of the surrender of the Axis armies in Tunisia to utter his famous words, stating, “These events did not mark the end or even the beginning of the end but merely the end of the beginning.” By analogy, our understanding of drug discovery for Alz- heimer’s disease (AD) is at a similar point, the end of the beginning. The development of therapies for AD represents a major challenge to academic, biotechnological, and pharmaceutical scientists. One of the reasons for this lies in the fact that the human brain, the organ that is the focus of these therapies, is the most complex structure in all biology. Despite the difficult task, neuroscientists, using the tools of modern neuroscience, neurology, pharmacology, chemistry, genomics, proteomics, psychometrics, and bioinformatics, have made good progress not only in understanding the pathophysiology of AD but also in identifying and validating new drug tar- gets that are the basis for novel therapeutic strate- gies. These developments mark the end of the beginning of our understanding of AD and hope- fully open the way to an era of therapeutic break- throughs against this dread disease. Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting approx 16 mil- lion people worldwide. The cause of AD is not known. What is known is that in most cases the dis- ease is not simply caused by a single gene but by a combination of multiple genetic and environmental factors. Clinically, AD is characterized by memory and cognitive loss, and currently available therapy treats these symptoms. This therapy is based on the cholinergic hypothesis of AD, which states that AD- related deficits in memory, learning, and cognition are caused by a decrease in cholinergic transmission owing to loss of cholinergic neurons in the septal and basalis nuclei (Allain et al., 2003). According to the cholinergic hypothesis, prolonging the actions of the cholingeric neurotransmitter acetylcholine at the synapse should improve memory and cognition in patients with AD. To accomplish this the most successful pharmacological approach has been to inhibit the enzymes, known as cholinesterases, which degrade acetylcholine. These cholinesterase inhibitors, donepezil, rivastigmine, and galanta- mine, were, until recently, the only FDA-approved drugs available for the treatment of AD. Although they certainly help sufferers of AD, cholinesterase inhibitors affect symptoms associated with late stages of the disease but have no effect on modify- ing the underlying disease or dementing process. Glutamate is the most important excitatory neurotransmitter in the central nervous system. Glutamatergic neurotransmission, an important process in learning and memory, is severely dis- rupted in patients with AD (Butterfield and Pocernich, 2003). The excitotoxic neurotransmitter glutamate has been implicated in the patho- physiology of AD; and under certain conditions, glutamate has a toxic action resulting from an acti- vation of specific glutamate receptors, which leads to acute or chronic death of nerve cells. Because of the toxic consequences of excess glutamate, thera- peutic strategies directed at the glutamatergic system might hold promise. The first of these glutamatergic therapies, memantine, an NMDA INTRODUCTION *Author to whom all correspondence and reprint requests should be addressed. E-mail: [email protected]

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Page 1: Drug discovery for Alzheimer’s disease

Drug Discovery for Alzheimer’s DiseaseThe End of the Beginning

Lorenzo M. Refolo*,1 and Howard M. Fillit 1

1The Institute for the Study of Aging, New York, NY

Journal of Molecular NeuroscienceCopyright © 2004 Humana Press Inc.All rights of any nature whatsoever reserved.ISSN0895-8696/04/24:1–8/$25.00

Journal of Molecular Neuroscience 1 Volume 24, 2004

Early in 1943, one of the great statesmen of thetwentieth century, Winston Churchill, took the occa-sion of the surrender of the Axis armies in Tunisiato utter his famous words, stating, “These events didnot mark the end or even the beginning of the endbut merely the end of the beginning.” By analogy,our understanding of drug discovery for Alz-heimer’s disease (AD) is at a similar point, the endof the beginning. The development of therapies forAD represents a major challenge to academic,biotechnological, and pharmaceutical scientists. Oneof the reasons for this lies in the fact that the humanbrain, the organ that is the focus of these therapies,is the most complex structure in all biology. Despitethe difficult task, neuroscientists, using the tools ofmodern neuroscience, neurology, pharmacology,chemistry, genomics, proteomics, psychometrics,and bioinformatics, have made good progress notonly in understanding the pathophysiology of ADbut also in identifying and validating new drug tar-gets that are the basis for novel therapeutic strate-gies. These developments mark the end of thebeginning of our understanding of AD and hope-fully open the way to an era of therapeutic break-throughs against this dread disease.

Alzheimer’s disease (AD) is the most commonneurodegenerative disease affecting approx 16 mil-lion people worldwide. The cause of AD is notknown. What is known is that in most cases the dis-ease is not simply caused by a single gene but by acombination of multiple genetic and environmentalfactors. Clinically, AD is characterized by memoryand cognitive loss, and currently available therapytreats these symptoms. This therapy is based on the

cholinergic hypothesis of AD, which states that AD-related deficits in memory, learning, and cognitionare caused by a decrease in cholinergic transmissionowing to loss of cholinergic neurons in the septaland basalis nuclei (Allain et al., 2003). According tothe cholinergic hypothesis, prolonging the actionsof the cholingeric neurotransmitter acetylcholine atthe synapse should improve memory and cognitionin patients with AD. To accomplish this the mostsuccessful pharmacological approach has been toinhibit the enzymes, known as cholinesterases,which degrade acetylcholine. These cholinesteraseinhibitors, donepezil, rivastigmine, and galanta-mine, were, until recently, the only FDA-approveddrugs available for the treatment of AD. Althoughthey certainly help sufferers of AD, cholinesteraseinhibitors affect symptoms associated with latestages of the disease but have no effect on modify-ing the underlying disease or dementing process.

Glutamate is the most important excitatoryneurotransmitter in the central nervous system.Glutamatergic neurotransmission, an importantprocess in learning and memory, is severely dis-rupted in patients with AD (Butterfield andPocernich, 2003). The excitotoxic neurotransmitterglutamate has been implicated in the patho-physiology of AD; and under certain conditions,glutamate has a toxic action resulting from an acti-vation of specific glutamate receptors, which leadsto acute or chronic death of nerve cells. Because ofthe toxic consequences of excess glutamate, thera-peutic strategies directed at the glutamatergicsystem might hold promise. The first of theseglutamatergic therapies, memantine, an NMDA

INTRODUCTION

*Author to whom all correspondence and reprint requests should be addressed. E-mail: [email protected]

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receptor antagonist that addresses glutamate exito-toxicity, has been approved in the United States andEurope for use in AD (Chen et al., 1992). The resultsof a clinical study of the effects of memantine onmoderate-to-severe AD recently have been pub-lished (Reisberg et al., 2003). In patients who weretreated for 28 wk, several outcome variables wereassessed, and it was found that memantine reducedclinical deterioration without significant adverseeffects. This study is important, as memantine isthe only treatment approved for patients with moreadvanced AD. Currently, there is some debate asto whether memantine therapy is palliative or dis-ease modifying (i.e., treating or preventing the corepathogenic process causing AD). In this volume,Dr. Ming-Ming Zhou reports on his work in under-standing the mechanisms of action of glutamatereceptors. Using recently developed methods ofstructure-based ligand design, he aims to developchemical ligands that can be used as novel tools tostudy the mechanisms of action of glutamate recep-tors and also help further development of potentialtherapeutic agents that modulate glutamate recep-tor function in AD.

Alzheimer’s disease (AD) is characterized neuro-pathologically by neuronal loss, extracellular senileplaques (SPs), and intracellular neurofibrillarytangles (NFTs). The SPs are chiefly comprised ofaggregates of β-amyloid (Aβ) peptides. The majorcomponent of NFTs is the microtubule-bindingprotein tau. Importantly, SPs and NFTs have providedneuroscientists with clues leading to the identifica-tion of new targets for drug discovery.

Twelve years ago the amyloid cascade hypothesiswas proposed to explain the neurodegenerationobserved in AD (Hardy and Higgins, 1992). Thismodel predicts that the primary influence drivingAD pathogenesis is the accumulation Aβ peptides inthe brain. Although there is no formal proof of Aβ-driven NFT formation, a number of studies suggestthat in AD, the Aβ deposits and NFTs are integrallyinvolved in the process leading to neuronal loss anddementia. Aggregates of Aβ are highly neurotoxicand are believed to play a central role in causing AD.Recently Dr. Bill Klein and colleagues (Lambert etal., 1998) discovered that small peptide aggregatesof Aβ, known as Aβ-derived diffusible ligands(ADDLs), are extremely neurotoxic. ADDLs are themost active, disease-causing form of Aβ and not onlykill neurons but inhibit memory and learning rapidlyand efficiently in rodent models. It is believed thatADDLs kill nerve cells by first binding to a cell-

surface toxicity receptor. Recognizing the therapeu-tic significance of these findings, the ISOAhas fundeda company founded by Dr. Klein, Acumen, for thepurpose of developing an in vitro assay system forthe screening of ADDL-blocking drug candidates(Chang et al., 2003).

We now know that Aβ peptides are derived fromthe proteolysis of the amyloid precursor protein(APP). This understanding has led to the identifica-tion of several proteases involved in the process; thetwo most important of these enzymes, the β- andγ-secretases, have been identified. Identification andvalidation of these therapeutic targets have led tothe therapeutic hypothesis that inhibition of theseenzymes will slow or prevent AD. Inhibitors for theseenzymes have been developed in academic, biotech-nological, and pharmaceutical laboratories. Manybiochemical tools, as well as the crystal structure ofβ-secretase, have led to the design of potent and rela-tively small transition-state inhibitors (He et al.,2003). On the basis of the X-ray crystal structure ofβ-secretase, Jordan Tang and colleagues (Ghosh et al.,2001) have developed a lead candidate peptido-mimetic inhibitor (OM99-2). By virtue of the fundingprovided to Dr. Tang and Zapaq, Inc., the ISOAcontinues to play a vital role in the development ofβ-secretase inhibitors (Tang et al., 2003). Recent devel-opments in the design and synthesis of β-secretaseinhibitors include hydroxyethylene-based peptido-mimetic compounds (Hom et al., 2004). Althoughdevelopment of a clinical candidate β-secretase drugremains a very challenging undertaking, progress sofar lends some optimism for future prospects.

Inhibition of γ-secretase has been problematicbecause of the specificity and toxicity issuesinvolved in inhibiting a multifunctional enzyme.In addition, inhibitor development has been hin-dered by the fact that the structure of the activeprotease has eluded identification until only veryrecently. Four membrane proteins are now knownto be members of the protease complex: presenilin,nicastrin, aph-1, and pen-2 (Kimberly and Wolfe,2003). Michael Wolfe (an ISOA-funded investigator)and colleagues (2002) have been successful in devel-oping transition-state analogs ([hydroxyethyl] ureapeptidomimetics) that inhibit γ-secretase activityat submicromolar concentrations. In addition, shorthelical peptides that mimic APP substrate confor-mation within the membrane lipid bilayer haveshown some promise as γ-secretase inhibitors (Daset al., 2003). Other γ-secretase inhibitors include anovel series of high-affinity, orally bioavailable

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3-amino-1,4-benzodiazepine-based compounds(Owens et al., 2003) and JLK isocoumarin com-pounds (Petit et al., 2003).

Recent studies have revealed additional prote-olytic enzyme targets for AD. The zinc metalloen-doproteases, neprilysin (Iwata et al., 2000) andinsulin-degrading enzyme (Farris et al., 2003), havebeen reported to be involved in the degradation ofAβ peptides. The significance of these enzymes inthe context of AD is that there is little evidence thatlate-onset, sporadic AD is attributable to overpro-duction of Aβ. However, an observable accumula-tion of Aβ in these AD cases leaves open thepossibility that deficits in Aβ degradation might bethe driving force behind the cerebral accumulationof Aβ in late-onset AD.

Immunotherapeutic approaches designed toinduce a humoral immune response to Aβ recentlyhave been undertaken for the treatment of AD. Intransgenic mice that overexpress the human mutatedAPP gene, immunization against Aβ(1-42) caused amarked reduction in the Aβ burden in the brain(Schenk et al., 2000). Follow-up research providedmore evidence that both active and passive Aβ immu-nization also reduced cognitive dysfunction in trans-genic mice. The ISOA has been actively involved inAD immunotherapy. Dr. Beka Solomon, one of thepioneers of immunotherapy for AD, has developedan immunization procedure for the production ofeffective anti-Aβ antibodies, using filamentousphage that display only four amino acids (Solomon2003). The EFRH sequence, encompassing aminoacids 3-6 of the 42 residues of Aβ peptide, wasfound previously to be the main regulatory site foramyloid modulation and the epitope of anti-aggregating antibodies. Engineered filamentousphage enable the display of various numbers ofEFRH copies on the phage and serve as potent car-riers of antigens. In a study presented in this volume,Dr. Solomon reports that phage displaying highEFRH copy number are effective in eliciting humoralresponse against the EFRH sequence, which in turnrelieves the amyloid burden in the brains of APPtransgenic AD mice and improves their ability toperform cognitive tasks relative to untreated mice.

In addition to active immunization, peripherallyadministered anti-Aβ antibodies have similar effects.These studies have led to the “peripheral-sink” hypo-thesis, stating that Aβ-binding molecules placed inthe periphery will alter the balance between Aβ inthe periphery and that in the brain, thus pulling Aβout of the brain (Holtzman et al., 2002).

Despite early uncertainties about the role of taupathology in AD, the discovery of multiple muta-tions in the tau gene that lead to NFTs and the onset/progression of the neurodegenerative diseaseFTDP-17 demonstrated that tau dysfunction issufficient to produce neurodegenerative disease(Hutton et al., 1998). FTDP-17, a neurodegnerativedisease related to AD and like AD, is characterizedby NFTs and dementia.

These findings have provided strong support forthe hypothesis that NFTs cause or play an importantrole in the dementia associated with AD and havemotivated scientists to initiate new experimentsaimed at understanding how changes in the struc-ture of tau, or how altered levels of specific forms oftau, could result in the abnormal production of NFTsand death of neurons. Among these new initiativeshas been the development of transgenic miceexpressing FTDP-17 mutations (Lewis et al., 2000).These mice have provided proof of concept that aber-rations in tau can lead to neurodegeneration thatclinically and neuropathologically recapitulates anumber of human diseases, including AD. More-over, these mice have revealed that mutations caus-ing FTDP-17 lead to NFT formation by specificcellular alterations in tau, including altered expres-sion, function, and biochemistry.

Unfortunately, the precise mechanisms by whichtau assembles into NFTs and causes neurodegener-ation in the human brain remain to be further eluci-dated. Continued investigation into the mechanismsof tau dysfunction, as well as the identification ofpotential disease-modifying factors, will provideadditional insight into novel strategies for the treat-ment and prevention of AD and related disorders.

Hyperphosphorylation of tau is believed to be oneof the mechanisms that triggers NFT formation. Themain feature of this mechanism is the chemical alter-ation of tau by the hyperaddition of phosphates,reducing its affinity for microtubules and leading toits aggregation and NFT formation. Two classes ofenzymes, kinases and phosphatases, contribute totau hyperphosphorylation. Kinases add phosphateto tau at specific sites in AD that are thought to con-tribute to hyperphosphorylation. Several kinaseshave been implicated in tau phosphorylation, includ-ing glycogen synthase kinase-3 (GSK-3β) Baum etal., 1996) and cyclin-dependent kinase-5 (cdK5) (Lauand Ahlijanian, 2003). Thus, these enzymes are ther-apeutic targets for AD.

Phosphatases, such as protein phosphatase 2A(PP2A), remove phosphate from tau; therefore,

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another approach to drug discovery in preventingor treating NFTs in AD would be to increase phos-phatase activity. Inhibition of phosphatase activityin AD might play a role in hyperphosphorylation(Planel et al., 2001). The ISOAhas been active in fund-ing programs aimed at inhibiting NFT formation,including studies by Drs. Khalid Iqbal and Ken Kosik,aimed at the development of high-throughput assaysto screen compound libraries for kinase inhibitorsand activators of PP2A (Kosik et al., 2002; Iqbal etal., 2003). Inhibiting tau:tau interactions that lead toNFT formation is another anti-tangle therapeuticstrategy for AD (Gamblin et al., 2003). The focus ofthis approach is to find small, blood-brain barrier-permeable molecules that inhibit abnormal tauaggregation; thus preventing NFT formation andsubsequent neurodegeneration. Several scenariosleading to pathogenic tau aggregation have beensuggested. In one, aggregation is triggered, as tau ishyperphosphorylated and no longer binds to micro-tubules; in another, aggregation occurs as a result ofa local increase in intracellular tau, perhaps fromincreased tau expression in neurons as they sproutnew neuritesin in an attempt to rescue themselvesfrom neurotoxic damage. This misregulation of tauleading to excess tau can clog axons leading toreduced axonal transport, starvation of neuronsleading to degenerating neurons, cell death, andcognitive loss (Mandelkow et al., 2003).

Neuroinflammation is a characteristic of patho-logically affected tissue in several neurodegenerativedisorders (McGeer and McGeer, 2003); these changesare observed particularly in brain areas most severelyaffected by AD. Morphological changes includean accumulation of large numbers of activatedmicroglia and astrocytes, as well as small numbersof T cells. Accompanying biochemical alterationsinclude the appearance or up-regulation of numer-ous molecules characteristic of inflammation andfree radical attack, including complement proteins,acute-phase reactants, and inflammatory cytokinesand chemokines. Epidemiological evidence sug-gests that nonsteroidal anti-inflammatory drugs(NSAIDs) might impede the onset and slow the pro-gression of AD (Launer, 2003). However, limited clin-ical data obtained with the NSAIDS rofecoxib ornaproxen have not slowed cognitive decline inpatients with mild-to-moderate AD (Aisen et al.,2003). These drugs, however, strike at the peripheryof the inflammatory reaction. Much better resultsmight be obtained if drugs were found that couldinhibit the activation of microglia or the complement

system in brain. In addition, combinations of drugsaimed at different inflammatory targets might bemuch more effective than single agents (Moore andO’Banion, 2002).

Progress has been made in synthesizing new,non-NSAID compounds. The new compounds targetgene-regulating protein kinases that are believed toplay a role in the neuroinflammatory response to Aβ.These enzymes, associated with glial activation, reg-ulate the production of inflammatory molecules suchas interleukin 1β (IL-1β) and nitric oxide (NO). Toblock Aβ-mediated increases in IL-1β, iNOS, andNO production by activated glia, a novel series of3-amino-6-phenylpyridazine derivatives have beendeveloped. These unique compounds selectivelyblock the production of inflammatory moleculeswithout inhibition of potentially beneficial glial func-tions, such as production of apolipoprotein E (Mir-zoeva et al., 2002). Dr. Martin Watterson reports inthis volume on progress in the synthesis and testingbioavailable aminopyridazines. Watterson and col-leagues have found that MW01-070C, an aminopy-ridazine that works via mechanisms distinct fromNSAIDs and p38 MAPK inhibitors, attenuatesAβ-induced neuroinflammation and neuronal dys-function in a dose-dependent manner and preventsAβ-induced behavioral impairment in a murinemodel.

A number of epidemiological studies point to alink between cholesterol metabolism and AD pathol-ogy (Wolozin 2004). Experimental studies supportthe proposed link between hypercholesterolemiaand AD and point to Aβ metabolism as the mecha-nistic connection. The exact mechanism by whichcholesterol regulates Aβ production on a cellularlevel is not known, but evidence shows that changesin membrane cholesterol content or in the ratio ofmembrane cholesterol to cytosolic cholesterol estersaffect the activity and subcellular distribution of APPsecretases and, consequently, Aβ production(Puglielli et al., 2001). In this volume, ISOA-fundedinvestigator, Dr. Dora Kovacs, has identified acyl-coenzyme A: cholesterol acyltransferase (ACAT), theenzyme regulating cholesterol ester levels, as a newdrug target for AD therapy. Her studies suggest thatACAT inhibitors might be useful for the therapeu-tic treatment or prevention of AD.

Studies with animal models, such as rabbits,guinea pigs, and Aβ-depositing transgenic mice,have provided proof of concept that cholesterol mod-ulates brain Aβ accumulation and deposition. Diet-induced hypercholesterolemia associated with

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increased brain Aβ accumulation and deposition,whereas pharmacologically induced hypocholes-terolemia attenuated brain Aβ accumulation anddeposition (Sparks et al., 2000; Refolo et al., 2000).

The hypothesis that AD is a disease in which braincholesterol homeostasis is disrupted gained strongsupport in retrospective epidemiological studies thathave reported a marked reduction in AD prevalenceor risk of developing AD in patients taking statinsfor the treatment of coronary artery disease com-pared with individuals taking nonstatin therapiesor not receiving treatment for this condition (Jick etal., 2000). Patients receiving simvastatin under-went a slower cognitive decline over time comparedwith placebo-treated patients (Simons et al., 2002).Additional randomized, placebo-controlled statintherapeutic trails are under way to confirm thesepreliminary findings. A number of experimentalstudies imply that one mechanism by which statinsreduce the risk of developing AD is the modulationof Aβ accumulation (Fassbender et al., 2001;Petanceska et al., 2002; Simons et al., 2002).

Additional evidence supporting a link betweencholesterol metabolism and AD comes from find-ings that the levels of 24S-hydroxycholesterol, a cyto-toxic elimination metabolite of cholesterol in brain,is elevated in plasma and cerebrospinal fluid (CSF)of patients with AD, and in the recent identificationof an intronic polymorphism in the gene for 24S-hydroxylase (CYP 46) as a risk factor for late-onsetAD (Kolsch et al., 2002). This polymorphism alsoassociates with increased brain Aβ levels, as well asincreased CSF phospho-tau (Papassotiropoulos etal., 2003).

Patients must receive a diagnosis before physi-cians can provide new medicines that are safe andeffective and provide care management counselingto patients and caregivers. There is considerable clin-ical value in detecting the earliest stages of AD andmonitoring subtle brain changes associated withearly, preclinical stages of the disease. Unfortunately,up to 75% of patients with AD do not receive an earlydiagnosis, and up to 2 yr passes between the onsetof first symptoms of memory problems and the timeof diagnosis. Currently, there are no sensitive, non-invasive methods for detecting the preclinical stagesof AD. Specific in vivo imaging agents targeting Aβplaques might serve as suitable markers for moni-toring the Aβ burden following disease progressionand further provide indication for therapeutic inter-vention. Currently, development of specific imag-ing agents available for direct mapping of Aβ

aggregates in the living brain has been investigated.Two methods available for the in vivo detection andquantitation of Aβ deposits in the brain are positronemission tomography (PET) and single photon emis-sion computed tomography (SPECT). Using PET andor SPECT to detect Aβ in the brains of patients withearly or preclinical AD could advance early diag-nosis. To extend the potential of these methodolo-gies, it is imperative to develop Aβ imaging agents.The best-case scenario would be the developmentof dual-amyloid tracers for either PET or the com-plementary SPECT. This would facilitate thevalidation of clinical SPECT studies based on quanti-tative PET studies. With these techniques it mightbe possible to detect Aβ in living human brain yearsbefore the onset of the clinical disease. This couldlead to major advances in prevention, although addi-tional research is needed to predict which patientswith Aβ deposits will ultimately get AD.

The ISOA has been very active in funding thedevelopment of amyloid imaging agents for earlydetection of AD (Kung et al., 2002, 2003; Wang et al.,2002, 2003). The power of this approach was recentlydemonstrated in imaging Aβ plaques in living trans-genic mice. Using a Congo red derivative, methoxy-X04 high-resolution fluorescent images of individualAβ deposits were distinguished in the brains of livingpresenilin I/APPmice (Klunk et al., 2002). In anotherstudy, a lipophilic thioflavin-T derivative (2-[4’-(methylamino)phenyl]benzothiazole-6) was usedfor PET imaging of Aβ in brains from living trans-genic mice (Mathis et al., 2002). Taken together, thesestudies demonstrate the feasibility of imaging Aβ inliving human brain in the not too distant future.

Despite significant progress made in under-standing the disease, identifying therapeutic targets,and initiating drug discovery programs aimed atthese targets, there is an urgent need for new medi-cines for the treatment of AD. Currently, it is estimatedthat there are 16 million people worldwide affectedby AD, and by the year 2050 this number will reachin excess of 60 million. The economic ramificationsof AD are very serious as well. Alzheimer’s disease(AD) is extremely costly to patients, their families,and society as a whole; in 2000, an estimated $100billion was spent in the United States on health careexpenses and lost wages for AD patients and theircaregivers. Further estimates predict that by 2030,$375 billion will be spent annually in the UnitedStates on AD. To address this need, the ISOA wasfounded with a mission to catalyze the discoveryand development of new medicines for the treatment

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of AD. Since 1998, the ISOA has provided more than$20 million to 89 research programs in academic andbiotechnology centers. During these years, the ISOAhas developed a diverse grants portfolio, as reflectedin the number of funded proposals addressing themajor therapeutic areas for AD, including anti-amy-loid, anti-oxidants, anti-tangles, anti-inflammation,neuroprotective, and cognitive enhancement thera-pies. To accomplish its mission of drug discovery forAD, the ISOA has forged a unique alliance betweentop-tier academic and biotechnology scientists com-mitted to accelerating drug discovery for AD. Com-bined, these scientists possess diverse skills andexperience that can hopefully be translated intomuch-needed new therapies for AD.

To fulfill its mission, the ISOAis committed to dis-seminate the scientific findings of its funded inves-tigators to both the scientific and lay communities.As part of this commitment, the ISOA holds anannual investigators meeting. This year, the fourthannual meeting was attended by 46 scientists from6 countries, and the proceedings are being publishedto achieve an even wider dissemination of informa-tion regarding the drug discovery and clinical accom-plishments of ISOA-funded investigators.

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Wang Y., Klunk W. E., Huang G. F., Debnath M. L., HoltD. P., and Mathis C. A. (2002) Synthesis and evaluationof 2-(3’-iodo-4’-aminophenyl)-6-hydroxybenzothiazolefor in vivo quantitation of amyloid deposits inAlzheimer’s disease. J. Mol. Neurosci. 19, 11−16.

Wang Y., Mathis C. A., Huang G. F., Debnath M. L., HoltD. P., Shao L., and Klunk W. E. (2003) Effects of lipophilic-

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