阿兹海默病：新药・市场・企业研究报告——Alzheimer disease - new drugs, markets and companies

2010-8

摘要

在全球主要的7个市场中、阿兹海默症患者约800万人、预测今后的病患数量会有増加的趋势。

本报告书内容包括：针对阿兹海默症的治疗药品开发动向及相关企业的信息等进行调查、内容纲要摘记如下：

目录

• 实施摘要
• 临床特性・免疫学・病理学
• 阿兹海默症的诊断处置
• 阿兹海默症的管理
• 阿兹海默症的研究
• 针对阿兹海默症的创新药物・开发
• 阿兹海默症的看护市场及资金支持
• 企业信息
• 参考

Abstract

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 171 clinical trials are listed, of which 127 are still in progress and 44 were discontinued for various reasons.

Alzheimer' s disease market in the seven major markets is analyzed for the year 2008. 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 2018. 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 140 companies involved in developing diagnostics and therapeutics for Alzheimer' s disease are presented along with 105 collaborations. The bibliography contains over 600 publications that are cited in the report.The report is supplemented with 42 tables and 14 figures.

Table of Contents

0. Executive Summary 17

1. Clinical Features, Epidemiology and Pathology 19

• Introduction 19
• Historical aspects 19
• Clinical features of Alzheimer disease 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
• Diagnostic criteria of AD 29
• Epidemiology 30
• Epidemiology of aging 30
• Epidemiology of dementia 31
• 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 Aβ deposits and pathogenesis of AD 37
• APP intracellular domain 38
• Role of secretases in amyloid cascade 38
• Role of exosomal proteins 40
• Role of nicastrin 40
• Neurotixicity of Aβ deposits 41
• Relation of Aβ deposits to synaptic activity 41
• Dysfunction of TGF-β signaling accelerates Aβ deposition 41
• Role of TMP21 in presenilin complexes and Aβ formation 42
• Role of Aβ dimers in the pathogenesis of AD 42
• Structure - neurotoxicity relationships of Aβ oligomers 43
• Aβ deposit and clearance 43
• Impairment of mitochondrial energy metabolism 44
• Aβ 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
• Blood-brain barrier in AD 47
• Blood vessel damage in AD 49
• Loss of serotonin 1A receptors in the brain 49
• Factors in pathogenesis of AD 49
• Astrocytes and AD 49
• Axonal transport failure in AD 50
• Cell-cycle hypothesis 50
• Chronic heart failure link with AD 50
• 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 51
• Glutamate transport dysfunction in AD 52
• Innate immune system and AD 53
• Insulin, diabetes and AD 53
• Mechanisms underlying cognitive deficits in AD 54
• Monoamine oxidase and AD 55
• Neuroinflammation and AD 55
• Neurotransmitter deficits 56
• Neurotrophic factors 56
• NF-kΒ signaling and the pathogenesis of neurodegeneration 57
• Nitric oxide and AD 57
• 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 63
• Transmission of AD 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 Aβ 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
• AD versus non-dementing changes in the aging brain 74
• AD and cognitive impairment with aging 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 82
• ApoE genotype and nitric oxide 83
• ApoE genotype modulates AD phenotype 83
• APOE genotype and age-related myelin breakdown 84
• ApoE receptor interaction with NMDA receptor 84
• ApoE and ApoER2 84
• ApoE receptor LR11 as regulator of Aβ 85
• Arctic mutation 85
• CALHM1 polymorphism and AD 85
• CLU, CRI and PICALM 86
• CYP46 and risk for AD 86
• DAPK1 gene variants and AD 86
• Genetic variants associated with late-onset AD 87
• LRRTM3 as a candidate gene for AD 87
• OGG1 mutations associated with AD 87
• SORL1 gene in AD 88
• TOMM40 gene and risk of AD 88
• Copy number variation (CNV) in LOAD 88
• Molecular neuropathology 88
• AD as a polygenic disorder 89
• Proteomics of AD 89
• Introduction 89
• Application of proteomic technologies to study AD 89
• Protein misfolding in AD 91
• Common denominators of AD and prion diseases 92
• Amyloid fibrils as a common feature of AD and prion diseases 92
• FE65 proteins and AD 93

2. 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
• 7-minute screen 97
• 15-point risk index 98
• Measurement of aggregation in anterior segment of the eye 98
• Activities of Daily Living 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
• Early detection of cataract associated with AD 100
• Retinal imaging to detect Aβ deposits 101
• Laboratory methods for diagnosis of AD 101
• Monitoring of synthesis and clearance rates of Aβ in the CSF 101
• Molecular diagnostics for AD 102
• Genetic tests for AD 103
• ApoE genotyping 103
• Gene expression patterns in AD 103
• 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 104
• Biomarkers of AD 104
• The ideal biomarker for AD 106
• CSF biomarkers of AD 107
• CSF sulfatide as a biomarker for AD 107
• Glycerophosphocholine as CSF biomarker in AD 107
• Protein biomarkers of AD in CSF 107
• Amyloid precursor protein 109
• Tau proteins in CSF 109
• Tests for the detection of Aβ in CSF 110
• Tests combining CSF tau and Aβ 110
• Urine tests for AD 111
• Blood tests for AD 111
• Blood Aβ levels 111
• Blood test for AD based on heme oxygenase-1 112
• Blood test for AD based on RNA hybridization 112
• GSK-3 elevation in white blood cells 113
• Lymphocyte Proliferation Test 113
• Protein kinase C in red blood cells 113
• Tests based on protein biomarkers in blood 113
• A skin test for early detection of AD 114
• Nanotechnology to measure Aβ derived diffusible ligands 114
• Simultaneous measurement of several biomarkers for AD 115
• Plasma biomarkers of drug response in AD 115
• Concluding remarks about biomarkers for AD 116
• Imaging in AD 116
• Computed tomography 116
• Magnetic resonance imaging 116
• Arterial spin labeling with MRI 117
• Magnetic resonance microscopy 117
• Magnetic resonance spectroscopy 118
• Single photon emission computed tomography and modifications 118
• Positron emission tomography 119
• In vivo imaging of Aβ deposits by PET 121
• Pittsburgh compound B and PET 121
• 18F-AV-45 and PET 122
• Florbetaben (BAY 94-9172) and PET 122
• In vivo detection of Aβ plaques by MRI 123
• Imaging agents for Aβ and neurofibrillary tangles 123
• Targeting of a chemokine receptor as biomarker for brain imaging 124
• Radioiodinated clioquinol as a biomarker for Aβ 124
• Imaging neuroinflammation in AD 125
• Preclinical diagnosis of AD 125
• Meta-analysis of literature on imaging in AD 126
• Alzheimer Disease Neuroimaging Initiative 126
• Concluding remarks on imaging for diagnosis of AD 127
• Diagnosis of MCI and prediction of AD 127
• Diagnosis of MCI 127
• Computer-Administered Neurophychological screen for MCI 127
• Infrared eye-tracking technology to detect MCI 127
• PET for detection of MCI 128
• MRI for detection of MCI 128
• Presymptomatic detection of AD 128
• PredictAD project 129
• Use of biomarkers to predict AD in patients with MCI 129
• Biochemical biomarkers in CSF for prediction of AD 129
• Structural MRI biomarkers for prediction of AD 130
• Magnetoencephalography for detection of MCI and AD 130
• Concluding remarks about prediction of AD in MCI 131
• Ethical aspects of diagnostics for AD 131
• Genetic testing for AD 131
• Ethical issues of brain imaging in AD 132
• Companies involved in diagnosis of AD 133

3. Management of Alzheimer Disease 135

• Introduction 135
• Cholinergic approaches 135
• Mechanism of action of cholinesterase inhibitors 136
• Choline and lecithin 137
• Donepezil 138
• Rivastigmine 139
• Galantamine 140
• Duration of treatment with ChE inhibitors 141
• Comparative studies of ChE inhibitors 141
• Donepezil versus rivastigmine 141
• Donepezil versus galantamine 142
• An assessment and future prospects of anticholinergic therapies 142
• Neuroprotection in Alzheimer' s disease 143
• Memantine 144
• Combination of memantine with ChE inhibitors 146
• Monoamine oxidase inhibitors 147
• Selegiline 147
• Synaptoprotection in AD 148
• Drugs for noncognitive symptoms in AD 148
• Antidepressants 148
• Antipsychotics 148
• ChE inhibitors for behavioral and psychological disorders in AD 149
• Concluding remarks and other drugs for agitation in AD 150
• Sensory stimulation 150
• Non-pharmacological treatments of AD 150
• Management of memory loss in AD 151
• Exposure to electromagnetic fields for treatment of AD 151
• Application of electrical fields for improvement of cerebral function 151
• High-frequency electromagnetic field treatment of AD 152
• Vagal nerve stimulation 152
• Cerebrospinal fluid shunting 153
• Omental transposition 153
• Microchip-based hippocampal prosthesis for AD 153
• Nutritional therapies for AD 154
• Cocktail of dietary supplements for AD 154
• Docosahexaenoic acid 154
• Magnesium 156
• Nicotinamide for the treatment of AD 156
• Omega-3 fatty acids 156
• Preventing decline of mental function with aging and dementia 157
• Prevention of Alzheimer disease 158
• Mental training 159
• Physical exercise 159
• Higher level of conscientiousness and decreased risk of AD 159
• Caloric restriction 160
• Nutritional factors in prevention of AD 160
• Grapes and red wine 160
• Black and green teas 161
• Caffeine 162
• Drugs to prevent Alzheimer disease 162
• Preimplantation genetic diagnosis of inherited Alzheimer disease 162
• Presymptomatic detection of AD 163
• Management of mild cognitive impairment 163
• Management of Down syndrome 164
• Guidelines for use of anti-dementia drugs in clinical practice 165
• Donepezil and/or memantine 166
• General care of the Alzheimer disease patients 166
• Strategies for the management of Alzheimer disease 166

4. Research in Alzheimer Disease 169

• Introduction 169
• Animal models of Alzheimer disease 169
• Lesional models 169
• Cerebroventricular injection of Aβ in rats 169
• Lentiviral vector-based models of amyloid pathology 170
• AAV-mediated gene transfer to increase hippocampal Aβ 170
• Transgenic mouse models 170
• Quantitative assessment of amyloid load in transgenic models 172
• In vivo magnetic resonance microimaging in transgenic models of AD 172
• Transgenic model of AD with suppression of Aβ production 172
• Transgenic AD11 anti-NGF mice 173
• Genetically altered mice with deficiency of vesicular ACh transporter 173
• Limitations of mouse models of Alzheimer disease 173
• Cholesterol-fed rabbits as models for AD 174
• Zebrafish model for AD 174
• Transgenic invertebrate models of Alzheimer disease 175
• Drosophila model of AD 175
• Caenorhabditis elegans Alzheimer disease model 176
• Cell systems for AD research 176
• In vitro neuronal cell Lines 176
• Single-gene expression system for use in cell culture 177
• Transgenic cells 177
• In silico models 178
• Estimation of progression rates of Alzheimer disease 178
• Clinical trial methods in Alzheimer disease 179
• Molecular imaging as a guide to drug development 179
• Use of MRI and PET in clinical trials 180
• Cognitive-function assessment in clinical trials 180
• Clinical trials in mild cognitive impairment 181
• Research in AD as a basis for future therapies 181
• Use of microarrays for studying pathogenesis of AD 181
• Computational brain mapping in AD 181
• Study of neurogenesis in AD 182
• Study of 3D structure of Aβ 182
• Solid-state NMR to study precursors of Aβ 182
• Research in Alzheimer disease at academic centers 182
• Role of NIH in AD research 183
• NIH Clinical Trials Database for AD 183
• Alzheimer Research Consortium 183
• The National Institute on Aging and AD research 183

5. Drug Discovery & Development for Alzheimer Disease 185

• Introduction 185
• Categories of drugs in development for AD 185
• Memory-enhancing drugs 187
• Enhancing memory by drugs that block eIF2α phosphorylation 187
• Drugs based on cholinergic approaches 187
• AP2238 188
• Butyrylcholinesterase inhibitors 188
• Donepezil-tacrine hybrids 188
• Drugs modulating gamma-aminobutyric acid receptors 189
• Ganstigmina 189
• Methanesulfonyl fluoride 189
• Muscarinic receptor modulators 190
• Muscarinic M1 agonists 190
• Muscarinic M2 antagonists 191
• Nicotine and nicotinic receptor modulators 191
• Nicotine 191
• Nicotinic receptor modulators 192
• GTS21 193
• Ispronicline 193
• JWB1-84-1 194
• Neuropeptide/neurotransmitters 194
• Somatostatin release enhancers 194
• Glutamate receptor modulators 194
• Physiology and pharmacology of glutamate receptors 195
• NMDA receptor ion channel complex 195
• Metabotropic glutamate receptors 196
• Glutamate receptor modulators as potential therapeutics for AD 197
• Non-competitive NMDA modulators 198
• AMPA modulators 198
• Drugs affecting multiple neurotransmitters 199
• Ensaculin 199
• NS2330 199
• RS-1259 199
• Lecozotan 200
• Vaccines for AD 200
• Active immunization with Aβ 200
• AN-1792 vaccine 200
• Complications in clinical trials with AN-1792 201
• Effects of Aβ vaccine on the brain 201
• Strategies to avoid undesirable effect of Aβ vaccination 202
• Passive immunization in AD with monoclonal antibodies 203
• Delivery of the passive antibody directly to the brain 205
• Systemic injection of MAbs to treat AD 205
• Combination of Aβ immunotherapy and CD40-CD40L blockade 206
• Shaping the immune responses elicited against Aβ 206
• Gene vaccination 206
• Modified Aβ nasal vaccine 207
• Transdermal Aβ vaccination 207
• Other vaccines for AD 207
• Nasal vaccination with Proteosome™ adjuvant 208
• T-cell vaccination with glatiramer acetate adjuvant 208
• Early start of immunotherapy to clear Aβ plaques 208
• Reversal of cholinergic dysfunction by anti-Aβ antibody 209
• Immune modulation via TRL9 to reduce Aβ 209
• Mechanisms by which Aβ antibodies reduce amyloid accumulation in the brain 209
• Perspectives on vaccines for AD 210
• Companies involved in AD vaccines 212
• Inhibition of amyloid precursor protein aggregation 212
• Secretase modulators 213
• Neuroprotection by α-secretase cleaved APP 213
• Inhibitors of β secretase 214
• Inhibitors of γ-secretase 215
• Amyloid-derived diffusible ligands 216
• GABA receptor modulation by etazolate and APP processing 216
• Depletion of serum amyloid P 216
• Trojan-horse approach to prevent build-up of Aβ aggregates 217
• Drugs that inhibit the formation of Aβ 217
• 22R-hydroxycholesterol 217
• Acylaminopyrazole 218
• Chelation therapy for AD 218
• Clioquinol and PBT2 218
• Copper chelation by FKBP52 220
• Zinc chelation from amyloid plaques 220
• Next generation multifunctional chelating agents for AD 220
• Tetrahydrocannabinol 221
• NSAIDs 221
• Flurbiprofen analogs with Aβ 2-lowering action 222
• Nitric oxide-donating NSAIDs 223
• In vivo demonstration of the effects of NSAIDs on brain in AD 223
• Imatinib mesylate 224
• Laminin 224
• Paclitaxel 224
• Phenserine 224
• Tolserine 225
• Platinum-based inhibitors of Aβ 225
• Heparin and its derivatives 226
• A reassessment of the role of heparin in AD 226
• Enoxaparin 226
• Heparan sulfate 226
• Scyllo-cyclohexanehexol 227
• Ubiquitin C-terminal hydrolase L1 227
• Drugs to prevent the formation of NFTs 227
• Tau suppression 228
• ApoE4 as a therapeutic target in AD 229
• Strategies to enhance clearance of Aβ 229
• Removal of Aβ deposits by nanotechnology 229
• Enhanced PKCT€ activity promotes clearance of Aβ 230
• Role of matrix metalloproteinases in clearance of Aβ 230
• Small molecule DAPH for clearance of amyloid 230
• Clearance of Aβ across the blood-brain barrier 231
• Therapeutics to reverse cerebral Aβ deposits 231
• 4,5-dianilinophthalimide for disruption of Aβ -42 fibrils 231
• ABCA1 overexpression to lower amyloid deposits 232
• Beta-sheet breakers 232
• Blocking ApoE/Aβ interaction to reduce Aβ plaques 233
• Inhibitors of Aβ dehydrogenase 233
• Intravenous immune globulin 233
• Meptides 234
• SAN-61 for cleavage of fibril and soluble amyloid 235
• Serum amyloid P component depletion 235
• Companies developing Aβ directed therapeutics for AD 235
• Antiinflammatory and antimicrobial drugs 237
• Dapsone 237
• Antimicrobial drugs against C. pneumoniae 237
• PPAR-gamma agonists 238
• Inhibitors of neuroinflammation 238
• Cyclophosphamide 238
• Etanercept 238
• MW01-5-188WH 239
• VP015 239
• Antidiabetic drugs 240
• Rosiglitazone 240
• Pioglitazone 241
• Nootropics 241
• Acetyl-L-carnitine 241
• Cerebrolysin 241
• Ergot derivatives 242
• Lisuride 242
• Dihydroergocryptine 242
• Neuroprotective effect drugs not primarily developed for AD 243
• Antihypertensive drugs 243
• Angiotensin-converting enzyme inhibitors 243
• Angiotensin receptor blockers 244
• Dimebolin 244
• Drugs acting on estrogen receptors 245
• Estrogen 245
• Raloxifene 246
• Neurosteroids 246
• Pregnenolone sulfate 246
• Dehydroepiandrosterone 247
• Lithium 247
• MAO-B inhibitors 248
• Ladostigil tartrate 248
• Memoquin 248
• Methylene blue 249
• Nimodipine 249
• Rapamycin 249
• Testosterone 250
• Valproic acid 251
• Future prospects of neuroprotection in AD 251
• Targeting Cdk5 pathway 251
• Antioxidants 252
• Colostrinin 252
• Curcumin 253
• Melatonin 253
• Synthetic catalytic scavengers 254
• Dehydroascorbic acid 254
• Omega-3 fatty acids 254
• Vitamins 255
• Vitamin E as antioxidant 255
• Vitamins to lower homocysteine 255
• Folic acid 255
• Aminopyridazines 256
• Nanobody-based drugs for AD 256
• Nitric oxide based therapeutics for AD 256
• Nitric oxide mimetics 256
• iNOS inhibitors for AD 257
• Novel drugs for AD from natural resources 257
• Berberine chloride 258
• Centella asiatica 258
• Ginko biloba 259
• Huperzine-A 260
• Hyperforin 260
• Melissa officinalis 261
• Nostocarboline derived from cyanobacteria 261
• PTI-00703 261
• Salvia 261
• Securinega suffruticosa 262
• Withania somnifera 262
• ZT-1 262
• Cholesterol and AD 263
• Role of statins in reducing the risk of Alzheimer disease 263
• Neuroprotective effect of statins unrelated to cholesterol lowering 264
• ACAT inhibitors 265
• Role of gene for cholesterol ester transfer protein 265
• Cholesterol 24S-hydroxylase as a drug target for AD 265
• Selectively increase of ApoA-I production 266
• Neurotrophic factors 266
• Activity-dependent neuroprotective protein 266
• Brain derived neurotrophic factor 267
• Insulin-like growth factor-1 267
• Nerve growth factor 267
• Neotrofin (AIT-082) 268
• Limitations of the use of NTFs for AD 269
• Role of serotonin modulators in AD 269
• Xaliproden 269
• 5-HT1A receptor antagonists 269
• 5-HT6 antagonists 270
• 5-HT4 receptor agonists 270
• PRX-03140 270
• Cell therapy for AD 271
• Stem cell transplantation for AD 271
• Potential benefits of grafting NSCs in AD 271
• NSCs improve cognition in AD via BDNF 272
• Drugs for enhancing neuronal differentiation of implanted NSCs 272
• Implantation of encapsulated cells for delivering NGF 272
• Gene therapy for AD 272
• ApoE gene therapy 273
• Humanin gene therapy 273
• Neprilysin gene therapy 273
• NGF gene therapy 274
• Targeting plasminogen activator inhibitor type-1 gene 274
• Antisense approaches to AD 275
• RNAi approaches to AD 275
• Combined therapeutic approaches to AD 276
• Drug delivery for Alzheimer disease 277
• Delivery of thyrotropin-releasing hormone analogs by molecular packaging 277
• Nanoparticle-based drug delivery for Alzheimer' s disease 278
• Transdermal drug delivery in Alzheimer' s disease 278
• Transdermal rivastigmine 278
• Intranasal delivery of therapeutics for AD 279
• Intranasal delivery of tacrine 279
• Intranasal delivery of nerve growth factor to the brain 279
• Circadian rhythms and timing of cholinesterase inhibitor therapy 279
• Clinical trials for AD 280
• Drugs for AD that were discontinued in clinical trials 284
• Evaluation of clinical trials of AD 286
• Monitoring of cognitive function during clinical trials 287
• Drug discovery for AD 287
• Drugs acting on signaling pathways 287
• Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 287
• Drugs to reverse inhibition of the PKA/CREB pathway in AD 288
• Inhibition of the CD40 signaling pathway 288
• JNK pathway as a target 289
• Mitogen-activated protein kinase pathway as target 289
• Protein kinase C activators 290
• Electrophysiological detection of drug target for neuroprotection in early AD 290
• Genomics-based drug discovery 290
• High through screening for AD drug candidates 290
• Proteomics and drug discovery for AD 291
• Small molecule compounds binding to neurotrophin receptor p75NTR 292
• Targeting Vav in tyrosine kinase signaling pathway 293
• Novels targets/receptors for AD drug discovery 293
• Activation of cerebral Rho GTPases 293
• Activators of insulin-degrading enzyme 293
• Blockade of TGF-β-Smad2/3 signaling in peripheral macrophages 294
• Blockers of Aβ calcium channel 294
• Casein kinase 1 294
• Cyclin-dependent kinase-5 295
• Heat shock protein 90 inhibitors 295
• Histone deacetylase 1 295
• Inactivation of aph-1 and pen-2 reduces APP cleavage 296
• NF-kβ inhibitors 296
• Kinases and phosphatases as targets for AD therapeutics 296
• Phosphodiesterase inhibitors 297
• Pin 1 as a target in AD 297
• Protein phosphatase 5 as a neuroprotective in AD 298
• Src homology-containing protein-1 inhibitors 298
• Targeting GABAergic system 298
• Pharmacogenomics of Alzheimer disease 298
• Personalized therapy of AD 299
• Genotyping and AD therapeutics 299
• Biomarkers of AD/companion diagnostics for cholinesterase inhibitors 300
• Regulatory aspects of drug development for AD 300
• EMEA guidelines for drug development for AD 300
• Concluding remarks and future prospects of drugs for AD 301

6. Markets & Finances of AD Care 303

• Introduction 303
• Pharmacoeconomics of treatment of AD 303
• Quality of Life in relation to economics of AD 303
• Costs associated with Alzheimer disease 303
• Pharmacoeconomics of donepezil 304
• Pharmacoeconomics studies using rivastigmine 304
• Pharmacoenonomics studies using galantamine 305
• A comparison of pharmacoenonomics outcomes with different ChE inhibitors 305
• Pharmacoenonomics studies using memantine 306
• Patterns of AD care in major markets 306
• Care of AD patients in the US 306
• Cost of care 306
• Medicare and AD 307
• Patterns of practice in AD care 308
• Opinions of physicians' organizations on drugs for dementia 308
• Care of AD patients in the UK 309
• Cost of care 309
• Patterns of practice in AD care 309
• Retraction of NICE recommendations to NHS 310
• Care of AD patients in Germany 311
• Care of AD patients in France 311
• Care of AD patients in Italy 312
• Care of AD patients in Spain 312
• Care of AD patients in Japan 312
• Markets for AD diagnostics 313
• Markets for AD therapeutics 313
• Geographical markets for AD 313
• Markets for currently approved drugs for AD 314
• Markets for generic AD drugs 314
• Future growth of AD market 315
• Statins 315
• Limitations of AD drug development by the biotechnology industry 315
• Unmet needs in the management of AD 316
• Drivers of AD markets 317
• Increase of the aged populations 318
• Increase in the number of approved drugs for AD 318
• Limitations of the current therapies 318
• Improvements in diagnosis 318
• Increasing awareness of the disease 319

7. Companies 321

• Introduction 321
• Profiles of companies 321
• Collaborations 467

8. References 471

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: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease 29
• Table 1 5: Relation of mutations in amyloid precursor protein to CNS disorders 36
• Table 1 6: Risk factors for Alzheimer' s disease 65
• Table 1 7: Genes linked to AD 80
• Table 1 8: Abnormalities of expression of brain proteins in Down' s syndrome and AD 90
• 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 106
• Table 2 6: Companies involved in the diagnosis of Alzheimer disease 133
• Table 3 1: Classification of treatments for Alzheimer disease 135
• Table 3 2: Cholinergic approaches used in the treatment of Alzheimer disease 136
• Table 3 3: Categories of neuroprotective agents for Alzheimer disease 143
• Table 3 4: Strategies for prevention of Alzheimer disease 158
• Table 3 5: Guidelines for the treatment of dementia 165
• Table 4 1: Transgenic mouse models of Alzheimer disease 170
• Table 5 1: Classification of therapies in development for Alzheimer disease 185
• Table 5 2: Drugs for AD targeting nACh receptors 192
• Table 5 3: Ionotropic glutamate receptors 195
• Table 5 4: Classification of mGluRs 195
• Table 5 5: Glutamate receptor modulators as potential therapeutic agents in AD 197
• Table 5 6: Companies involved in developing vaccines for AD 212
• Table 5 7: Secretase modulators in clinical trials 213
• Table 5 8: Companies developing Aβ directed therapeutics for AD 235
• Table 5 9: Innovative neuroprotective approaches for Alzheimer disease 243
• Table 5 10: Herbal therapies for AD 258
• Table 5 11: Novel drug delivery methods for Alzheimer disease therapies 277
• Table 5 12: Clinical trials in Alzheimer disease 280
• Table 5 13: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 284
• Table 6 1: Direct and indirect costs associated with Alzheimer disease 304
• Table 6 2: Prevalence of AD in major markets 2009-2019 313
• Table 6 3: AD market values from 2009-2019 in the seven major world markets 314
• Table 6 4: Markets for currently approved AD drugs 2009-2019 314
• Table 6 5: Potential markets for drugs in development 2009-2019 315
• Table 6 6: Limitations of AD drug discovery and development by the biotechnology industry 316
• Table 6 7: Factors that drive AD markets 317
• Table 7 1: Major players in Alzheimer' s disease therapeutics 321
• Table 7 2: Collaborations relevant to Alzheimer disease 467

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 Aβ 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 Aβ generation and neurodegeneration 65
• Figure 1 7: Pathomechanism of AD 77
• Figure 3 1: Metabolism of acetylcholine 137
• Figure 3 2: Neuroprotective effective of galantamine in AD 141
• Figure 3 3: Strategies for the management of Alzheimer disease 167
• Figure 5 1: NMDA receptor ion channel complex 196
• Figure 5 2: Neurotoxicity due to misfolding of Aβ -42 232
• Figure 5 3: Role of proteomics in drug discovery and development for Alzheimer disease 291
• Figure 6 1: Unmet needs in the management of Alzheimer disease 317