Alzheimer disease - New drugs, markets and companies

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Alzheimer disease - New drugs, markets and companies Published on September 2011

Report Summary Alzheimer's disease remains a challenge in management. With nearly 8 million sufferers from this condition in the seven major markets of the world and anticipated increases in the future. Considerable research is in progress to understand the pathomechanism of the disease and find a cure. The only drugs approved currently are acetylcholinesterase inhibitors but they do not correct the basic pathology of the disease, beta amyloid deposits and neurofibrillary tangles. Several new approaches emphasize neuroprotection as well. Early diagnosis of Alzheimer's disease is an important first step in management. Several biomarkers in cerebrospinal fluid, blood and urine can detect the disease. They provide a valuable aid to the clinical examination and neuropsychological testing which are the main diagnostic methods supplemented by brain imaging. Genotyping, particularly of ApoE gene alleles is also useful in the evaluation of cases and planning management. The current management of Alzheimer's disease is reviewed and it involves a multidisciplinary approach. Acetylcholinesterase inhibitors are mostly a symptomatic treatment but some claims are made about a neuroprotective effect. Currently the only approved neuroprotective therapy in is memantine. Management of these patients also require neuroleptics for aggressive behavior and antidepressants. There is an emphasis on early detection at the stage of mild cognitive impairment and early institution of neuroprotective measures. The value of mental exercise in delaying the onset of Alzheimer's disease is being recognized. Research in Alzheimer's disease still aims at elucidating the basic pathomechanisms. Animal models are important for research, particularly in testing some of the potential therapeutic approaches. There is considerable research in progress at the various centers, some of which is funded by the National Institute of Aging of the National Institutes of Health. Over 300 different compounds are at various stages of development for the treatment of Alzheimer's disease. These are classified and described. There are non-pharmacological approaches such as vagal nerve stimulation and cerebrospinal fluid shunting, which are in clinical trials. Over 176 clinical trials are listed, of which 126 are still in progress and 50 were discontinued for various reasons. Alzheimer's disease market in the seven major markets is analyzed for the year 2010. Several new therapies are expected to be in the market and the shares of various types of approaches are estimated for the future up to the year 2020. As a background to the markets, pharmacoeconomic aspects of care of Alzheimer disease patients and patterns of practice are reviewed in the seven major markets. Profiles of 141 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 107 collaborations. The bibliography contains over 600 publications that are cited in the report.The report is supplemented with 44 tables and 14 figures.

Table of Content TABLE OF CONTENTS

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20

Seven stages of Alzheimer disease 22 AD as a terminal illness 24 Detection of AD in the preclinical phase 24 Differentiation of AD from other dementias 24 Differentiation of AD from non-dementing disorders 25 Cerebral insufficiency and AD

26

Memory deficits and preclinical AD 26 Mild cognitive impairment 27 Evolution of diagnostic criteria of AD 29 Revised criteria for the clinical diagnosis of AD

30

Epidemiology 31 Epidemiology of aging 31 Epidemiology of dementia 32 Epidemiology of AD 32 Prevalence of AD according to age

33

Mortality in AD 33 Pathophysiology of AD 33 Cerebral atrophy and neuronal loss 33 Neuritic plaques and neurofibrillary tangles 34 Sp proteins as markers of neuronal death in AD 34 Role of tau in the pathogenesis of AD 35 Amyloid precursor protein 36 Relation of APP mutations to CNS disorders

36

Relation of APP to A' deposits and pathogenesis of AD 37 APP intracellular domain 38 Role of secretases in amyloid cascade 39 Role of exosomal proteins

40

Role of nicastrin 41 Neurotixicity of A' deposits

41

Relation of A' deposits to synaptic activity 41 Dysfunction of TGF-' signaling accelerates A' deposition 42 Role of TMP21 in presenilin complexes and A' formation

42

Role of A' dimers in the pathogenesis of AD 43 Structure'neurotoxicity relationships of A' oligomers 43 A' deposit and clearance

43

Impairment of mitochondrial energy metabolism

44

A'-binding alcohol dehydrogenase links AD to mitochondrial toxicity 45 Neural thread protein 45 Loss of synaptic proteins 45 AD and Down syndrome

46

Overlapping pathologies of AD and Parkinson disease 46 AD and age-related macular degeneration 47 Myelin hypothesis of AD

47

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49

Aerobic glycolysis and AD 49 Astrocytes and AD 49 Axonal transport failure in AD 50 Cell-cycle hypothesis 50 Chronic heart failure link with AD 51 Creatine and AD 51 Disturbances of interaction of nervous system proteins 51 DENN/MADD expression and enhanced pro-apoptotic signaling in AD 51 Gonadotrophins and AD

52

Glutamate transport dysfunction in AD

52

Innate immune system and AD 53 Insulin, diabetes and AD 54 Mechanisms underlying cognitive deficits in AD 54 Monoamine oxidase and AD 55 Neuroinflammation and AD 55 Neurotransmitter deficits 56 Neurotrophic factors 57 NF-'B signaling and the pathogenesis of neurodegeneration 57 Nitric oxide and AD

58

Nogo receptor pathway 60 Oxidative stress and AD

60

Prostaglandins and AD 62 Quinolinic acid and AD 62 Retromer deficiency 62 Serotonin and AD

63

Spherotoxin 63 Synaptic failure in AD Transmission of AD

63 64

Ubiquitin-proteasome system in pathogenesis of AD

64

Risk factors in the etiology of AD 65 Aging and developmental abnormalities of the cholinergic system 66 Cholesterol, dietary lipids, and A' 66 Exposure to magnetic fields 67 Family history of AD 67 Homocysteine and AD

67

Level of education/type of job and risk of AD 68 Metals and AD 69 Obesity 70 Proneness to psychological distress and risk of AD 71 Reduced muscle strength 71 Sleep deprivation

71

Traumatic brain injury and AD

72

Vascular risk factors for AD 73 Vitamin B12 and folate 74

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74

75

Pathomechanism of memory impairment and AD

75

Concluding remarks on pathophysiology of AD 76 Genetics of AD 77 Familial AD 77 Presenilins and calcium channel leak in pathogenesis of familial AD

79

Late onset AD 79 Genomics of AD 79 Introduction to genomics

79

Genes associated with Alzheimer disease 80 AlzGene database 81 ApoE gene 81 ApoE genotype and nitric oxide 82 ApoE genotype modulates AD phenotype

83

APOE genotype and age-related myelin breakdown 83 ApoE receptor interaction with NMDA receptor 84 ApoE and ApoER2 84 ApoE receptor LR11 as regulator of A' 85 Arctic mutation

85

CALHM1 polymorphism and AD 85 CLU, CRI and PICALM

85

CYP46 and risk for AD 86 DAPK1 gene variants and AD 86 Genetic variants associated with late-onset AD

86

Copy number variation (CNV) in LOAD 87 LRRTM3 as a candidate gene for AD 87 MTHFD1L gene variant associated with AD 87 OGG1 mutations associated with AD 88 SORL1 gene in AD 88 TOMM40 gene and risk of AD 88 International Genomics of Alzheimer's Project 88 Molecular neuropathology 89 Role of microRNAs in AD 89 AD as a polygenic disorder 90 Proteomics of AD 90 Introduction

90

Application of proteomic technologies to study AD 90 Protein misfolding in AD 92 Common denominators of AD and prion diseases

93

Amyloid fibrils as a common feature of AD and prion diseases 94 FE65 proteins and AD 94 Diagnostic Procedures for Alzheimer Disease 95 Importance of the diagnosis of Alzheimer disease 95 Methods of diagnosis of AD 95 Self-administered olfactory test

96

Neuropsychological testing 96 Assessment and evaluation

97

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98

Alzheimer Disease Cooperative Study 99 CDR-SOB score

99

Clinician's Interview-Based Impression of Change

99

Resource Utilization in Dementia Battery 99 DETECT' System

99

Electrophysiology

100

EEG-based bispectral index 100 Event-related potentials 100 Correlation of electrical activity of the brain with cognition 100 Early detection of cataract associated with AD 101 Retinal imaging to detect A' deposits 101 Laboratory methods for diagnosis of AD 101 Monitoring of synthesis and clearance rates of A' in the CSF Molecular diagnostics for AD Genetic tests for AD

101

102

103

ApoE genotyping 103 Gene expression patterns in AD 104 Molecular fingerprinting of the immune system in AD 104 Microarray-based tests for AD 104 Monoclonal antibody-based in vitro diagnosis of AD from brain tissues Biomarkers of AD

105

105

The ideal biomarker for AD 107 CSF biomarkers of AD 107 CSF sulfatide as a biomarker for AD 107 Glycerophosphocholine as CSF biomarker in AD 108 Protein biomarkers of AD in CSF 108 Amyloid precursor protein 110 Tau proteins in CSF 110 Tests for the detection of A' in CSF

110

Tests combining CSF tau and A' 111 Urine tests for AD 111 Blood tests for AD 112 Blood A' levels 112 Blood test for AD based on heme oxygenase-1 113 Blood test for AD based on RNA hybridization 113 GSK-3 elevation in white blood cells 113 Lymphocyte Proliferation Test 114 Protein kinase C in red blood cells 114 Sphingolipids 114 Tests based on protein biomarkers in blood 114 A skin test for early detection of AD 115 Saliva A'42 level as a biomarker of AD

115

Nanotechnology to measure A'-derived diffusible ligands 115 Simultaneous measurement of several biomarkers for AD 116

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117

Imaging in AD 118 Computed tomography 118 Magnetic resonance imaging 118 Arterial spin labeling with MRI 119 Magnetic resonance microscopy 119 Magnetic resonance spectroscopy 119 Single photon emission computed tomography and modifications Positron emission tomography

120

121

In vivo imaging of A' deposits by PET 122 Pittsburgh compound B and PET 123 Florbetapir-PET 124 Florbetaben-PET 124 In vivo detection of A' plaques by MRI

124

Imaging agents for A' and neurofibrillary tangles

125

Targeting of a chemokine receptor as biomarker for brain imaging 126 Radioiodinated clioquinol as a biomarker for A'

126

Imaging neuroinflammation in AD 126 Preclinical diagnosis of AD

126

Meta-analysis of literature on imaging in AD 127 Alzheimer Disease Neuroimaging Initiative 128 Concluding remarks on imaging for diagnosis of AD 128 Diagnosis of MCI and prediction of AD

129

Diagnosis of MCI 129 Computer-Administered Neurophychological screen for MCI 129 Infrared eye-tracking technology to detect MCI 129 PET for detection of MCI

129

MRI for detection of MCI

130

Presymptomatic detection of AD PredictAD project

130

131

Prediction of AD in patients with MCI

131

Combination of MMSE and a memory test for prediction of AD 131 Biochemical biomarkers in CSF for prediction of AD 131 Structural MRI biomarkers for prediction of AD 132 Magnetoencephalography for detection of MCI and AD 132 Concluding remarks about prediction of AD in MCI

133

Criteria for diagnosis of AD 133 Role of biomarkers in diagnosis of AD dementia

133

Ethical aspects of diagnostics for AD 134 Genetic testing for AD 134 Ethical issues of brain imaging in AD

135

Companies involved in diagnosis of AD 135 3 Management of Alzheimer Disease

137

Introduction 137 Cholinergic approaches 137 Mechanism of action of cholinesterase inhibitors 138

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139

Donepezil 140 Rivastigmine

141

Galantamine 142 Duration of treatment with ChE inhibitors 143 Comparative studies of ChE inhibitors Donepezil versus rivastigmine

144

Donepezil versus galantamine

144

143

An assessment and future prospects of anticholinergic therapies 144 Neuroprotection in Alzheimer's disease 145 Memantine

146

Combination of memantine with ChE inhibitors 149 Monoamine oxidase inhibitors 149 Selegiline

150

Synaptoprotection in AD 150 Drugs for noncognitive symptoms in AD

150

Antidepressants 150 Antipsychotics 151 ChE inhibitors for behavioral and psychological disorders in AD

151

Concluding remarks and other drugs for agitation in AD 152 Sensory stimulation 152 Non-pharmacological treatments of AD 153 Management of memory loss in AD 153 Exposure to electromagnetic fields for treatment of AD 154 Application of electrical fields for improvement of cerebral function 154 High-frequency electromagnetic field treatment of AD 154 Vagal nerve stimulation

154

Cerebrospinal fluid shunting

155

Omental transposition 156 Microchip-based hippocampal prosthesis for AD

156

Nutritional therapies for AD 156 Axona 156 Cocktail of dietary supplements for AD 156 Docosahexaenoic acid 157 Magnesium 158 Nicotinamide for the treatment of AD Omega-3 fatty acids

159

159

Preventing decline of mental function with aging and dementia Prevention of Alzheimer disease

160

160

Mental training 161 Physical exercise 161 Higher level of conscientiousness and decreased risk of AD

162

Caloric restriction 162 Nutritional factors in prevention of AD 162 Grapes and red wine 163 Black and green teas 164 Caffeine 164 Drugs to prevent Alzheimer disease 165

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165

165

Management of mild cognitive impairment 165 Management of Down syndrome

167

Guidelines for use of anti-dementia drugs in clinical practice 167 Donepezil and/or memantine 168 General care of the Alzheimer disease patients 169 Strategies for the management of Alzheimer disease 169 4 Research in Alzheimer Disease

171

Introduction 171 Animal models of Alzheimer disease

171

Lesional models 171 Cerebroventricular injection of A' in rats 171 Lentiviral vector-based models of amyloid pathology

172

AAV-mediated gene transfer to increase hippocampal A' Transgenic mouse models

172

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Quantitative assessment of amyloid load in transgenic models 174 In vivo magnetic resonance microimaging in transgenic models of AD

174

Transgenic model of AD with suppression of A' production 174 Transgenic AD11 anti-NGF mice 175 Genetically altered mice with deficiency of vesicular ACh transporter 175 Limitations of mouse models of Alzheimer disease

175

Cholesterol-fed rabbits as models for AD 176 Zebrafish model for AD 176 Transgenic invertebrate models of Alzheimer disease 177 Drosophila model of AD 177 Caenorhabditis elegans Alzheimer disease model 178 Cell systems for AD research 178 In vitro neuronal cell Lines 178 Single-gene expression system for use in cell culture 179 Transgenic cells 179 In silico models 180 Estimation of progression rates of Alzheimer disease 180 Clinical trial methods in Alzheimer disease 181 Molecular imaging as a guide to drug development 181 Use of MRI and PET in clinical trials

182

Cognitive-function assessment in clinical trials 182 Clinical trials in mild cognitive impairment 183 Research in AD as a basis for future therapies

183

Use of microarrays for studying pathogenesis of AD

183

Computational brain mapping in AD 183 Study of neurogenesis in AD 184 Study of 3D structure of A' 184 Solid-state NMR to study precursors of A' 184 Research in Alzheimer disease at academic centers

184

Role of NIH in AD research 185 NIH Clinical Trials Database for AD

185

Alzheimer Research Consortium 185

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187

Introduction 187 Categories of drugs in development for AD 187 Memory-enhancing drugs 189 Enhancing memory by drugs that block eIF2' phosphorylation

189

Drugs based on cholinergic approaches 189 AP2238 190 Butyrylcholinesterase inhibitors 190 Donepezil-tacrine hybrids 190 Drugs modulating gamma-aminobutyric acid receptors 191 Ganstigmina 191 Methanesulfonyl fluoride 191 Muscarinic receptor modulators 192 Muscarinic M1 agonists 192 Muscarinic M2 antagonists 193 Nicotine and nicotinic receptor modulators 193 Nicotine 193 Nicotinic receptor modulators 194 GTS21 195 Ispronicline

195

JWB1-84-1 195 Neuropeptide/neurotransmitters 196 Somatostatin release enhancers

196

Glutamate receptor modulators 196 Physiology and pharmacology of glutamate receptors 197 NMDA receptor ion channel complex 197 Metabotropic glutamate receptors 198 Glutamate receptor modulators as potential therapeutics for AD 199 Non-competitive NMDA modulators

200

AMPA modulators 200 Drugs affecting multiple neurotransmitters 201 Ensaculin 201 NS2330 201 RS-1259

201

Lecozotan 202 Vaccines for AD 202 Active immunization with A'

203

AN-1792 vaccine 203 Complications in clinical trials with AN-1792

203

Effects of A' vaccine on the brain 203 Strategies to avoid undesirable effect of A' vaccination 204 Passive immunization in AD 205 Passive immunization with MAbs 205 Delivery of the passive antibody directly to the brain

207

Systemic injection of MAbs to treat AD 208 Combination of A' immunotherapy and CD40-CD40L blockade

208

Shaping the immune responses elicited against A' 208

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209

Gene vaccination 209 Modified A' nasal vaccine 209 Transdermal A' vaccination 209 Other vaccines for AD

210

Nasal vaccination with Proteosome' adjuvant

210

T-cell vaccination with glatiramer acetate adjuvant 211 Early start of immunotherapy to clear A' plaques 211 Reversal of cholinergic dysfunction by anti-A' antibody 211 Immune modulation via TRL9 to reduce A'

211

Mechanisms by which A' antibodies reduce amyloid accumulation in the brain 212 Perspectives on vaccines for AD 212 Companies involved in AD vaccines 214 Inhibition of amyloid precursor protein aggregation 215 Secretase modulators

215

Neuroprotection by '-secretase cleaved APP Inhibitors of '-secretase

216

Inhibitors of '-secretase

217

216

Amyloid-derived diffusible ligands 218 GABA receptor modulation by etazolate and APP processing 219 Depletion of serum amyloid P 219 Trojan-horse approach to prevent build-up of A' aggregates Drugs that inhibit the formation of A' 22R-hydroxycholesterol

219

220

220

Acylaminopyrazole 221 Cadmium telluride nanoparticles prevent A' fibril formation 221 Cannabinoids

221

Chelation therapy for AD 222 Clioquinol and PBT2 222 Copper chelation by FKBP52 223 Zinc chelation from amyloid plaques 224 Next generation multifunctional chelating agents for AD 224 Heparin and its derivatives 224 A reassessment of the role of heparin in AD

224

Enoxaparin 225 Heparan sulfate

225

Imatinib mesylate 225 Laminin 226 NSAIDs 226 Flurbiprofen analogs with A'42-lowering action 227 Nitric oxide-donating NSAIDs 228 In vivo demonstration of the effects of NSAIDs on brain in AD 228 Paclitaxel 228 Phenserine

229

Tolserine 229 Platinum-based inhibitors of A' 230 Scyllo-cyclohexanehexol 230 Ubiquitin C-terminal hydrolase L1 230

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232

Strategies to prevent deposits and enhance clearance of A' 232 4,5-dianilinophthalimide for disruption of A'1-42 fibrils 233 ABCA1 overexpression to lower amyloid deposits 234 Beta-sheet breakers 234 Blocking ApoE/A' interaction to reduce A' plaques 234 Clearance of A' across the blood-brain barrier 235 Enhanced PKC' activity promotes clearance of A' Galantamine-induced A' clearance

235

235

Inhibitors of A' dehydrogenase 236 Intravenous immune globulin 236 Meptides

237

Monoclonal antibody to bind and remove A' 237 Nanotechnology for removal of A' deposits

237

Role of matrix metalloproteinases in clearance of A' 238 SAN-61 for cleavage of fibril and soluble amyloid 238 Serum amyloid P component depletion

238

Small molecule DAPH for clearance of amyloid 239 Companies developing A'-directed therapeutics for AD 239 Antiinflammatory and antimicrobial drugs Dapsone

240

240

Antimicrobial drugs against C pneumoniae

241

PPAR-gamma agonists 241 Inhibitors of neuroinflammation 242 Cyclophosphamide 242 Etanercept 242 MW01-5-188WH 243 Antidiabetic drugs 243 Rosiglitazone

243

Pioglitazone 244 Nootropics

244

Acetyl-L-carnitine

244

Cerebrolysin 245 Ergot derivatives 245 Lisuride 245 Dihydroergocryptine

245

Neuroprotective effect drugs not primarily developed for AD 246 Antihypertensive drugs 247 Angiotensin-converting enzyme inhibitors

247

Angiotensin receptor blockers 247 Dimebolin 247 Drugs acting on estrogen receptors 248 Estrogen 248 Raloxifene 249 Neurosteroids 249 Pregnenolone sulfate 250

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250

Lithium 250 MAO-B inhibitors 251 Ladostigil tartrate 251 Memoquin 251 Methylene blue

252

Nimodipine

252

Rapamycin

253

Statins 253 Testosterone

254

Valproic acid 255 Future prospects of neuroprotection in AD 255 Targeting Cdk5 pathway Antioxidants Colostrinin

255

256 256

Curcumin 257 Melatonin 258 Synthetic catalytic scavengers

258

Dehydroascorbic acid 258 Omega-3 fatty acids 259 Vitamins 259 Vitamin E as antioxidant 259 Vitamins to lower homocysteine 259 Folic acid 260 Aminopyridazines 260 Nanobody-based drugs for AD

260

Nitric oxide based therapeutics for AD

261

Nitric oxide mimetics 261 iNOS inhibitors for AD

261

Novel drugs for AD from natural resources 261 Berberine chloride 262 Centella asiatica 263 Ginko biloba 263 Huperzine-A 264 Hyperforin 265 Melissa officinalis

265

Nostocarboline derived from cyanobacteria

265

PTI-00703 265 Salvia 266 Securinega suffruticosa 266 Withania somnifera ZT-1

266

266

Cholesterol and AD 267 ACAT inhibitors

268

Role of gene for cholesterol ester transfer protein

269

Cholesterol 24S-hydroxylase as a drug target for AD 269 Selectively increase of ApoA-I production Neurotrophic factors

269

269

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270

Brain derived neurotrophic factor 270 Insulin-like growth factor-1 270 Nerve growth factor 271 Neotrofin (AIT-082) 272 Limitations of the use of NTFs for AD

272

Role of serotonin modulators in AD 272 Xaliproden

273

5-HT1A receptor antagonists

273

5-HT6 antagonists 273 5-HT4 receptor agonists 273 PRX-03140 274 Cell therapy for AD

274

Stem cell transplantation for AD

275

Potential benefits of grafting NSCs in AD 275 NSCs improve cognition in AD via BDNF

275

Drugs for enhancing neuronal differentiation of implanted NSCs 275 Implantation of encapsulated cells for delivering NGF 276 Gene therapy for AD

276

ApoE gene therapy 276 Humanin gene therapy 276 Neprilysin gene therapy

277

NGF gene therapy 277 Targeting plasminogen activator inhibitor type-1 gene Antisense approaches to AD

278

278

RNAi approaches to AD 279 Combined therapeutic approaches to AD 280 Drug delivery for Alzheimer disease

280

Delivery of thyrotropin-releasing hormone analogs by molecular packaging 281 Nanoparticle-based drug delivery for Alzheimer's disease 281 Transdermal drug delivery in Alzheimer's disease 282 Transdermal rivastigmine 282 Intranasal delivery of therapeutics for AD 282 Intranasal delivery of tacrine

282

Intranasal delivery of nerve growth factor to the brain 283 Circadian rhythms and timing of cholinesterase inhibitor therapy

283

Clinical trials for AD 283 Drugs for AD that were discontinued in clinical trials 287 Evaluation of clinical trials of AD

290

Monitoring of cognitive function during clinical trials

290

Drug discovery for AD 291 Drugs acting on signaling pathways 291 Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 291 Drugs to reverse inhibition of the PKA/CREB pathway in AD 291 Inhibition of the CD40 signaling pathway 292 JNK pathway as a target

292

Mitogen-activated protein kinase pathway as target 293 Protein kinase C activators

293

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294

Proteomics and drug discovery for AD 294 Small molecule compounds binding to neurotrophin receptor p75NTR

295

Targeting Vav in tyrosine kinase signaling pathway 296 Novels targets/receptors for AD drug discovery

296

Activation of cerebral Rho GTPases 296 Activators of insulin-degrading enzyme 297 Blockade of TGF-'-Smad2/3 signaling in peripheral macrophages

297

Calcium channel blockers 297 Casein kinase 1 298 Cyclin-dependent kinase-5

298

Heat shock protein 90 inhibitors 298 Histone deacetylase 1 299 Inactivation of aph-1 and pen-2 reduces APP cleavage 299 NF-'B inhibitors

300

Kinases and phosphatases as targets for AD therapeutics 300 Neutral sphingomyelinase inhibitors 300 Phosphodiesterase inhibitors Pin 1 as a target in AD

300

301

Protein phosphatase 5 as a neuroprotective in AD 301 Src homology-containing protein-1 inhibitors 302 Targeting GABAergic system 302 Pharmacogenomics of Alzheimer disease 302 Personalized therapy of AD 302 Genotyping and AD therapeutics

303

Biomarkers and companion diagnostics for AD 304 Regulatory aspects of drug development for AD

304

EMEA guidelines for drug development for AD 304 Concluding remarks and future prospects of drugs for AD Markets & Finances of AD Care

305

307

Introduction 307 Pharmacoeconomics of treatment of AD

307

Quality of Life in relation to economics of AD 307 Costs associated with Alzheimer disease 307 Pharmacoeconomics of donepezil 308 Pharmacoeconomics studies using rivastigmine

308

Pharmacoenonomics studies using galantamine

309

A comparison of pharmacoenonomics outcomes with different ChE inhibitors 309 Pharmacoenonomics studies using memantine 310 Patterns of AD care in major markets 310 Care of AD patients in the US 310 Cost of care

310

Medicare and AD 311 Patterns of practice in AD care 312 Opinions of physicians' organizations on drugs for dementia 312 Care of AD patients in the UK 313

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313

Patterns of practice in AD care 313 Retraction of NICE recommendations to NHS 314 Care of AD patients in Germany 315 Care of AD patients in France 315 Care of AD patients in Italy 316 Care of AD patients in Spain

316

Care of AD patients in Japan 316 Markets for AD diagnostics 317 Markets for AD therapeutics

317

Geographical markets for AD 317 Markets for currently approved drugs for AD 318 Markets for generic AD drugs 318 Future growth of AD market

319

Statins 319 Limitations of AD drug development by the biotechnology industry

319

Unmet needs in the management of AD 320 Drivers of AD markets 321 Increase of the aged populations 322 Increase in the number of approved drugs for AD

322

Limitations of the current therapies 322 Improvements in diagnosis 322 Increasing awareness of the disease 323 Companies 325 Introduction 325 Profiles of companies 325 Collaborations 473 References 477 List of Tables Table 1-1: Historical landmarks relevant to Alzheimer disease 19 Table 1-2: Clinical features of Alzheimer disease 20 Table 1-3: Non-Alzheimer dementias 25 Table 1-4: A guide to evaluation for MCI due to AD 28 Table 1-5: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease 29 Table 1-6: Relation of mutations in amyloid precursor protein to CNS disorders 37 Table 1-7: Risk factors for Alzheimer's disease 65 Table 1-8: Genes linked to AD

80

Table 1-9: Abnormalities of expression of brain proteins in Down's syndrome and AD 91 Table 2-1: Classification of methods of diagnosis of Alzheimer disease 95 Table 2-2: Neuropsychological test batteries and scales for Alzheimer's disease

96

Table 2-3: Available molecular diagnostic tests for Alzheimer disease 102 Table 2-4: Classification of biomarkers of AD in blood and CSF 105 Table 2-5: Characteristics of an ideal biomarker for Alzheimer disease 107 Table 2-6: Role of biomarkers in diagnosis of AD dementia

134

Table 2-7: Companies involved in the diagnosis of Alzheimer disease 135 Table 3-1: Classification of treatments for Alzheimer disease

137

Table 3-2: Cholinergic approaches used in the treatment of Alzheimer disease

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167

Table 4-1: Transgenic mouse models of Alzheimer disease 172 Table 5-1: Classification of therapies in development for Alzheimer disease 187 Table 5-2: Drugs for AD targeting nACh receptors

194

Table 5-3: Ionotropic glutamate receptors 196 Table 5-4: Classification of mGluRs

197

Table 5-5: Glutamate receptor modulators as potential therapeutic agents in AD

199

Table 5-6: Companies involved in developing vaccines for AD 214 Table 5-7: Secretase modulators in clinical trials 215 Table 5-8: Companies developing A'-directed therapeutics for AD 239 Table 5-9: Innovative neuroprotective approaches for Alzheimer disease 246 Table 5-10: Herbal therapies for AD 262 Table 5-11: Novel drug delivery methods for Alzheimer disease therapies 280 Table 5-12: Clinical trials in Alzheimer disease 283 Table 5-13: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 288 Table 6-1: Direct and indirect costs associated with Alzheimer disease 308 Table 6-2: Prevalence of AD in major markets 2010-2020 317 Table 6-3: AD market values from 2010-2020 in the seven major world markets 318 Table 6-4: Markets for currently approved AD drugs 2010-2020 318 Table 6-5: Potential markets for drugs in development 2010-2020 319 Table 6-6: Limitations of AD drug discovery and development by the biotechnology industry 320 Table 6-7: Factors that drive AD markets 321 Table 7-1: Major players in Alzheimer's disease therapeutics 325 Table 7-2: Collaborations relevant to Alzheimer disease 473 List of Figures Figure 1-1: Percentages of world population of people over the age of 65 according to more developed and less developed portions ' 2000 to 2050 31 Figure 1-2: Prevalence of different types of dementia 32 Figure 1-3: Mechanisms of A' clearance 44 Figure 1-4: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease

59

Figure 1-5: Oxidative stress and Alzheimer disease 61 Figure 1-6: Role of proteosome inhibition in A' generation and neurodegeneration 65 Figure 1-7: Pathomechanism of AD 77 Figure 3-1: Metabolism of acetylcholine

139

Figure 3-2: Neuroprotective effective of galantamine in AD

143

Figure 3-3: Strategies for the management of Alzheimer disease 169 Figure 5-1: NMDA receptor ion channel complex

198

Figure 5-2: Neurotoxicity due to misfolding of A'1-42 233 Figure 5-3: Role of proteomics in drug discovery and development for Alzheimer disease

294

Figure 6-1: Unmet needs in the management of Alzheimer disease 321

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