阿兹海默病：新药・市场・企业

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 167 clinical trials are listed, of which 125 are still in progress and 42 were discontinued for various reasons.

Alzheimer' s disease market in the seven major markets is analyzed for the year 2006. 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 2017. 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 132 companies involved in developing diagnostics and therapeutics for Alzheimer' s disease are presented along with 100 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
• Detection of AD in the preclinical phase 23
• Differentiation of AD from other dementias 24
• Differentiation of AD from non-dementing disorders 25
• Cerebral insufficiency and AD 25
• Memory deficits and preclinical AD 26
• Mild cognitive impairment 26
• Diagnostic criteria of AD 28
• Epidemiology 30
• Epidemiology of aging 30
• Epidemiology of dementia 31
• Epidemiology of AD 31
• Prevalence of AD according to age 32
• Mortality in AD 32
• Pathophysiology of AD 32
• Cerebral atrophy and neuronal loss 32
• Neuritic plaques and neurofibrillary tangles 33
• Sp proteins as markers of neuronal death in AD 33
• Role of tau in the pathogenesis of AD 33
• Amyloid precursor protein 35
• Relation of APP mutations to CNS disorders 35
• Relation of APP to Aβ deposits and pathogenesis of AD 35
• Role of secretases in amyloid cascade 37
• Role of exosomal proteins 39
• Role of nicastrin 39
• Neurotixicity of Aβ deposits 39
• Relation of Aβ deposits to synaptic activity 39
• Dysfunction of TGF-β signaling accelerates Aβ deposition 40
• Role of TMP21 in presenilin complexes and Aβ formation 40
• Role of Aβ dimers in the pathogenesis of AD 41
• Aβ deposit and clearance 41
• Impairment of mitochondrial energy metAβ olism 42
• Aβ-binding alcohol dehydrogenase links AD to mitochondrial toxicity 42
• Neural thread protein 42
• Loss of synaptic proteins 43
• AD and Down syndrome 43
• Overlapping pathologies of AD and Parkinson disease 44
• AD and age-related macular degeneration 44
• Myelin hypothesis of AD 44
• Blood-brain barrier in AD 45
• Blood vessel damage in AD 46
• Loss of serotonin 1A receptors in the brain 46
• Factors in pathogenesis of AD 46
• Astrocytes and AD 46
• Axonal transport failure in AD 47
• Cell-cycle hypothesis 47
• Creatine and AD 47
• Disturbances of interaction of nervous system proteins 48
• DENN/MADD expression and enhanced pro-apoptotic signaling in AD 48
• Gonadotrophins and AD 48
• Glutamate transport dysfunction in AD 49
• Innate immune system and AD 50
• Insulin, diabetes and AD 50
• Mechanisms underlying cognitive deficits in AD 51
• Monoamine oxidase and AD 52
• Neuroinflammation and AD 52
• Neurotransmitter deficits 53
• Neurotrophic factors 53
• NF-k signaling and the pathogenesis of neurodegeneration 54
• Nitric oxide and AD 54
• Nogo receptor pathway 57
• Oxidative stress and AD 57
• Prostaglandins and AD 59
• Quinolinic acid and AD 59
• Retromer deficiency 59
• Serotonin and AD 60
• Spherotoxin 60
• Synaptic failure in AD 60
• Transmission of AD 61
• Ubiquitin-proteasome system in pathogenesis of AD 61
• Risk factors in the etiology of AD 62
• Aging and developmental abnormalities of the cholinergic system 63
• Cholesterol, dietary lipids, and Aβ 63
• Exposure to magnetic fields 64
• Family history of AD 64
• Homocysteine and AD 64
• Level of education/type of job and risk of AD 65
• Metals and AD 66
• Obesity 67
• Proneness to psychological distress and risk of AD 67
• Traumatic brain injury and AD 68
• Vascular risk factors for AD 68
• Vitamin B12 and folate 70
• AD versus non-dementing changes in the aging brain 70
• AD and cognitive impairment with aging 71
• Pathomechanism of memory impairment and AD 71
• Concluding remarks on pathophysiology of AD 71
• Genetics of AD 73
• Familial AD 73
• Presenilins and calcium channel leak in pathogenesis of familial AD 74
• Late onset AD 75
• Genomics of AD 75
• Introduction to genomics 75
• Genes associated with Alzheimer disease 75
• ApoE gene 77
• ApoE genotype and nitric oxide 78
• APOE genotype and age-related myelin breakdown 79
• CALHM1 polymorphism and AD 79
• Interaction between ApoE receptor and NMDA receptor 79
• ApoE and ApoER2 80
• LR11 receptor for ApoE as regulator of Aβ 80
• DAPK1 gene variants and AD 80
• CYP46 and risk for AD 81
• Genetic variants associated with late-onset AD 81
• OGG1 mutations associated with AD 81
• Role of SORL1 gene in AD 82
• The Arctic mutation 82
• LRRTM3 as a candidate gene for AD 82
• AlzGene database 82
• Molecular neuropathology 83
• AD as a polygenic disorder 83
• Proteomics of AD 83
• Introduction 83
• Application of proteomic technologies to study AD 84
• Protein misfolding in AD 85
• Common denominators of AD and prion diseases 86
• Amyloid fibrils as a common feature of AD and prion diseases 87

2. Diagnostic Procedures for Alzheimer Disease 89

• Importance of the diagnosis of Alzheimer disease 89
• Methods of diagnosis of AD 89
• Self-administered olfactory test 90
• Neuropsychological testing 90
• Assessment and evaluation 91
• The seven minute screen 91
• Measurement of aggregation in anterior segment of the eye 92
• Activities of Daily Living 92
• Alzheimer Disease Cooperative Study 92
• CDR-SOB score 92
• Clinician' s Interview-Based Impression of Change 92
• Resource Utilization in Dementia Battery 93
• DETECT™ System 93
• Electrophysiology 93
• EEG-based bispectral index 93
• Event-related potentials 94
• Early detection of cataract associated with AD 94
• Laboratory methods for diagnosis of AD 94
• Monitoring of synthesis and clearance rates of Aβ in the CSF 94
• Molecular diagnostics for AD 95
• Genetic tests for AD 96
• ApoE genotyping 96
• Gene expression patterns in AD 97
• Molecular fingerprinting of the immune system in AD 97
• Microarray-based tests for AD 97
• Monoclonal antibody-based in vitro diagnosis of AD from brain tissues 97
• Biomarkers of AD 98
• The ideal biomarker for AD 99
• CSF biomarkers of AD 100
• CSF sulfatide as a biomarker for AD 100
• Glycerophosphocholine as CSF biomarker in AD 100
• Protein biomarkers of AD in CSF 100
• Amyloid precursor protein 102
• Tau proteins in CSF 102
• Tests for the detection of Aβ in CSF 103
• Tests combining CSF tau and Aβ 103
• Urine tests for AD 104
• Blood tests for AD 104
• Blood Aβ levels 104
• Blood test for AD based on heme oxygenase-1 105
• Blood test for AD based on RNA hybridization 105
• GSK-3 elevation in white blood cells 106
• Lymphocyte Proliferation Test 106
• Protein kinase C in red blood cells 106
• Tests based on protein biomarkers in blood 107
• A skin test for early detection of AD 107
• Nanotechnology to measure amyloid-derived diffusible ligands 107
• Simultaneous measurement of several biomarkers for AD 108
• Concluding remarks about biomarkers for AD 108
• Imaging in AD 108
• Computed tomography 109
• Magnetic resonance imaging 109
• Arterial spin labeling with MRI 109
• Magnetic resonance microscopy 110
• Magnetic resonance spectroscopy 110
• Single photon emission computed tomography and modifications 111
• Positron emission tomography 111
• In vivo imaging of Aβ deposits by PET 113
• In vivo detection of Aβ plaques by MRI 114
• Imaging agents for Aβ and neurofibrillary tangles 115
• Targeting of chemokine receptor as biomarker for brain imaging 116
• Radioiodinated clioquinol as a biomarker for Aβ 116
• Imaging neuroinflammation in AD 116
• Preclinical diagnosis of AD 116
• Meta-analysis of literature on imaging in AD 117
• Alzheimer Disease Neuroimaging Initiative 117
• Diagnosis of MCI and prediction of AD 118
• Diagnosis of MCI 118
• Computer-Administered Neurophychological screen for MCI 118
• Infrared eye-tracking technology to detect MCI 119
• PET for detection of MCI 119
• MRI for detection of MCI 119
• Presymptomatic detection of AD 120
• PredictAD project 120
• Use of biomarkers to predict AD in patients with MCI 121
• Magnetoencephalography for detection of MCI and AD 121
• Concluding remarks about prediction of AD in MCI 122
• Ethical aspects of diagnostics for AD 122
• Genetic testing for AD 122
• Ethical issues of brain imaging in AD 123
• Companies involved in diagnosis of AD 123

3. Management of Alzheimer Disease 125

• Introduction 125
• Cholinergic approaches 125
• Mechanism of action of cholinesterase inhibitors 126
• Choline and lecithin 127
• Donepezil 128
• Rivastigmine 129
• Galantamine 130
• Duration of treatment with ChE inhibitors 131
• Comparative studies of ChE inhibitors 131
• Donepezil versus rivastigmine 131
• Donepezil versus galantamine 132
• An assessment and future prospects of anticholinergic therapies 132
• Neuroprotection in Alzheimer' s disease 133
• Memantine 134
• Combination of memantine with ChE inhibitors 136
• Monoamine oxidase inhibitors 137
• Selegiline 137
• Synaptoprotection in AD 138
• Drugs for noncognitive symptoms in AD 138
• Antidepressants 138
• Antipsychotics 138
• ChE inhibitors for behavioral and psychological disorders in AD 139
• Concluding remarks and other drugs for agitation in AD 140
• Sensory stimulation 140
• Non-pharmacological treatments of AD 140
• Management of memory loss in AD 141
• Application of electrical fields for improvement of cerebral function in AD 141
• Vagal nerve stimulation 142
• Cerebrospinal fluid shunting 142
• Omental transposition 143
• Microchip-based hippocampal prosthesis for AD 143
• Nutritional therapies for AD 143
• Cocktail of dietary supplements for AD 144
• Docosahexaenoic acid 144
• Nicotinamide for the treatment of AD 145
• Omega-3 fatty acids 146
• Preventing decline of mental function with aging and dementia 146
• Prevention of Alzheimer disease 147
• Mental training 148
• Physical exercise 148
• Higher level of conscientiousness and decreased risk of AD 148
• Caloric restriction 149
• Nutritional factors in prevention of AD 149
• Red wine antioxidants 149
• Black and green teas 150
• Caffeine 150
• Drugs to prevent Alzheimer disease 151
• Preimplantation genetic diagnosis of inherited Alzheimer disease 151
• Presymptomatic detection of AD 151
• Management of mild cognitive impairment 151
• Management of Down syndrome 152
• Guidelines for use of anti-dementia drugs in clinical practice 153
• General care of the Alzheimer disease patients 154
• Strategies for the management of Alzheimer disease 154

4. Research in Alzheimer Disease 157

• Introduction 157
• Animal models of Alzheimer disease 157
• Lesional models 157
• Cerebroventricular injection of Aβ in rats 157
• Lentiviral vector-based models of amyloid pathology 158
• AAV-mediated gene transfer to increase hippocampal Aβ 158
• Transgenic mouse models 158
• Quantitative assessment of amyloid load in transgenic models 160
• In vivo magnetic resonance microimaging in transgenic models of AD 160
• Transgenic model of AD with suppression of Aβ production 160
• Transgenic AD11 anti-NGF mice 161
• Genetically altered mice with deficiency of vesicular ACh transporter 161
• Limitations of mouse models of Alzheimer disease 161
• Cholesterol-fed rabbits as models for AD 162
• Zebrafish model for AD 162
• Transgenic invertebrate models of Alzheimer disease 163
• Drosophila model of AD 163
• Caenorhabditis elegans Alzheimer disease model 164
• Cell systems for AD research 164
• In vitro neuronal cell Lines 164
• Single-gene expression system for use in cell culture 165
• Transgenic cells 165
• In silico models 165
• Estimation of progression rates of Alzheimer disease 166
• Clinical trial methods in Alzheimer disease 167
• Molecular imaging as a guide to drug development 167
• Use of MRI and PET in clinical trials 168
• Cognitive-function assessment in clinical trials 168
• Clinical trials in mild cognitive impairment 168
• Research in AD as a basis for future therapies 169
• Use of microarrays for studying pathogenesis of AD 169
• Computational brain mapping in AD 169
• Study of neurogenesis in AD 169
• Study of 3D structure of Aβ170
• Solid-state NMR to study precursors of Aβ170
• Research in Alzheimer disease at academic centers 170
• Role of NIH in AD research 170
• NIH Clinical Trials Database for AD 170
• Alzheimer Research Consortium 171
• The National Institute on Aging and AD research 171

5. Drug Discovery & Development for Alzheimer Disease 173

• Introduction 173
• Categories of drugs in development for AD 173
• Memory-enhancing drugs 175
• Enhancing memory by drugs that block eIF2α phosphorylation 175
• Drugs based on cholinergic approaches 175
• AP2238 176
• Ganstigmina 176
• T-82 176
• Butyrylcholinesterase inhibitors 176
• Muscarinic receptor modulators 177
• Muscarinic M1 agonists 177
• Muscarinic M2 antagonists 178
• Nicotinic receptor modulators 178
• Nicotine 178
• Nicotinic receptor modulators 179
• Drugs modulating gamma-aminobutyric acid receptors 181
• Neuropeptide/neurotransmitters 181
• Somatostatin release enhancers 181
• Glutamate receptor modulators 182
• Physiology and pharmacology of glutamate receptors 182
• NMDA receptor ion channel complex 183
• Metabotropic glutamate receptors 184
• Glutamate receptor modulators as potential therapeutics for AD 184
• Non-competitive NMDA modulators 185
• AMPA modulators 185
• Drugs affecting multiple neurotransmitters 186
• Ensaculin 186
• NS2330 186
• RS-1259 187
• Lecozotan 187
• Vaccines for AD 187
• Active immunization with Aβ188
• AN-1792 vaccine 188
• Complications in clinical trials with AN-1792 188
• Effects of Aβ vaccine on the brain 189
• Strategies to avoid undesirable effect of Aβ vaccination 190
• Passive immunization in AD with monoclonal antibodies 190
• Delivery of the passive antibody directly to the brain 191
• Systemic injection of MAbs to treat AD 192
• Combination of Aβ immunotherapy and CD40-CD40L blockade 192
• Shaping the immune responses elicited against Aβ 192
• Gene vaccination 193
• Modified Aβ nasal vaccine 193
• Transdermal Aβ vaccination 193
• Other vaccines for AD 194
• Nasal vaccination with Proteosome™ adjuvant 194
• T-cell vaccination with glatiramer acetate adjuvant 195
• Early start of immunotherapy to clear Aβ plaques 195
• Reversal of cholinergic dysfunction by anti-Aβ antibody 195
• Mechanisms by which Aβ antibodies reduce amyloid accumulation in the brain 195
• Perspectives on vaccines for AD 196
• Companies involved in AD vaccines 198
• Inhibition of amyloid precursor protein aggregation 198
• Secretase inhibitors 198
• Neuroprotection by αsecretase cleaved APP 199
• β-secretase inhibitors 199
• γsecretase inhibitors 200
• Substrate-targeting big γ-secretase modulators 201
• Amyloid-derived diffusible ligands 201
• GABA receptor modulation by etazolate and APP processing 201
• Depletion of serum amyloid P 202
• Trojan-horse approach to prevent build-up of Aβ aggregates 202
• Drugs that inhibit the formation of Aβ 202
• 22R-hydroxycholesterol 203
• Acylaminopyrazole 203
• Antihypertensive drugs 203
• Valsartan 204
• Clioquinol and PBT2 204
• Copper chelation by FKBP52 205
• Zinc chelation from amyloid plaques 206
• Tetrahydrocannabinol 206
• NSAIDs 207
• Flurbiprofen analogs with Aβ 42-lowering action 207
• Nitric oxide-donating NSAIDs 208
• In vivo demonstration of the effects of NSAIDs on brain in AD 208
• Imatinib mesylate 209
• Laminin 209
• Paclitaxel 209
• Phenserine 210
• Tolserine 210
• Platinum-based inhibitors of Aβ 211
• Heparin and its derivatives 211
• A reassessment of the role of heparin in AD 211
• Enoxaparin 212
• Heparan sulfate 212
• Scyllo-cyclohexanehexol 212
• Ubiquitin C-terminal hydrolase L1 212
• Drugs to prevent the formation of NFTs 213
• Tau suppression 213
• ApoE4 as a therapeutic target in AD 214
• Strategies to enhance clearance of Aβ 214
• Removal of Aβ deposits by nanotechnology 215
• Enhanced PKCT activity promotes clearance of Aβ 215
• Role of matrix metalloproteinases in clearance of Aβ 215
• Small molecule DAPH for clearance of amyloid 216
• Therapeutics to reverse cerebral Aβ deposits 216
• ABCA1 overexpression to lower amyloid deposits 216
• β -sheet breakers 216
• Intravenous immune globulin 217
• Meptides 218
• 4,5-dianilinophthalimide for disruption of Aβ 1-42 fibrils 218
• Blocking ApoE/Aβ interaction to reduce Aβ plaques 219
• Inhibitors of Aβ dehydrogenase 219
• Companies developing Aβ-directed therapeutics for AD 220
• Antiinflammatory and antimicrobial drugs 221
• Dapsone 221
• Antimicrobial drugs against C. pneumoniae 222
• PPAR-gamma agonists 222
• Inhibitors of neuroinflammation 222
• Cyclophosphamide 222
• Etanercept 223
• MW01-5-188WH 223
• VP015 224
• Antidiabetic drugs 224
• Rosiglitazone 224
• Pioglitazone 225
• Nootropics 225
• Acetyl-L-carnitine 225
• Cerebrolysin 226
• Ergot derivatives 226
• Lisuride 226
• Dihydroergocryptine 227
• Neuroprotective effect drugs not primarily developed for AD 227
• Angiotensin-converting enzyme inhibitors 228
• Dimebon 228
• Drugs acting on estrogen receptors 229
• Estrogen 229
• Raloxifene 230
• Neurosteroids 230
• Pregnenolone sulfate 230
• Dehydroepiandrosterone 231
• Lithium 231
• MAO-B inhibitors 231
• Ladostigil tartrate 232
• Memoquin 232
• Methylene blue 232
• Nimodipine 233
• Testosterone 233
• Valproic acid 234
• Future prospects of neuroprotection in AD 235
• Targeting Cdk5 pathway 235
• Antioxidants 235
• Colostrinin 236
• Curcumin 236
• Melatonin 237
• Synthetic catalytic scavengers 237
• Dehydroascorbic acid 237
• Omega-3 fatty acids 238
• Vitamins 238
• Vitamin E as antioxidant 238
• Vitamins to lower homocysteine 239
• Folic acid 239
• Aminopyridazines 239
• Nanobody-based drugs for AD 240
• Nitric oxide based therapeutics for AD 240
• Nitric oxide mimetics 240
• iNOS inhibitors for AD 240
• Novel drugs for AD from natural resources 241
• Berberine chloride 242
• Centella asiatica 242
• Ginko biloba 242
• Gilatide (from saliva of the Gila monster) 243
• Huperzine-A 244
• Hyperforin 244
• Melissa officinalis 244
• Nostocarboline derived from cyanobacteria 245
• PTI-00703 245
• Salvia 245
• Securinega suffruticosa 245
• Withania somnifera 246
• ZT-1 246
• Cholesterol and AD 246
• Role of statins in reducing the risk of Alzheimer disease 247
• Neuroprotective effect of statins unrelated to cholesterol lowering 248
• ACAT inhibitors 248
• Role of gene for cholesterol ester transfer protein 249
• Cholesterol 24S-hydroxylase as a drug target for AD 249
• Selectively increase of ApoA-I production 249
• Neurotrophic factors 250
• Activity-dependent neuroprotective protein 250
• Brain derived neurotrophic factor 250
• Insulin-like growth factor-1 250
• Nerve growth factor 251
• Neotrofin (AIT-082) 252
• Limitations of the use of NTFs for AD 252
• Role of serotonin modulators in AD 253
• Xaliproden 253
• 5-HT1A receptor antagonists 253
• 5-HT6 antagonists 253
• 5-HT4 receptor agonists 254
• PRX-03140 254
• Cell therapy for AD 255
• Stem cell transplantation 255
• Implantation of encapsulated cells for delivering NGF 256
• Gene therapy for AD 256
• ApoE gene therapy 256
• Humanin gene therapy 256
• Neprilysin gene therapy 257
• NGF gene therapy 257
• Targeting plasminogen activator inhibitor type-1 gene 258
• Antisense approaches to AD 258
• RNAi approaches to AD 259
• Combined therapeutic approaches to AD 260
• Drug delivery for Alzheimer disease 260
• Delivery of thyrotropin-releasing hormone analogs by molecular packaging 261
• Nanoparticle-based drug delivery for Alzheimer' s disease 261
• Transdermal drug delivery in Alzheimer' s disease 261
• Intranasal delivery of therapeutics for AD 262
• Intranasal delivery of tacrine 262
• Intranasal delivery of nerve growth factor to the brain 262
• Circadian rhythms and timing of cholinesterase inhibitor therapy 262
• Clinical trials for AD 263
• Drugs for AD that were discontinued in clinical trials 267
• Evaluation of clinical trials of AD 269
• Monitoring of cognitive function during clinical trials 269
• Drug discovery for AD 270
• Genomics-based drug discovery 270
• Proteomics and drug discovery for AD 270
• High through screening for AD drug candidates 271
• Drugs acting on signaling pathways 271
• Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 271
• Drugs to reverse inhibition of the PKA/CREB pathway in AD 272
• Inhibition of the CD40 signaling pathway 272
• JNK pathway as a target 273
• Mitogen-activated protein kinase pathway as target 273
• Protein kinase C activators 274
• Small molecule compounds binding to neurotrophin receptor p75NTR 274
• Targeting Vav in tyrosine kinase signaling pathway 275
• Novels targets/receptors for AD drug discovery 275
• Activation of cerebral Rho GTPases 275
• Blockade of TGF-βSmad2/3 signaling in peripheral macrophages 275
• Casein kinase 1 276
• Cyclin-dependent kinase-5 276
• Heat shock protein 90 inhibitors 276
• Inactivation of aph-1 and pen-2 reduces APP cleavage 277
• NF-kβ inhibitors 277
• Kinases and phosphatases as targets for AD therapeutics 277
• Phosphodiesterase inhibitors 278
• Pin 1 as a target in AD 278
• Receptor for advanced glycation end products 279
• Src homology-containing protein-1 inhibitors 279
• Targeting GABAergic system 280
• Pharmacogenomics of Alzheimer disease 280
• Personalized therapy of AD 280
• Genotyping and AD therapeutics 280
• Biomarkers of AD/companion diagnostics for cholinesterase inhibitors 281
• Regulatory aspects of drug development for AD 282
• EMEA guidelines for drug development for AD 282
• Concluding remarks and future prospects of drugs for AD 282

6. Markets & Finances of AD Care 283

• Introduction 283
• Pharmacoeconomics of treatment of AD 283
• Costs associated with Alzheimer disease 283
• Pharmacoeconomics of donepezil 284
• Pharmacoeconomics studies using rivastigmine 284
• Pharmacoenonomics studies using galantamine 284
• A comparison of pharmacoenonomics outcomes with different ChE inhibitors 285
• Pharmacoenonomics studies using memantine 285
• Patterns of AD care in major markets 285
• Care of AD patients in the US 286
• Cost of care 286
• Medicare and AD 286
• Patterns of practice in AD care 287
• Opinions of physicians' organizations on drugs for dementia 288
• Care of AD patients in the UK 288
• Cost of care 288
• Patterns of practice in AD care 289
• Retraction of NICE recommendations to NHS 290
• Care of AD patients in Germany 290
• Care of AD patients in France 291
• Care of AD patients in Italy 291
• Care of AD patients in Spain 292
• Care of AD patients in Japan 292
• Markets for AD diagnostics 292
• Markets for AD therapeutics 293
• Geographical markets for AD 293
• Markets for currently approved drugs for AD 294
• Markets for generic AD drugs 294
• Future growth of AD market 294
• Statins 295
• Limitations of AD drug development by the biotechnology industry 295
• Unmet needs in the management of AD 296
• Drivers of AD markets 297
• Increase of the aged populations 297
• Increase in the number of approved drugs for AD 297
• Limitations of the current therapies 298
• Improvements in diagnosis 298
• Increasing awareness of the disease 298

7. Companies 299

• Introduction 299
• Profiles of companies 299
• Collaborations 437

8. References 441

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 24
• Table 1 4: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease 28
• Table 1 5: Relation of mutations in amyloid precursor protein to CNS disorders 35
• Table 1 6: Risk factors for Alzheimer' s disease 62
• Table 1 7: Genes linked to AD 76
• Table 1 8: Abnormalities of expression of brain proteins in Down' s syndrome and AD 85
• Table 2 1: Classification of methods of diagnosis of Alzheimer disease 89
• Table 2 2: Neuropsychological test batteries and scales for Alzheimer' s disease 90
• Table 2 3: Available molecular diagnostic tests for Alzheimer disease 95
• Table 2 4: Classification of biochemical markers of AD in blood and CSF 98
• Table 2 5: Characteristics of an ideal biomarker for Alzheimer disease 99
• Table 2 6: Companies involved in the diagnosis of Alzheimer disease 124
• Table 3 1: Classification of treatments for Alzheimer disease 125
• Table 3 2: Cholinergic approaches used in the treatment of Alzheimer disease 126
• Table 3 3: Categories of neuroprotective agents for Alzheimer disease 133
• Table 3 4: Strategies for prevention of Alzheimer disease 147
• Table 3 5: Guidelines for the treatment of dementia 153
• Table 4 1: Transgenic mouse models of Alzheimer disease 158
• Table 5 1: Classification of therapies in development for Alzheimer disease 173
• Table 5 2: Drugs for AD targeting nACh receptors 179
• Table 5 3: Ionotropic glutamate receptors 182
• Table 5 4: Classification of mGluRs 182
• Table 5 5: Glutamate receptor modulators as potential therapeutic agents in AD 185
• Table 5 6: Companies involved in developing vaccines for AD 198
• Table 5 7: Companies developing Aβdirected therapeutics for AD 220
• Table 5 8: Innovative neuroprotective approaches for Alzheimer disease 227
• Table 5 9: Herbal therapies for AD 241
• Table 5 10: Novel drug delivery methods for Alzheimer disease therapies 260
• Table 5 11: Clinical trials in Alzheimer disease 263
• Table 5 12: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 267
• Table 6 1: Direct and indirect costs associated with Alzheimer disease 283
• Table 6 2: Prevalence of AD in major markets 2007-2017 293
• Table 6 3: AD market values from 2007-2017 in the seven major world markets 293
• Table 6 4: Markets for currently approved AD drugs 2007-2017 294
• Table 6 5: Potential markets for drugs in development 2007-2017 295
• Table 6 6: Limitations of AD drug discovery and development by the biotechnology industry 295
• Table 6 7: Factors that drive AD markets 297
• Table 7 1: Major players in Alzheimer' s disease therapeutics 299
• Table 7 2: Collaborations relevant to Alzheimer disease 437

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. 30
• Figure 1 2: Prevalence of different types of dementia 31
• Figure 1 3: Mechanisms of Aβ clearance 41
• Figure 1 4: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease 56
• Figure 1 5: Oxidative stress and Alzheimer disease 58
• Figure 1 6: Role of proteosome inhibition in Aβ generation and neurodegeneration 62
• Figure 1 7: Pathomechanism of AD 73
• Figure 3 1: Metabolism of acetylcholine 127
• Figure 3 2: Neuroprotective effective of galantamine in AD 131
• Figure 3 3: Strategies for the management of Alzheimer disease 155
• Figure 5 1: NMDA receptor ion channel complex. 183
• Figure 5 2: Neurotoxicity due to misfolding of Aβ1-42 219
• Figure 5 3: Role of proteomics in drug discovery and development for Alzheimer disease 270
• Figure 6 1: Unmet needs in the management of Alzheimer disease 296