Alzheimer disease - new drugs, markets and companies

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 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 33
• Cerebral atrophy and neuronal loss 33
• Neuritic plaques and neurofibrillary tangles 33
• Sp proteins as markers of neuronal death in AD 34
• 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
• APP intracellular domain 37
• Role of secretases in amyloid cascade 38
• Role of exosomal proteins 39
• Role of nicastrin 40
• Neurotixicity of Aβ deposits 40
• Relation of Aβ deposits to synaptic activity 40
• Dysfunction of TGF-β signaling accelerates Aβ deposition 41
• Role of TMP21 in presenilin complexes and Aβ formation 41
• Role of Aβ dimers in the pathogenesis of AD 42
• Structure - neurotoxicity relationships of Aβ oligomers 42
• Aβ deposit and clearance 42
• Impairment of mitochondrial energy metabolism 43
• Aβ binding alcohol dehydrogenase links AD to mitochondrial toxicity 44
• Neural thread protein 44
• Loss of synaptic proteins 44
• AD and Down syndrome 45
• Overlapping pathologies of AD and Parkinson disease 45
• AD and age-related macular degeneration 46
• Myelin hypothesis of AD 46
• Blood-brain barrier in AD 46
• Blood vessel damage in AD 48
• Loss of serotonin 1A receptors in the brain 48
• Factors in pathogenesis of AD 48
• Astrocytes and AD 48
• Axonal transport failure in AD 49
• Cell-cycle hypothesis 49
• Creatine and AD 49
• Disturbances of interaction of nervous system proteins 50
• DENN/MADD expression and enhanced pro-apoptotic signaling in AD 50
• Gonadotrophins and AD 50
• Glutamate transport dysfunction in AD 51
• Innate immune system and AD 52
• Insulin, diabetes and AD 52
• Mechanisms underlying cognitive deficits in AD 53
• Monoamine oxidase and AD 53
• Neuroinflammation and AD 54
• Neurotransmitter deficits 55
• Neurotrophic factors 55
• NF-kβ signaling and the pathogenesis of neurodegeneration 56
• Nitric oxide and AD 56
• Nogo receptor pathway 58
• Oxidative stress and AD 59
• Prostaglandins and AD 60
• Quinolinic acid and AD 60
• Retromer deficiency 61
• Serotonin and AD 61
• Spherotoxin 61
• Synaptic failure in AD 62
• Transmission of AD 62
• Ubiquitin-proteasome system in pathogenesis of AD 63
• Risk factors in the etiology of AD 64
• Aging and developmental abnormalities of the cholinergic system 64
• Cholesterol, dietary lipids, and Aβ 64
• Exposure to magnetic fields 65
• Family history of AD 65
• Homocysteine and AD 66
• Level of education/type of job and risk of AD 66
• Metals and AD 67
• Obesity 69
• Proneness to psychological distress and risk of AD 69
• Sleep deprivation 69
• Traumatic brain injury and AD 70
• Vascular risk factors for AD 71
• Vitamin B12 and folate 72
• AD versus non-dementing changes in the aging brain 72
• AD and cognitive impairment with aging 73
• Pathomechanism of memory impairment and AD 73
• Concluding remarks on pathophysiology of AD 74
• Genetics of AD 75
• Familial AD 75
• Presenilins and calcium channel leak in pathogenesis of familial AD 77
• Late onset AD 77
• Genomics of AD 77
• Introduction to genomics 77
• Genes associated with Alzheimer disease 78
• AlzGene database 79
• ApoE gene 80
• ApoE genotype and nitric oxide 81
• APOE genotype and age-related myelin breakdown 81
• ApoE receptor interaction with NMDA receptor 82
• ApoE and ApoER2 82
• ApoE receptor LR11 as regulator of Aβ 82
• Arctic mutation 83
• CALHM1 polymorphism and AD 83
• CLU, CRI and PICALM 83
• CYP46 and risk for AD 84
• DAPK1 gene variants and AD 84
• Genetic variants associated with late-onset AD 84
• LRRTM3 as a candidate gene for AD 85
• OGG1 mutations associated with AD 85
• SORL1 gene in AD 85
• TOMM40 gene and risk of AD 86
• Molecular neuropathology 86
• AD as a polygenic disorder 86
• Proteomics of AD 86
• Introduction 86
• Application of proteomic technologies to study AD 87
• Protein misfolding in AD 89
• Common denominators of AD and prion diseases 89
• Amyloid fibrils as a common feature of AD and prion diseases 90
• FE65 proteins and AD 90

2. Diagnostic Procedures for Alzheimer Disease 91

• Importance of the diagnosis of Alzheimer disease 91
• Methods of diagnosis of AD 91
• Self-administered olfactory test 92
• Neuropsychological testing 92
• Assessment and evaluation 93
• 7-minute screen 93
• 15-point risk index 94
• Measurement of aggregation in anterior segment of the eye 94
• Activities of Daily Living 94
• Alzheimer Disease Cooperative Study 95
• CDR-SOB score 95
• Clinician' s Interview-Based Impression of Change 95
• Resource Utilization in Dementia Battery 95
• DETECT™ System 95
• Electrophysiology 96
• EEG-based bispectral index 96
• Event-related potentials 96
• Early detection of cataract associated with AD 96
• Laboratory methods for diagnosis of AD 97
• Monitoring of synthesis and clearance rates of Aβ in the CSF 97
• Molecular diagnostics for AD 98
• Genetic tests for AD 98
• ApoE genotyping 99
• Gene expression patterns in AD 99
• Molecular fingerprinting of the immune system in AD 100
• Microarray-based tests for AD 100
• Monoclonal antibody-based in vitro diagnosis of AD from brain tissues 100
• Biomarkers of AD 100
• The ideal biomarker for AD 102
• CSF biomarkers of AD 102
• CSF sulfatide as a biomarker for AD 102
• Glycerophosphocholine as CSF biomarker in AD 103
• Protein biomarkers of AD in CSF 103
• Amyloid precursor protein 105
• Tau proteins in CSF 105
• Tests for the detection of Aβ in CSF 106
• Tests combining CSF tau and Aβ 106
• Urine tests for AD 107
• Blood tests for AD 107
• Blood Aβ levels 107
• Blood test for AD based on heme oxygenase-1 108
• Blood test for AD based on RNA hybridization 108
• GSK-3 elevation in white blood cells 108
• Lymphocyte Proliferation Test 108
• Protein kinase C in red blood cells 109
• Tests based on protein biomarkers in blood 109
• A skin test for early detection of AD 109
• Nanotechnology to measure Aβ derived diffusible ligands 110
• Simultaneous measurement of several biomarkers for AD 110
• Plasma biomarkers of drug response in AD 111
• Concluding remarks about biomarkers for AD 111
• Imaging in AD 112
• Computed tomography 112
• Magnetic resonance imaging 112
• Arterial spin labeling with MRI 113
• Magnetic resonance microscopy 113
• Magnetic resonance spectroscopy 113
• Single photon emission computed tomography and modifications 114
• Positron emission tomography 115
• In vivo imaging of Aβ deposits by PET 116
• In vivo detection of Aβ plaques by MRI 118
• Imaging agents for Aβ and neurofibrillary tangles 118
• Targeting of a chemokine receptor as biomarker for brain imaging 119
• Radioiodinated clioquinol as a biomarker for Aβ 120
• Imaging neuroinflammation in AD 120
• Preclinical diagnosis of AD 120
• Meta-analysis of literature on imaging in AD 121
• Alzheimer Disease Neuroimaging Initiative 121
• Concluding remarks on imaging for diagnosis of AD 122
• Diagnosis of MCI and prediction of AD 122
• Diagnosis of MCI 122
• Computer-Administered Neurophychological screen for MCI 122
• Infrared eye-tracking technology to detect MCI 123
• PET for detection of MCI 123
• MRI for detection of MCI 123
• Presymptomatic detection of AD 124
• PredictAD project 124
• Use of biomarkers to predict AD in patients with MCI 125
• Biochemical biomarkers in CSF for prediction of AD 125
• Structural MRI biomarkers for prediction of AD 125
• Magnetoencephalography for detection of MCI and AD 125
• Concluding remarks about prediction of AD in MCI 126
• Ethical aspects of diagnostics for AD 127
• Genetic testing for AD 127
• Ethical issues of brain imaging in AD 127
• Companies involved in diagnosis of AD 128

3. Management of Alzheimer Disease 131

• Introduction 131
• Cholinergic approaches 131
• Mechanism of action of cholinesterase inhibitors 132
• Choline and lecithin 133
• Donepezil 134
• Rivastigmine 135
• Galantamine 136
• Duration of treatment with ChE inhibitors 137
• Comparative studies of ChE inhibitors 137
• Donepezil versus rivastigmine 137
• Donepezil versus galantamine 138
• An assessment and future prospects of anticholinergic therapies 138
• Neuroprotection in Alzheimer' s disease 139
• Memantine 140
• Combination of memantine with ChE inhibitors 142
• Monoamine oxidase inhibitors 143
• Selegiline 143
• Synaptoprotection in AD 144
• Drugs for noncognitive symptoms in AD 144
• Antidepressants 144
• Antipsychotics 144
• ChE inhibitors for behavioral and psychological disorders in AD 145
• Concluding remarks and other drugs for agitation in AD 146
• Sensory stimulation 146
• Non-pharmacological treatments of AD 146
• Management of memory loss in AD 147
• Application of electrical fields for improvement of cerebral function in AD 147
• Vagal nerve stimulation 148
• Cerebrospinal fluid shunting 148
• Omental transposition 149
• Microchip-based hippocampal prosthesis for AD 149
• Nutritional therapies for AD 149
• Cocktail of dietary supplements for AD 150
• Docosahexaenoic acid 150
• Nicotinamide for the treatment of AD 151
• Omega-3 fatty acids 152
• Preventing decline of mental function with aging and dementia 152
• Prevention of Alzheimer disease 153
• Mental training 154
• Physical exercise 154
• Higher level of conscientiousness and decreased risk of AD 154
• Caloric restriction 155
• Nutritional factors in prevention of AD 155
• Grapes and red wine 155
• Black and green teas 157
• Caffeine 157
• Drugs to prevent Alzheimer disease 157
• Preimplantation genetic diagnosis of inherited Alzheimer disease 157
• Presymptomatic detection of AD 158
• Management of mild cognitive impairment 158
• Management of Down syndrome 159
• Guidelines for use of anti-dementia drugs in clinical practice 160
• General care of the Alzheimer disease patients 161
• Strategies for the management of Alzheimer disease 161

4. Research in Alzheimer Disease 163

• Introduction 163
• Animal models of Alzheimer disease 163
• Lesional models 163
• Cerebroventricular injection of Aβ in rats 163
• Lentiviral vector-based models of amyloid pathology 164
• AAV-mediated gene transfer to increase hippocampal Aβ 164
• Transgenic mouse models 164
• Quantitative assessment of amyloid load in transgenic models 166
• In vivo magnetic resonance microimaging in transgenic models of AD 166
• Transgenic model of AD with suppression of Aβ production 166
• Transgenic AD11 anti-NGF mice 167
• Genetically altered mice with deficiency of vesicular ACh transporter 167
• Limitations of mouse models of Alzheimer disease 167
• Cholesterol-fed rabbits as models for AD 168
• Zebrafish model for AD 168
• Transgenic invertebrate models of Alzheimer disease 169
• Drosophila model of AD 169
• Caenorhabditis elegans Alzheimer disease model 170
• Cell systems for AD research 170
• In vitro neuronal cell Lines 170
• Single-gene expression system for use in cell culture 171
• Transgenic cells 171
• In silico models 172
• Estimation of progression rates of Alzheimer disease 172
• Clinical trial methods in Alzheimer disease 173
• Molecular imaging as a guide to drug development 173
• Use of MRI and PET in clinical trials 174
• Cognitive-function assessment in clinical trials 174
• Clinical trials in mild cognitive impairment 175
• Research in AD as a basis for future therapies 175
• Use of microarrays for studying pathogenesis of AD 175
• Computational brain mapping in AD 175
• Study of neurogenesis in AD 176
• Study of 3D structure of Aβ 176
• Solid-state NMR to study precursors of Aβ 176
• Research in Alzheimer disease at academic centers 176
• Role of NIH in AD research 177
• NIH Clinical Trials Database for AD 177
• Alzheimer Research Consortium 177
• The National Institute on Aging and AD research 177

5. Drug Discovery & Development for Alzheimer Disease 179

• Introduction 179
• Categories of drugs in development for AD 179
• Memory-enhancing drugs 181
• Enhancing memory by drugs that block eIF2α phosphorylation 181
• Drugs based on cholinergic approaches 181
• AP2238 182
• Butyrylcholinesterase inhibitors 182
• Donepezil-tacrine hybrids 182
• Drugs modulating gamma-aminobutyric acid receptors 183
• Ganstigmina 183
• Methanesulfonyl fluoride 183
• Muscarinic receptor modulators 184
• Muscarinic M1 agonists 184
• Muscarinic M2 antagonists 185
• Nicotine and nicotinic receptor modulators 185
• Nicotine 185
• Nicotinic receptor modulators 186
• GTS21 187
• Ispronicline 187
• JWB1-84-1 188
• Neuropeptide/neurotransmitters 188
• Somatostatin release enhancers 188
• Glutamate receptor modulators 188
• Physiology and pharmacology of glutamate receptors 189
• NMDA receptor ion channel complex 189
• Metabotropic glutamate receptors 190
• Glutamate receptor modulators as potential therapeutics for AD 191
• Non-competitive NMDA modulators 192
• AMPA modulators 192
• Drugs affecting multiple neurotransmitters 193
• Ensaculin 193
• NS2330 193
• RS-1259 193
• Lecozotan 194
• Vaccines for AD 194
• Active immunization with Aβ 194
• AN-1792 vaccine 194
• Complications in clinical trials with AN-1792 195
• Effects of Aβ vaccine on the brain 195
• Strategies to avoid undesirable effect of Aβ vaccination 196
• Passive immunization in AD with monoclonal antibodies 197
• Delivery of the passive antibody directly to the brain 198
• Systemic injection of MAbs to treat AD 199
• Combination of Aβ immunotherapy and CD40-CD40L blockade 199
• Shaping the immune responses elicited against Aβ 200
• Gene vaccination 200
• Modified Aβ nasal vaccine 200
• Transdermal Aβ vaccination 201
• Other vaccines for AD 201
• Nasal vaccination with Proteosome™ adjuvant 202
• T-cell vaccination with glatiramer acetate adjuvant 202
• Early start of immunotherapy to clear Aβ plaques 202
• Reversal of cholinergic dysfunction by anti-Aβ antibody 202
• Immune modulation via TRL9 to reduce Aβ 203
• Mechanisms by which Aβ antibodies reduce amyloid accumulation in the brain 203
• Perspectives on vaccines for AD 204
• Companies involved in AD vaccines 205
• Inhibition of amyloid precursor protein aggregation 206
• Secretase inhibitors 206
• Neuroprotection by γ-secretase cleaved APP 207
• β secretase inhibitors 207
• γsecretase inhibitors 208
• Substrate-targeting by γ-secretase modulators 209
• Amyloid-derived diffusible ligands 209
• GABA receptor modulation by etazolate and APP processing 209
• Depletion of serum amyloid P 210
• Trojan-horse approach to prevent build-up of Aβ aggregates 210
• Drugs that inhibit the formation of Aβ 210
• 22R-hydroxycholesterol 211
• Acylaminopyrazole 211
• Antihypertensive drugs 211
• Valsartan 212
• Chelation therapy for AD 212
• Clioquinol and PBT2 212
• Copper chelation by FKBP52 213
• Zinc chelation from amyloid plaques 214
• Next generation multifunctional chelating agents for AD 214
• Tetrahydrocannabinol 214
• NSAIDs 215
• Flurbiprofen analogs with Aβ 2-lowering action 216
• Nitric oxide-donating NSAIDs 217
• In vivo demonstration of the effects of NSAIDs on brain in AD 217
• Imatinib mesylate 217
• Laminin 218
• Paclitaxel 218
• Phenserine 218
• Tolserine 219
• Platinum-based inhibitors of Aβ 219
• Heparin and its derivatives 219
• A reassessment of the role of heparin in AD 219
• Enoxaparin 220
• Heparan sulfate 220
• Scyllo-cyclohexanehexol 220
• Ubiquitin C-terminal hydrolase L1 221
• Drugs to prevent the formation of NFTs 221
• Tau suppression 222
• ApoE4 as a therapeutic target in AD 222
• Strategies to enhance clearance of Aβ 223
• Removal of Aβ deposits by nanotechnology 223
• Enhanced PKC€ activity promotes clearance of Aβ 223
• Role of matrix metalloproteinases in clearance of Aβ 224
• Small molecule DAPH for clearance of amyloid 224
• Clearance of Aβ across the blood-brain barrier 224
• Therapeutics to reverse cerebral Aβ deposits 225
• 4,5-dianilinophthalimide for disruption of Aβ -42 fibrils 225
• ABCA1 overexpression to lower amyloid deposits 226
• β sheet breakers 226
• Blocking ApoE/Aβ interaction to reduce Aβ plaques 226
• Inhibitors of Aβ dehydrogenase 227
• Intravenous immune globulin 227
• Meptides 228
• SAN-61 for cleavage of fibril and soluble amyloid 228
• Serum amyloid P component depletion 229
• Companies developing Aβ directed therapeutics for AD 229
• Antiinflammatory and antimicrobial drugs 231
• Dapsone 231
• Antimicrobial drugs against C. pneumoniae 231
• PPAR-gamma agonists 231
• Inhibitors of neuroinflammation 232
• Cyclophosphamide 232
• Etanercept 232
• MW01-5-188WH 233
• VP015 233
• Antidiabetic drugs 233
• Rosiglitazone 234
• Pioglitazone 234
• Nootropics 234
• Acetyl-L-carnitine 235
• Cerebrolysin 235
• Ergot derivatives 236
• Lisuride 236
• Dihydroergocryptine 236
• Neuroprotective effect drugs not primarily developed for AD 236
• Angiotensin-converting enzyme inhibitors 237
• Dimebolin 237
• Drugs acting on estrogen receptors 238
• Estrogen 239
• Raloxifene 239
• Neurosteroids 240
• Pregnenolone sulfate 240
• Dehydroepiandrosterone 240
• Lithium 241
• MAO-B inhibitors 241
• Ladostigil tartrate 241
• Memoquin 242
• Methylene blue 242
• Nimodipine 242
• Testosterone 243
• Valproic acid 244
• Future prospects of neuroprotection in AD 244
• Targeting Cdk5 pathway 244
• Antioxidants 245
• Colostrinin 245
• Curcumin 246
• Melatonin 246
• Synthetic catalytic scavengers 247
• Dehydroascorbic acid 247
• Omega-3 fatty acids 247
• Vitamins 248
• Vitamin E as antioxidant 248
• Vitamins to lower homocysteine 248
• Folic acid 248
• Aminopyridazines 249
• Nanobody-based drugs for AD 249
• Nitric oxide based therapeutics for AD 250
• Nitric oxide mimetics 250
• iNOS inhibitors for AD 250
• Novel drugs for AD from natural resources 250
• Berberine chloride 251
• Centella asiatica 252
• Ginko biloba 252
• Gilatide (from saliva of the Gila monster) 253
• Huperzine-A 253
• Hyperforin 254
• Melissa officinalis 254
• Nostocarboline derived from cyanobacteria 254
• PTI-00703 255
• Salvia 255
• Securinega suffruticosa 255
• Withania somnifera 255
• ZT-1 256
• Cholesterol and AD 256
• Role of statins in reducing the risk of Alzheimer disease 256
• Neuroprotective effect of statins unrelated to cholesterol lowering 257
• ACAT inhibitors 258
• Role of gene for cholesterol ester transfer protein 258
• Cholesterol 24S-hydroxylase as a drug target for AD 259
• Selectively increase of ApoA-I production 259
• Neurotrophic factors 259
• Activity-dependent neuroprotective protein 259
• Brain derived neurotrophic factor 260
• Insulin-like growth factor-1 260
• Nerve growth factor 261
• Neotrofin (AIT-082) 262
• Limitations of the use of NTFs for AD 262
• Role of serotonin modulators in AD 262
• Xaliproden 263
• 5-HT1A receptor antagonists 263
• 5-HT6 antagonists 263
• 5-HT4 receptor agonists 263
• PRX-03140 264
• Cell therapy for AD 264
• Stem cell transplantation for AD 265
• Potential benefits of grafting NSCs in AD 265
• NSCs improve cognition in AD via BDNF 265
• Drugs for enhancing neuronal differentiation of implanted NSCs 265
• Implantation of encapsulated cells for delivering NGF 266
• Gene therapy for AD 266
• ApoE gene therapy 266
• Humanin gene therapy 266
• Neprilysin gene therapy 267
• NGF gene therapy 267
• Targeting plasminogen activator inhibitor type-1 gene 268
• Antisense approaches to AD 268
• RNAi approaches to AD 269
• Combined therapeutic approaches to AD 270
• Drug delivery for Alzheimer disease 270
• Delivery of thyrotropin-releasing hormone analogs by molecular packaging 271
• Nanoparticle-based drug delivery for Alzheimer' s disease 271
• Transdermal drug delivery in Alzheimer' s disease 271
• Transdermal rivastigmine 272
• Intranasal delivery of therapeutics for AD 272
• Intranasal delivery of tacrine 272
• Intranasal delivery of nerve growth factor to the brain 272
• Circadian rhythms and timing of cholinesterase inhibitor therapy 273
• Clinical trials for AD 273
• Drugs for AD that were discontinued in clinical trials 277
• Evaluation of clinical trials of AD 280
• Monitoring of cognitive function during clinical trials 280
• Drug discovery for AD 280
• Genomics-based drug discovery 280
• Proteomics and drug discovery for AD 280
• High through screening for AD drug candidates 281
• Drugs acting on signaling pathways 282
• Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 282
• Drugs to reverse inhibition of the PKA/CREB pathway in AD 282
• Inhibition of the CD40 signaling pathway 283
• JNK pathway as a target 284
• Mitogen-activated protein kinase pathway as target 284
• Protein kinase C activators 284
• Small molecule compounds binding to neurotrophin receptor p75NTR 285
• Targeting Vav in tyrosine kinase signaling pathway 285
• Novels targets/receptors for AD drug discovery 286
• Activation of cerebral Rho GTPases 286
• Blockade of TGF-β-Smad2/3 signaling in peripheral macrophages 286
• Blockers of Aβ calcium channel 287
• Casein kinase 1 287
• Cyclin-dependent kinase-5 287
• Heat shock protein 90 inhibitors 287
• Histone deacetylase 1 288
• Inactivation of aph-1 and pen-2 reduces APP cleavage 288
• NF-kβ inhibitors 289
• Kinases and phosphatases as targets for AD therapeutics 289
• Phosphodiesterase inhibitors 289
• Pin 1 as a target in AD 289
• Protein phosphatase 5 as a neuroprotective in AD 290
• Src homology-containing protein-1 inhibitors 290
• Targeting GABAergic system 291
• Pharmacogenomics of Alzheimer disease 291
• Personalized therapy of AD 291
• Genotyping and AD therapeutics 292
• Biomarkers of AD/companion diagnostics for cholinesterase inhibitors 292
• Regulatory aspects of drug development for AD 293
• EMEA guidelines for drug development for AD 293
• Concluding remarks and future prospects of drugs for AD 293

6. Markets & Finances of AD Care 295

• Introduction 295
• Pharmacoeconomics of treatment of AD 295
• Quality of Life in relation to economics of AD 295
• Costs associated with Alzheimer disease 295
• Pharmacoeconomics of donepezil 296
• Pharmacoeconomics studies using rivastigmine 296
• Pharmacoenonomics studies using galantamine 297
• A comparison of pharmacoenonomics outcomes with different ChE inhibitors 297
• Pharmacoenonomics studies using memantine 298
• Patterns of AD care in major markets 298
• Care of AD patients in the US 298
• Cost of care 298
• Medicare and AD 299
• Patterns of practice in AD care 300
• Opinions of physicians' organizations on drugs for dementia 300
• Care of AD patients in the UK 301
• Cost of care 301
• Patterns of practice in AD care 301
• Retraction of NICE recommendations to NHS 302
• Care of AD patients in Germany 303
• Care of AD patients in France 303
• Care of AD patients in Italy 304
• Care of AD patients in Spain 304
• Care of AD patients in Japan 304
• Markets for AD diagnostics 305
• Markets for AD therapeutics 305
• Geographical markets for AD 305
• Markets for currently approved drugs for AD 306
• Markets for generic AD drugs 306
• Future growth of AD market 307
• Statins 307
• Limitations of AD drug development by the biotechnology industry 307
• Unmet needs in the management of AD 308
• Drivers of AD markets 309
• Increase of the aged populations 310
• Increase in the number of approved drugs for AD 310
• Limitations of the current therapies 310
• Improvements in diagnosis 310
• Increasing awareness of the disease 311

7. Companies 313

• Introduction 313
• Profiles of companies 313
• Collaborations 455

8. References 459

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 29
• Table 1 5: Relation of mutations in amyloid precursor protein to CNS disorders 36
• Table 1 6: Risk factors for Alzheimer' s disease 64
• Table 1 7: Genes linked to AD 78
• Table 1 8: Abnormalities of expression of brain proteins in Down' s syndrome and AD 88
• Table 2 1: Classification of methods of diagnosis of Alzheimer disease 91
• Table 2 2: Neuropsychological test batteries and scales for Alzheimer' s disease 92
• Table 2 3: Available molecular diagnostic tests for Alzheimer disease 98
• Table 2 4: Classification of biomarkers of AD in blood and CSF 101
• Table 2 5: Characteristics of an ideal biomarker for Alzheimer disease 102
• Table 2 6: Companies involved in the diagnosis of Alzheimer disease 128
• Table 3 1: Classification of treatments for Alzheimer disease 131
• Table 3 2: Cholinergic approaches used in the treatment of Alzheimer disease 132
• Table 3 3: Categories of neuroprotective agents for Alzheimer disease 139
• Table 3 4: Strategies for prevention of Alzheimer disease 153
• Table 3 5: Guidelines for the treatment of dementia 160
• Table 4 1: Transgenic mouse models of Alzheimer disease 164
• Table 5 1: Classification of therapies in development for Alzheimer disease 179
• Table 5 2: Drugs for AD targeting nACh receptors 186
• Table 5 3: Ionotropic glutamate receptors 189
• Table 5 4: Classification of mGluRs 189
• Table 5 5: Glutamate receptor modulators as potential therapeutic agents in AD 191
• Table 5 6: Companies involved in developing vaccines for AD 206
• Table 5 7: Companies developing Aβ-directed therapeutics for AD 229
• Table 5 8: Innovative neuroprotective approaches for Alzheimer disease 236
• Table 5 9: Herbal therapies for AD 251
• Table 5 10: Novel drug delivery methods for Alzheimer disease therapies 270
• Table 5 11: Clinical trials in Alzheimer disease 273
• Table 5 12: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 278
• Table 6 1: Direct and indirect costs associated with Alzheimer disease 296
• Table 6 2: Prevalence of AD in major markets 2008-2018 305
• Table 6 3: AD market values from 2008-2018 in the seven major world markets 306
• Table 6 4: Markets for currently approved AD drugs 2008-2018 306
• Table 6 5: Potential markets for drugs in development 2008-2018 307
• Table 6 6: Limitations of AD drug discovery and development by the biotechnology industry 308
• Table 6 7: Factors that drive AD markets 309
• Table 7 1: Major players in Alzheimer' s disease therapeutics 313
• Table 7 2: Collaborations relevant to Alzheimer disease 455

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 43
• Figure 1 4: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease 57
• Figure 1 5: Oxidative stress and Alzheimer disease 59
• Figure 1 6: Role of proteosome inhibition in Aβ generation and neurodegeneration 63
• Figure 1 7: Pathomechanism of AD 75
• Figure 3 1: Metabolism of acetylcholine 133
• Figure 3 2: Neuroprotective effective of galantamine in AD 137
• Figure 3 3: Strategies for the management of Alzheimer disease 161
• Figure 5 1: NMDA receptor ion channel complex 190
• Figure 5 2: Neurotoxicity due to misfolding of Aβ -42 225
• Figure 5 3: Role of proteomics in drug discovery and development for Alzheimer disease 281
• Figure 6 1: Unmet needs in the management of Alzheimer disease 309