阿茲海默病：新藥・市場・企業

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 165 clinical trials are listed, of which 122 are still in progress and 43 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 135 companies involved in developing diagnostics and therapeutics for Alzheimer' s disease are presented along with 102 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 24
• 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 34
• Amyloid precursor protein 35
• Relation of APP mutations to CNS disorders 35
• Relation of APP to Aβ deposits and pathogenesis of AD 36
• 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 40
• 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 metabolism 42
• Aβ binding alcohol dehydrogenase links AD to mitochondrial toxicity 42
• Neural thread protein 43
• 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 45
• 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 47
• Astrocytes and AD 47
• Axonal transport failure in AD 47
• Cell-cycle hypothesis 48
• Creatine and AD 48
• Disturbances of interaction of nervous system proteins 48
• DENN/MADD expression and enhanced pro-apoptotic signaling in AD 48
• Gonadotrophins and AD 49
• Glutamate transport dysfunction in AD 49
• Innate immune system and AD 50
• Insulin, diabetes and AD 51
• Mechanisms underlying cognitive deficits in AD 51
• Monoamine oxidase and AD 52
• Neuroinflammation and AD 52
• Neurotransmitter deficits 53
• Neurotrophic factors 54
• NF-kβ signaling and the pathogenesis of neurodegeneration 54
• Nitric oxide and AD 55
• 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 72
• 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 76
• 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 81
• CYP46 and risk for AD 81
• Genetic variants associated with late-onset AD 81
• OGG1 mutations associated with AD 82
• Role of SORL1 gene in AD 82
• The Arctic mutation 82
• LRRTM3 as a candidate gene for AD 83
• AlzGene database 83
• Molecular neuropathology 83
• AD as a polygenic disorder 83
• Proteomics of AD 84
• Introduction 84
• Application of proteomic technologies to study AD 84
• Protein misfolding in AD 86
• Common denominators of AD and prion diseases 87
• 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
• Plasma biomarkers of drug response in AD 108
• Concluding remarks about biomarkers for AD 108
• Imaging in AD 109
• Computed tomography 109
• Magnetic resonance imaging 109
• Arterial spin labeling with MRI 110
• Magnetic resonance microscopy 110
• Magnetic resonance spectroscopy 111
• Single photon emission computed tomography and modifications 111
• Positron emission tomography 112
• In vivo imaging of Aβ deposits by PET 113
• In vivo detection of Aβ plaques by MRI 115
• Imaging agents for Aβ and neurofibrillary tangles 116
• Targeting of chemokine receptor as biomarker for brain imaging 116
• Radioiodinated clioquinol as a biomarker for Aβ 117
• Imaging neuroinflammation in AD 117
• Preclinical diagnosis of AD 117
• Meta-analysis of literature on imaging in AD 118
• Alzheimer Disease Neuroimaging Initiative 118
• Diagnosis of MCI and prediction of AD 119
• Diagnosis of MCI 119
• Computer-Administered Neurophychological screen for MCI 119
• Infrared eye-tracking technology to detect MCI 120
• PET for detection of MCI 120
• MRI for detection of MCI 120
• Presymptomatic detection of AD 120
• PredictAD project 121
• Use of biomarkers to predict AD in patients with MCI 121
• Magnetoencephalography for detection of MCI and AD 122
• Concluding remarks about prediction of AD in MCI 123
• Ethical aspects of diagnostics for AD 123
• Genetic testing for AD 123
• Ethical issues of brain imaging in AD 124
• Companies involved in diagnosis of AD 124

3. Management of Alzheimer Disease 127

• Introduction 127
• Cholinergic approaches 127
• Mechanism of action of cholinesterase inhibitors 128
• Choline and lecithin 129
• Donepezil 130
• Rivastigmine 131
• Galantamine 132
• Duration of treatment with ChE inhibitors 133
• Comparative studies of ChE inhibitors 133
• Donepezil versus rivastigmine 133
• Donepezil versus galantamine 134
• An assessment and future prospects of anticholinergic therapies 134
• Neuroprotection in Alzheimer' s disease 135
• Memantine 136
• Combination of memantine with ChE inhibitors 138
• Monoamine oxidase inhibitors 139
• Selegiline 139
• Synaptoprotection in AD 140
• Drugs for noncognitive symptoms in AD 140
• Antidepressants 140
• Antipsychotics 140
• ChE inhibitors for behavioral and psychological disorders in AD 141
• Concluding remarks and other drugs for agitation in AD 142
• Sensory stimulation 142
• Non-pharmacological treatments of AD 142
• Management of memory loss in AD 143
• Application of electrical fields for improvement of cerebral function in AD 143
• Vagal nerve stimulation 144
• Cerebrospinal fluid shunting 144
• Omental transposition 145
• Microchip-based hippocampal prosthesis for AD 145
• Nutritional therapies for AD 145
• Cocktail of dietary supplements for AD 146
• Docosahexaenoic acid 146
• Nicotinamide for the treatment of AD 147
• Omega-3 fatty acids 148
• Preventing decline of mental function with aging and dementia 148
• Prevention of Alzheimer disease 149
• Mental training 150
• Physical exercise 150
• Higher level of conscientiousness and decreased risk of AD 150
• Caloric restriction 151
• Nutritional factors in prevention of AD 151
• Red wine antioxidants 151
• Black and green teas 152
• Caffeine 152
• Drugs to prevent Alzheimer disease 153
• Preimplantation genetic diagnosis of inherited Alzheimer disease 153
• Presymptomatic detection of AD 153
• Management of mild cognitive impairment 154
• Management of Down syndrome 155
• Guidelines for use of anti-dementia drugs in clinical practice 155
• General care of the Alzheimer disease patients 156
• Strategies for the management of Alzheimer disease 156

4. Research in Alzheimer Disease 159

• Introduction 159
• Animal models of Alzheimer disease 159
• Lesional models 159
• Cerebroventricular injection of Aβ in rats 159
• Lentiviral vector-based models of amyloid pathology 160
• AAV-mediated gene transfer to increase hippocampal Aβ 160
• Transgenic mouse models 160
• Quantitative assessment of amyloid load in transgenic models 162
• In vivo magnetic resonance microimaging in transgenic models of AD 162
• Transgenic model of AD with suppression of Aβ production 162
• Transgenic AD11 anti-NGF mice 163
• Genetically altered mice with deficiency of vesicular ACh transporter 163
• Limitations of mouse models of Alzheimer disease 163
• Cholesterol-fed rabbits as models for AD 164
• Zebrafish model for AD 164
• Transgenic invertebrate models of Alzheimer disease 165
• Drosophila model of AD 165
• Caenorhabditis elegans Alzheimer disease model 166
• Cell systems for AD research 166
• In vitro neuronal cell Lines 166
• Single-gene expression system for use in cell culture 167
• Transgenic cells 167
• In silico models 168
• Estimation of progression rates of Alzheimer disease 168
• Clinical trial methods in Alzheimer disease 169
• Molecular imaging as a guide to drug development 169
• Use of MRI and PET in clinical trials 170
• Cognitive-function assessment in clinical trials 170
• Clinical trials in mild cognitive impairment 171
• Research in AD as a basis for future therapies 171
• Use of microarrays for studying pathogenesis of AD 171
• Computational brain mapping in AD 171
• Study of neurogenesis in AD 172
• Study of 3D structure of Aβ 172
• Solid-state NMR to study precursors of Aβ 172
• Research in Alzheimer disease at academic centers 172
• Role of NIH in AD research 173
• NIH Clinical Trials Database for AD 173
• Alzheimer Research Consortium 173
• The National Institute on Aging and AD research 173

5. Drug Discovery & Development for Alzheimer Disease 175

• Introduction 175
• Categories of drugs in development for AD 175
• Memory-enhancing drugs 177
• Enhancing memory by drugs that block eIF2α phosphorylation 177
• Drugs based on cholinergic approaches 177
• AP2238 178
• Butyrylcholinesterase inhibitors 178
• Donepezil-tacrine hybrids 178
• Drugs modulating gamma-aminobutyric acid receptors 179
• Ganstigmina 179
• Methanesulfonyl fluoride 179
• Muscarinic receptor modulators 180
• Muscarinic M1 agonists 180
• Muscarinic M2 antagonists 181
• Nicotinic receptor modulators 181
• Nicotine 181
• Nicotinic receptor modulators 181
• T-82 183
• Neuropeptide/neurotransmitters 184
• Somatostatin release enhancers 184
• Glutamate receptor modulators 184
• Physiology and pharmacology of glutamate receptors 185
• NMDA receptor ion channel complex 185
• Metabotropic glutamate receptors 186
• Glutamate receptor modulators as potential therapeutics for AD 187
• Non-competitive NMDA modulators 188
• AMPA modulators 188
• Drugs affecting multiple neurotransmitters 189
• Ensaculin 189
• NS2330 189
• RS-1259 189
• Lecozotan 190
• Vaccines for AD 190
• Active immunization with Aβ 190
• AN-1792 vaccine 190
• Complications in clinical trials with AN-1792 191
• Effects of Aβ vaccine on the brain 191
• Strategies to avoid undesirable effect of Aβ vaccination 192
• Passive immunization in AD with monoclonal antibodies 193
• Delivery of the passive antibody directly to the brain 194
• Systemic injection of MAbs to treat AD 195
• Combination of Aβ immunotherapy and CD40-CD40L blockade 195
• Shaping the immune responses elicited against Aβ 196
• Gene vaccination 196
• Modified Aβ nasal vaccine 196
• Transdermal Aβ vaccination 197
• Other vaccines for AD 197
• Nasal vaccination with Proteosome™ adjuvant 198
• T-cell vaccination with glatiramer acetate adjuvant 198
• Early start of immunotherapy to clear Aβ plaques 198
• Reversal of cholinergic dysfunction by anti-Aβ antibody 198
• Mechanisms by which Aβ antibodies reduce amyloid accumulation in the brain 199
• Perspectives on vaccines for AD 199
• Companies involved in AD vaccines 201
• Inhibition of amyloid precursor protein aggregation 202
• Secretase inhibitors 202
• Neuroprotection by α secretase cleaved APP 202
• β secretase inhibitors 202
• γ secretase inhibitors 203
• Substrate-targeting by γ-secretase modulators 204
• Amyloid-derived diffusible ligands 204
• GABA receptor modulation by etazolate and APP processing 205
• Depletion of serum amyloid P 205
• Trojan-horse approach to prevent build-up of Aβ aggregates 205
• Drugs that inhibit the formation of Aβ 206
• 22R-hydroxycholesterol 206
• Acylaminopyrazole 207
• Antihypertensive drugs 207
• Valsartan 207
• Chelation therapy for AD 207
• Clioquinol and PBT2 207
• Copper chelation by FKBP52 209
• Zinc chelation from amyloid plaques 209
• Next generation multifunctional chelating agents for AD 209
• Tetrahydrocannabinol 210
• NSAIDs 210
• Flurbiprofen analogs with Aβ 2-lowering action 211
• Nitric oxide-donating NSAIDs 212
• In vivo demonstration of the effects of NSAIDs on brain in AD 212
• Imatinib mesylate 213
• Laminin 213
• Paclitaxel 213
• Phenserine 213
• Tolserine 214
• Platinum-based inhibitors of Aβ 214
• Heparin and its derivatives 215
• A reassessment of the role of heparin in AD 215
• Enoxaparin 215
• Heparan sulfate 216
• Scyllo-cyclohexanehexol 216
• Ubiquitin C-terminal hydrolase L1 216
• Drugs to prevent the formation of NFTs 216
• Tau suppression 217
• ApoE4 as a therapeutic target in AD 218
• Strategies to enhance clearance of Aβ 218
• Removal of Aβ deposits by nanotechnology 218
• Enhanced PKC€ activity promotes clearance of Aβ 219
• Role of matrix metalloproteinases in clearance of Aβ 219
• Small molecule DAPH for clearance of amyloid 219
• Therapeutics to reverse cerebral Aβ deposits 220
• 4,5-dianilinophthalimide for disruption of Aβ -42 fibrils 220
• ABCA1 overexpression to lower amyloid deposits 221
• β sheet breakers 221
• Blocking ApoE/Aβ interaction to reduce Aβ plaques 221
• Inhibitors of Aβ dehydrogenase 222
• Intravenous immune globulin 222
• Meptides 223
• SAN-61 for cleavage of fibril and soluble amyloid 223
• Serum amyloid P component depletion 224
• Companies developing Aβ directed therapeutics for AD 224
• Antiinflammatory and antimicrobial drugs 226
• Dapsone 226
• Antimicrobial drugs against C. pneumoniae 226
• PPAR-gamma agonists 226
• Inhibitors of neuroinflammation 227
• Cyclophosphamide 227
• Etanercept 227
• MW01-5-188WH 228
• VP015 228
• Antidiabetic drugs 228
• Rosiglitazone 229
• Pioglitazone 229
• Nootropics 229
• Acetyl-L-carnitine 230
• Cerebrolysin 230
• Ergot derivatives 231
• Lisuride 231
• Dihydroergocryptine 231
• Neuroprotective effect drugs not primarily developed for AD 231
• Angiotensin-converting enzyme inhibitors 232
• Dimebon 232
• Drugs acting on estrogen receptors 233
• Estrogen 233
• Raloxifene 234
• Neurosteroids 234
• Pregnenolone sulfate 235
• Dehydroepiandrosterone 235
• Lithium 235
• MAO-B inhibitors 236
• Ladostigil tartrate 236
• Memoquin 237
• Methylene blue 237
• Nimodipine 237
• Testosterone 238
• Valproic acid 239
• Future prospects of neuroprotection in AD 239
• Targeting Cdk5 pathway 239
• Antioxidants 240
• Colostrinin 240
• Curcumin 241
• Melatonin 241
• Synthetic catalytic scavengers 242
• Dehydroascorbic acid 242
• Omega-3 fatty acids 242
• Vitamins 243
• Vitamin E as antioxidant 243
• Vitamins to lower homocysteine 243
• Folic acid 243
• Aminopyridazines 244
• Nanobody-based drugs for AD 244
• Nitric oxide based therapeutics for AD 244
• Nitric oxide mimetics 244
• iNOS inhibitors for AD 245
• Novel drugs for AD from natural resources 245
• Berberine chloride 246
• Centella asiatica 246
• Ginko biloba 247
• Gilatide (from saliva of the Gila monster) 248
• Huperzine-A 248
• Hyperforin 249
• Melissa officinalis 249
• Nostocarboline derived from cyanobacteria 249
• PTI-00703 249
• Salvia 250
• Securinega suffruticosa 250
• Withania somnifera 250
• ZT-1 250
• Cholesterol and AD 251
• Role of statins in reducing the risk of Alzheimer disease 251
• Neuroprotective effect of statins unrelated to cholesterol lowering 252
• ACAT inhibitors 253
• Role of gene for cholesterol ester transfer protein 253
• Cholesterol 24S-hydroxylase as a drug target for AD 253
• Selectively increase of ApoA-I production 254
• Neurotrophic factors 254
• Activity-dependent neuroprotective protein 254
• Brain derived neurotrophic factor 255
• Insulin-like growth factor-1 255
• Nerve growth factor 255
• Neotrofin (AIT-082) 256
• Limitations of the use of NTFs for AD 257
• Role of serotonin modulators in AD 257
• Xaliproden 257
• 5-HT1A receptor antagonists 258
• 5-HT6 antagonists 258
• 5-HT4 receptor agonists 258
• PRX-03140 259
• Cell therapy for AD 259
• Stem cell transplantation 259
• Implantation of encapsulated cells for delivering NGF 260
• Gene therapy for AD 260
• ApoE gene therapy 260
• Humanin gene therapy 261
• Neprilysin gene therapy 261
• NGF gene therapy 261
• Targeting plasminogen activator inhibitor type-1 gene 262
• Antisense approaches to AD 262
• RNAi approaches to AD 263
• Combined therapeutic approaches to AD 264
• Drug delivery for Alzheimer disease 264
• Delivery of thyrotropin-releasing hormone analogs by molecular packaging 265
• Nanoparticle-based drug delivery for Alzheimer' s disease 266
• Transdermal drug delivery in Alzheimer' s disease 266
• Transdermal rivastigmine 266
• Intranasal delivery of therapeutics for AD 267
• Intranasal delivery of tacrine 267
• Intranasal delivery of nerve growth factor to the brain 267
• Circadian rhythms and timing of cholinesterase inhibitor therapy 267
• Clinical trials for AD 267
• Drugs for AD that were discontinued in clinical trials 272
• Evaluation of clinical trials of AD 274
• Monitoring of cognitive function during clinical trials 274
• Drug discovery for AD 274
• Genomics-based drug discovery 274
• Proteomics and drug discovery for AD 275
• High through screening for AD drug candidates 276
• Drugs acting on signaling pathways 276
• Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 276
• Drugs to reverse inhibition of the PKA/CREB pathway in AD 277
• Inhibition of the CD40 signaling pathway 277
• JNK pathway as a target 278
• Mitogen-activated protein kinase pathway as target 278
• Protein kinase C activators 279
• Small molecule compounds binding to neurotrophin receptor p75NTR 279
• Targeting Vav in tyrosine kinase signaling pathway 280
• Novels targets/receptors for AD drug discovery 280
• Activation of cerebral Rho GTPases 280
• Blockade of TGF-β-Smad2/3 signaling in peripheral macrophages 280
• Blockers of Aβ calcium channel 281
• Casein kinase 1 281
• Cyclin-dependent kinase-5 281
• Heat shock protein 90 inhibitors 282
• Histone deacetylase 1 282
• Inactivation of aph-1 and pen-2 reduces APP cleavage 282
• NF-kβ inhibitors 283
• Kinases and phosphatases as targets for AD therapeutics 283
• Phosphodiesterase inhibitors 283
• Pin 1 as a target in AD 284
• Receptor for advanced glycation end products 284
• Src homology-containing protein-1 inhibitors 285
• Targeting GABAergic system 285
• Pharmacogenomics of Alzheimer disease 285
• Personalized therapy of AD 285
• Genotyping and AD therapeutics 286
• Biomarkers of AD/companion diagnostics for cholinesterase inhibitors 287
• Regulatory aspects of drug development for AD 287
• EMEA guidelines for drug development for AD 287
• Concluding remarks and future prospects of drugs for AD 288

6. Markets & Finances of AD Care 289

• Introduction 289
• Pharmacoeconomics of treatment of AD 289
• Costs associated with Alzheimer disease 289
• Pharmacoeconomics of donepezil 290
• Pharmacoeconomics studies using rivastigmine 290
• Pharmacoenonomics studies using galantamine 290
• A comparison of pharmacoenonomics outcomes with different ChE inhibitors 291
• Pharmacoenonomics studies using memantine 291
• Patterns of AD care in major markets 291
• Care of AD patients in the US 292
• Cost of care 292
• Medicare and AD 292
• Patterns of practice in AD care 293
• Opinions of physicians' organizations on drugs for dementia 294
• Care of AD patients in the UK 294
• Cost of care 294
• Patterns of practice in AD care 295
• Retraction of NICE recommendations to NHS 296
• Care of AD patients in Germany 296
• Care of AD patients in France 297
• Care of AD patients in Italy 297
• Care of AD patients in Spain 298
• Care of AD patients in Japan 298
• Markets for AD diagnostics 298
• Markets for AD therapeutics 299
• Geographical markets for AD 299
• Markets for currently approved drugs for AD 299
• Markets for generic AD drugs 300
• Future growth of AD market 300
• Statins 301
• Limitations of AD drug development by the biotechnology industry 301
• Unmet needs in the management of AD 302
• Drivers of AD markets 303
• Increase of the aged populations 303
• Increase in the number of approved drugs for AD 303
• Limitations of the current therapies 303
• Improvements in diagnosis 304
• Increasing awareness of the disease 304

7. Companies 305

• Introduction 305
• Profiles of companies 305
• Collaborations 446

8. References 451

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 biomarkers 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 127
• Table 3 2: Cholinergic approaches used in the treatment of Alzheimer disease 128
• Table 3 3: Categories of neuroprotective agents for Alzheimer disease 135
• Table 3 4: Strategies for prevention of Alzheimer disease 149
• Table 3 5: Guidelines for the treatment of dementia 155
• Table 4 1: Transgenic mouse models of Alzheimer disease 160
• Table 5 1: Classification of therapies in development for Alzheimer disease 175
• Table 5 2: Drugs for AD targeting nACh receptors 182
• Table 5 3: Ionotropic glutamate receptors 184
• Table 5 4: Classification of mGluRs 185
• Table 5 5: Glutamate receptor modulators as potential therapeutic agents in AD 187
• Table 5 6: Companies involved in developing vaccines for AD 201
• Table 5 7: Companies developing Aβ directed therapeutics for AD 224
• Table 5 8: Innovative neuroprotective approaches for Alzheimer disease 231
• Table 5 9: Herbal therapies for AD 246
• Table 5 10: Novel drug delivery methods for Alzheimer disease therapies 264
• Table 5 11: Clinical trials in Alzheimer disease 268
• Table 5 12: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 272
• Table 6 1: Direct and indirect costs associated with Alzheimer disease 289
• Table 6 2: Prevalence of AD in major markets 2008-2018 299
• Table 6 3: AD market values from 2008-2018 in the seven major world markets 299
• Table 6 4: Markets for currently approved AD drugs 2008-2018 300
• Table 6 5: Potential markets for drugs in development 2008-2018 300
• Table 6 6: Limitations of AD drug discovery and development by the biotechnology industry 301
• Table 6 7: Factors that drive AD markets 303
• Table 7 1: Major players in Alzheimer' s disease therapeutics 305
• Table 7 2: Collaborations relevant to Alzheimer disease 446

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 42
• 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 129
• Figure 3 2: Neuroprotective effective of galantamine in AD 133
• Figure 3 3: Strategies for the management of Alzheimer disease 157
• Figure 5 1: NMDA receptor ion channel complex. 186
• Figure 5 2: Neurotoxicity due to misfolding of Aβ -42 220
• Figure 5 3: Role of proteomics in drug discovery and development for Alzheimer disease 275
• Figure 6 1: Unmet needs in the management of Alzheimer disease 302