Alzheimer disease - new drugs, markets and companies

Introduction

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. Selected 189 clinical trials are listed, of which 135 are still in progress and 54 were discontinued for various reasons.

Alzheimer's disease market in the seven major markets is analyzed for the year 2012. 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 2022. 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 144 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 97 collaborations. The bibliography contains over 850 publications that are cited in the report.The report is supplemented with 45 tables and 16 figures.

Table of Contents

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 26
• Cerebral insufficiency and AD 26
• Memory deficits and preclinical AD 26
• Sleep disorders and AD 27
• Mild cognitive impairment 27
• Evolution of diagnostic criteria of AD 29
• Revised criteria for the clinical diagnosis of AD 30
• Epidemiology 31
• Epidemiology of aging 31
• Epidemiology of dementia 34
• Epidemiology of AD 34
• Prevalence of AD according to age 35
• Mortality in AD 35
• Pathophysiology of AD 36
• Cerebral atrophy and neuronal loss 36
• Neuritic plaques and neurofibrillary tangles 36
• Sp proteins as markers of neuronal death in AD 37
• Role of tau in the pathogenesis of AD 37
• RNA-binding proteins and AD 38
• Amyloid precursor protein 38
• Relation of APP mutations to CNS disorders 39
• Relation of APP to Aβ deposits and pathogenesis of AD 39
• APP intracellular domain 41
• Role of secretases in amyloid cascade 41
• Role of exosomal proteins 43
• Role of nicastrin 43
• Neurotixicity of Aβ deposits 43
• Dysfunction of TGF-β signaling accelerates Aβ deposition 44
• Relation of Aβ deposits to synaptic activity 44
• Role of TMP21 in presenilin complexes and Aβ formation 45
• Role of Aβ dimers in the pathogenesis of AD 45
• Role of dsDNA breaks in neurodegeneration due to Aβ 46
• Structure-neurotoxicity relationships of Aβ oligomers 46
• Aβ production and clearance 46
• Impairment of mitochondrial energy metabolism 47
• Aβ-binding alcohol dehydrogenase links AD to mitochondrial toxicity 48
• Neural thread protein 48
• Loss of synaptic proteins 48
• AD and Down syndrome 49
• Overlapping pathologies of AD and Parkinson disease 49
• AD and age-related macular degeneration 50
• Myelin hypothesis of AD 50
• Blood-brain barrier in AD 50
• Blood vessel damage in AD 52
• Loss of serotonin 1A receptors in the brain 52
• Factors in pathogenesis of AD 52
• Aerobic glycolysis and AD 52
• Astrocytes and AD 52
• Axonal transport failure in AD 53
• Cell-cycle hypothesis 53
• Chronic heart failure link with AD 54
• Creatine and AD 54
• Disturbances of interaction of nervous system proteins 54
• DENN/MADD expression and enhanced pro-apoptotic signaling in AD 54
• Gonadotrophins and AD 55
• Glutamate transport dysfunction in AD 55
• Innate immune system and AD 56
• Insulin, diabetes and AD 57
• Mechanisms underlying cognitive deficits in AD 57
• Monoamine oxidase and AD 58
• Neuroinflammation and AD 58
• Neurotransmitter deficits 60
• Neurotrophic factors 60
• NF-κB signaling and the pathogenesis of neurodegeneration 61
• Nitric oxide and AD 61
• Nogo receptor pathway 64
• Oxidative stress and AD 64
• Prostaglandins and AD 66
• Quinolinic acid and AD 66
• Retromer deficiency 66
• Serotonin and AD 67
• Spread of neurodegeneration 67
• Synaptic failure in AD 67
• Transmission of AD 68
• Ubiquitin-proteasome system in pathogenesis of AD 69
• Risk factors in the etiology of AD 70
• Aging and developmental abnormalities of the cholinergic system 70
• Cholesterol, dietary lipids, and Aβ 70
• Exposure to magnetic fields 71
• Family history of AD 71
• Homocysteine and AD 72
• Level of education/type of job and risk of AD 72
• Metals and AD 73
• Obesity 75
• Proneness to psychological distress and risk of AD 75
• Reduced muscle strength 75
• Sleep deprivation 76
• Traumatic brain injury and AD 76
• Vascular risk factors for AD 77
• Vitamin B12 and folate 79
• AD versus non-dementing changes in the aging brain 79
• AD and cognitive impairment with aging 79
• Pathomechanism of memory impairment and AD 80
• Concluding remarks on pathophysiology of AD 80
• Genetics of AD 82
• Familial AD 82
• Presenilins and calcium channel leak in pathogenesis of familial AD 83
• Late onset AD 84
• Genomics of AD 84
• Introduction to genomics 84
• Genes associated with Alzheimer disease 84
• AlzGene database 86
• ApoE gene 86
• ApoE genotype and nitric oxide 87
• ApoE genotype modulates AD phenotype 88
• APOE genotype and age-related myelin breakdown 88
• ApoE receptor interaction with NMDA receptor 89
• ApoE and ApoER2 89
• ApoE receptor LR11 as regulator of Aβ 89
• Arctic mutation 90
• BCHE gene 90
• CALHM1 polymorphism and AD 90
• CLU, CRI and PICALM 90
• CYP46 and risk for AD 91
• DAPK1 gene variants and AD 91
• Genetic variants associated with early-onset AD 91
• Genetic variants associated with late-onset AD 92
• Copy number variation (CNV) in LOAD 92
• LRRTM3 as a candidate gene for AD 92
• MTHFD1L gene variant associated with AD 93
• Mutation in APP gene with protective effect against AD 93
• OGG1 mutations associated with AD 93
• SORL1 gene in AD 93
• TOMM40 gene and risk of AD 94
• TREM2 variants in AD 94
• International Genomics of Alzheimer's Project 95
• Sequencing in Alzheimer disease 95
• Molecular neuropathology 96
• Role of microRNAs in AD 96
• AD as a polygenic disorder 97
• Proteomics of AD 97
• Introduction 97
• Application of proteomic technologies to study AD 97
• Protein misfolding in AD 99
• Common denominators of AD and prion diseases 100
• Amyloid fibrils as a common feature of AD and prion diseases 101
• FE65 proteins and AD 101

2. Diagnostic Procedures for Alzheimer Disease 103

• Importance of the diagnosis of Alzheimer disease 103
• Methods of diagnosis of AD 103
• Self-administered olfactory test 104
• Neuropsychological testing 104
• Assessment and evaluation 105
• 7-minute screen 105
• 15-point risk index 106
• Measurement of aggregation in anterior segment of the eye 106
• Activities of Daily Living 106
• Alzheimer Disease Cooperative Study 107
• CDR-SOB score 107
• Clinician's Interview-Based Impression of Change 107
• Resource Utilization in Dementia Battery 107
• DETECT™ System 107
• Electrophysiology 108
• EEG-based bispectral index 108
• Event-related potentials 108
• Correlation of electrical activity of the brain with cognition 108
• Early detection of cataract associated with AD 109
• Retinal imaging to detect Aβ deposits 109
• Laboratory methods for diagnosis of AD 109
• Monitoring of synthesis and clearance rates of Aβ in the CSF 109
• Molecular diagnostics for AD 110
• Genetic tests for AD 111
• ApoE genotyping 111
• Gene expression patterns in AD 112
• Molecular fingerprinting of the immune system in AD 112
• Microarray-based tests for AD 112
• Monoclonal antibody-based in vitro diagnosis of AD from brain tissues 113
• Biomarkers of AD 113
• The ideal biomarker for AD 115
• CSF biomarkers of AD 115
• CSF sulfatide as a biomarker for AD 115
• Glycerophosphocholine as CSF biomarker in AD 116
• Protein biomarkers of AD in CSF 116
• Amyloid precursor protein 118
• Tau proteins in CSF 118
• Tests for the detection of Aβ in CSF 118
• Tests combining CSF tau and Aβ 119
• Concluding remarks abut CSF biomarkers of AD 119
• Urine tests for AD 120
• Blood tests for AD 120
• Blood Aβ levels 120
• Blood test for AD based on heme oxygenase-1 121
• Blood test for AD based on RNA hybridization 121
• GSK-3 elevation in white blood cells 122
• Lymphocyte Proliferation Test 122
• Metabolomic biomarker profiling 122
• MGAT3 as biomarker for prognosis of AD 122
• Protein kinase C in red blood cells 123
• Sphingolipids 123
• Tests based on protein biomarkers in blood 123
• A skin test for early detection of AD 124
• Saliva-based tests for AD 124
• Saliva Aβ42 level as a biomarker of AD 124
• Nanotechnology to measure Aβ-derived diffusible ligands 125
• Simultaneous measurement of several biomarkers for AD 125
• Nutritional biomarkers in plasma of AD patients 126
• Plasma biomarkers of drug response in AD 126
• A serum protein-based algorithm for the detection of AD 126
• Concluding remarks about biomarkers for AD 127
• Imaging in AD 127
• Computed tomography 127
• Magnetic resonance imaging 128
• Arterial spin labeling with MRI 128
• Magnetic resonance microscopy 129
• Magnetic resonance spectroscopy 129
• Single photon emission computed tomography and modifications 130
• Positron emission tomography 130
• In vivo imaging of Aβ deposits by PET 132
• Pittsburgh compound B and PET 132
• Florbetapir-PET 133
• Florbetaben-PET 134
• In vivo detection of Aβ plaques by MRI 134
• Imaging agents for Aβ and neurofibrillary tangles 135
• Targeting of a chemokine receptor as biomarker for brain imaging 136
• Radioiodinated clioquinol as a biomarker for Aβ 136
• Imaging neuroinflammation in AD 136
• Preclinical diagnosis of AD 137
• Meta-analysis of literature on imaging in AD 137
• Alzheimer Disease Neuroimaging Initiative 138
• Computer aided diagnosis systems for AD based on imaging data 138
• Concluding remarks on imaging for diagnosis of AD 139
• Diagnosis of MCI and prediction of AD 139
• Diagnosis of MCI 139
• Computer-Administered Neurophychological screen for MCI 140
• Infrared eye-tracking technology to detect MCI 140
• PET for detection of MCI 140
• MRI for detection of MCI 141
• Presymptomatic detection of AD 141
• Biomarker changes in autosomal dominantly inherited AD 141
• PredictAD project 142
• Prediction of AD in patients with MCI 142
• Combination of MMSE and a memory test for prediction of AD 142
• Biochemical biomarkers in CSF for prediction of AD 142
• Structural MRI biomarkers for prediction of AD 143
• Magnetoencephalography for detection of MCI and AD 143
• MRI-based index to measure the severity of AD in MCI 144
• Concluding remarks about prediction of AD in MCI 144
• Criteria for diagnosis of AD 145
• Role of biomarkers in diagnosis of AD dementia 145
• Ethical aspects of diagnostics for AD 146
• Genetic testing for AD 146
• Ethical issues of brain imaging in AD 147
• Companies involved in diagnosis of AD 147

3. Management of Alzheimer Disease 149

• Introduction 149
• Cholinergic approaches 149
• Mechanism of action of cholinesterase inhibitors 150
• Choline and lecithin 151
• Donepezil 152
• Rivastigmine 153
• Galantamine 154
• Duration of treatment with ChE inhibitors 155
• Comparative studies of ChE inhibitors 155
• Donepezil versus rivastigmine 156
• Donepezil versus galantamine 156
• An assessment and future prospects of anticholinergic therapies 156
• Neuroprotection in Alzheimer's disease 157
• Memantine 158
• Combination of memantine with ChE inhibitors 161
• Monoamine oxidase inhibitors 162
• Selegiline 162
• Synaptoprotection in AD 162
• Drugs for noncognitive symptoms in AD 162
• Antidepressants 163
• Antipsychotics 163
• ChE inhibitors for behavioral and psychological disorders in AD 163
• Concluding remarks and other drugs for agitation in AD 164
• Sensory stimulation 165
• Non-pharmacological treatments of AD 165
• Management of memory loss in AD 165
• Exposure to electromagnetic fields for treatment of AD 166
• Application of electrical fields for improvement of cerebral function 166
• High-frequency electromagnetic field treatment of AD 166
• Vagal nerve stimulation 167
• Cerebrospinal fluid shunting 167
• Omental transposition 168
• Microchip-based hippocampal prosthesis for AD 168
• Nutritional therapies for AD 168
• Axona 168
• Cocktail of dietary supplements for AD 168
• Docosahexaenoic acid 169
• Magnesium 170
• Nicotinamide for the treatment of AD 171
• Omega-3 fatty acids 171
• Preventing decline of mental function with aging and dementia 172
• Prevention of Alzheimer disease 172
• Mental training 173
• Physical exercise 174
• Higher level of conscientiousness and decreased risk of AD 174
• Nutritional factors in prevention of AD and MCI 175
• Black and green teas 175
• Caffeine 175
• Caloric restriction 176
• Cocoa flavonol consumption 176
• Grapes and red wine 176
• Drugs to prevent Alzheimer disease 178
• Preimplantation genetic diagnosis of inherited Alzheimer disease 178
• Presymptomatic detection of AD 178
• Management of mild cognitive impairment 178
• Management of Down syndrome 179
• Guidelines for use of anti-dementia drugs in clinical practice 180
• Donepezil and/or memantine 181
• General care of the Alzheimer disease patients 181
• Strategies for the management of Alzheimer disease 182

4. Research in Alzheimer Disease 183

• Introduction 183
• Animal models of Alzheimer disease 183
• Lesional models 183
• Cerebroventricular injection of Aβ in rats 183
• Lentiviral vector-based models of amyloid pathology 184
• AAV-mediated gene transfer to increase hippocampal Aβ 184
• Transgenic mouse models 184
• Quantitative assessment of amyloid load in transgenic models 186
• In vivo magnetic resonance microimaging in transgenic models of AD 186
• Transgenic model of AD with suppression of Aβ production 186
• Transgenic AD11 anti-NGF mice 187
• Genetically altered mice with deficiency of vesicular ACh transporter 187
• Limitations of mouse models of Alzheimer disease 187
• Improved mouse models of AD expressing human genes 188
• Cholesterol-fed rabbits as models for AD 188
• Zebrafish model for AD 189
• Transgenic invertebrate models of Alzheimer disease 189
• Drosophila model of AD 190
• Caenorhabditis elegans Alzheimer disease model 190
• Cell systems for AD research 191
• In vitro neuronal cell Lines 191
• Single-gene expression system for use in cell culture 191
• Transgenic cells 192
• In silico models 192
• Estimation of progression rates of Alzheimer disease 192
• Clinical trial methods in Alzheimer disease 193
• Molecular imaging as a guide to drug development 194
• Use of MRI and PET in clinical trials 194
• Cognitive-function assessment in clinical trials 195
• Clinical trials in mild cognitive impairment 195
• Research in AD as a basis for future therapies 195
• Use of microarrays for studying pathogenesis of AD 196
• Computational brain mapping in AD 196
• Study of neurogenesis in AD 196
• Study of 3D structure of Aβ 196
• Solid-state NMR to study precursors of Aβ 197
• Research in Alzheimer disease at academic centers 197
• Role of NIH in AD research 197
• NIH Clinical Trials Database for AD 197
• Alzheimer Research Consortium 197
• The National Institute on Aging and AD research 198

5. Drug Discovery & Development for Alzheimer Disease 199

• Introduction 199
• Categories of drugs in development for AD 199
• Memory-enhancing drugs 201
• Enhancing memory by drugs that block eIF2α phosphorylation 201
• Drugs based on cholinergic approaches 201
• AP2238 202
• Butyrylcholinesterase inhibitors 202
• Donepezil-tacrine hybrids 202
• Drugs modulating gamma-aminobutyric acid receptors 203
• Ganstigmina 203
• Methanesulfonyl fluoride 203
• Muscarinic receptor modulators 204
• Muscarinic M1 agonists 204
• Muscarinic M2 antagonists 205
• Nicotine and nicotinic receptor modulators 205
• Nicotine 205
• Nicotinic receptor modulators 206
• GTS21 207
• Ispronicline 207
• JWB1-84-1 208
• Neuropeptide/neurotransmitters 208
• Somatostatin release enhancers 208
• Glutamate receptor modulators 208
• Physiology and pharmacology of glutamate receptors 209
• NMDA receptor ion channel complex 209
• Metabotropic glutamate receptors 210
• Glutamate receptor modulators as potential therapeutics for AD 211
• N20C 211
• AMPA modulators 212
• Glutamate release inhibitors 213
• INI-0602 213
• Drugs affecting multiple neurotransmitters 213
• Ensaculin 213
• NS2330 213
• RS-1259 213
• Lecozotan 214
• Vaccines for AD 214
• Active immunization with Aβ 215
• AN-1792 vaccine 215
• Complications in clinical trials with AN-1792 215
• Effects of Aβ vaccine on the brain 215
• Strategies to avoid undesirable effect of Aβ vaccination 216
• Passive immunization in AD 217
• Passive immunization with MAbs 217
• Delivery of the passive antibody directly to the brain 219
• Systemic injection of MAbs to treat AD 220
• Combination of Aβ immunotherapy and CD40-CD40L blockade 220
• Shaping the immune responses elicited against Aβ 220
• Delivery of AD vaccines 221
• Gene vaccination 221
• Modified Aβ nasal vaccine 222
• Transdermal Aβ vaccination 222
• Other vaccines for AD 222
• Nasal vaccination with Proteosome™ adjuvant 223
• T-cell vaccination with glatiramer acetate adjuvant 223
• Early start of immunotherapy to clear Aβ plaques 223
• Reversal of cholinergic dysfunction by anti-Aβ antibody 223
• Immune modulation via Toll-like receptors to reduce Aβ 224
• Mechanisms by which Aβ antibodies reduce amyloid accumulation in the brain 224
• Perspectives on vaccines for AD 225
• Companies involved in AD vaccines 227
• Inhibition of amyloid precursor protein aggregation 227
• Secretase modulators 228
• Neuroprotection by α-secretase cleaved APP 228
• Inhibitors of β-secretase 229
• Inhibitors of γ-secretase 230
• Amyloid-derived diffusible ligands 231
• GABA receptor modulation by etazolate and APP processing 231
• Depletion of serum amyloid P 232
• Trojan-horse approach to prevent build-up of Aβ aggregates 232
• Drugs that inhibit the formation of Aβ 232
• 22R-hydroxycholesterol 233
• Acylaminopyrazole 233
• Cadmium telluride nanoparticles prevent Aβ fibril formation 233
• Cannabinoids 234
• Chelation therapy for AD 234
• Clioquinol and PBT2 234
• Copper chelation by FKBP52 236
• Zinc chelation from amyloid plaques 236
• Next generation multifunctional chelating agents for AD 236
• Heparin and its derivatives 237
• A reassessment of the role of heparin in AD 237
• Enoxaparin 238
• Heparan sulfate 238
• Imatinib mesylate 238
• Laminin 238
• NSAIDs 239
• Flurbiprofen analogs with Aβ42-lowering action 239
• Nitric oxide-donating NSAIDs 240
• In vivo demonstration of the effects of NSAIDs on brain in AD 241
• Paclitaxel 241
• Phenserine 241
• Tolserine 242
• Platinum-based inhibitors of Aβ 242
• Retro-inverso peptide inhibitor 242
• Scyllo-cyclohexanehexol 243
• Ubiquitin C-terminal hydrolase L1 243
• Drugs to prevent the formation of NFTs 243
• Tau suppression 244
• ApoE4 as a therapeutic target in AD 245
• Strategies to prevent deposits and enhance clearance of Aβ 245
• 4,5-dianilinophthalimide for disruption of Aβ1-42 fibrils 246
• ABCA1 overexpression to lower amyloid deposits 247
• ANAVEX 2-73 247
• Beta-sheet breakers 247
• Bexarotene 248
• Blocking ApoE/Aβ interaction to reduce Aβ plaques 248
• Clearance of Aβ across the blood-brain barrier 248
• Enhanced PKCє activity promotes clearance of Aβ 249
• Galantamine-induced Aβ clearance 249
• Inhibitors of Aβ dehydrogenase 249
• Intravenous immune globulin 250
• Meptides 251
• Monoclonal antibodies for removal of Aβ 251
• Crenezumab 251
• Gantenerumab 251
• Solanezumab 252
• Nanotechnology for removal of Aβ deposits 252
• Role of matrix metalloproteinases in clearance of Aβ 252
• SAN-61 for cleavage of fibril and soluble amyloid 253
• Serum amyloid P component depletion 253
• Small molecule DAPH for clearance of amyloid 253
• Companies developing Aβ-directed therapeutics for AD 253
• Antiinflammatory and antimicrobial drugs 255
• Dapsone 255
• Antimicrobial drugs against C. pneumoniae 256
• PPAR-gamma agonists 256
• Inhibitors of neuroinflammation 256
• Ceramide 256
• Cyclophosphamide 257
• Etanercept 257
• MW01-5-188WH 257
• Antidiabetic drugs 258
• Rosiglitazone 258
• Pioglitazone 259
• Nootropics 259
• Acetyl-L-carnitine 259
• Cerebrolysin 259
• Ergot derivatives 260
• Lisuride 260
• Dihydroergocryptine 260
• Neuroprotective effect drugs not primarily developed for AD 261
• Antihypertensive drugs 261
• Angiotensin-converting enzyme inhibitors 261
• Angiotensin receptor blockers 262
• Dimebon 262
• Drugs acting on estrogen receptors 263
• Estrogen 263
• Raloxifene 264
• Neurosteroids 264
• Pregnenolone sulfate 264
• Dehydroepiandrosterone 265
• Levetiracetam 265
• Lithium 265
• MAO-B inhibitors 266
• Ladostigil tartrate 266
• Memoquin 267
• Methylene blue 267
• Nimodipine 267
• Rapamycin 268
• Statins 268
• Testosterone 269
• Valproic acid 270
• Future prospects of neuroprotection in AD 270
• Targeting Cdk5 pathway 270
• Antioxidants 271
• Colostrinin 271
• Curcumin 272
• Dehydroascorbic acid 272
• Melatonin 273
• Omega-3 fatty acids 273
• Reservatrol 273
• Synthetic catalytic scavengers 274
• Vitamins 274
• Vitamin E as antioxidant 274
• Vitamins to lower homocysteine 275
• Folic acid 275
• Aminopyridazines 275
• Nanobody-based drugs for AD 276
• Nitric oxide based therapeutics for AD 276
• Nitric oxide mimetics 276
• iNOS inhibitors for AD 277
• Novel drugs for AD from natural resources 277
• Berberine chloride 278
• Centella asiatica 278
• Ginko biloba 278
• Huperzine-A 280
• Hyperforin 280
• Melissa officinalis 280
• Nostocarboline derived from cyanobacteria 281
• PTI-00703 281
• Salvia 281
• Securinega suffruticosa 281
• Withania somnifera 282
• ZT-1 282
• Cholesterol and AD 282
• ACAT inhibitors 284
• Role of gene for cholesterol ester transfer protein 284
• Cholesterol 24S-hydroxylase as a drug target for AD 284
• Selectively increase of ApoA-I production 285
• Neurotrophic factors 285
• Activity-dependent neuroprotective protein 285
• Brain derived neurotrophic factor 286
• Insulin-like growth factor-1 286
• Nerve growth factor 286
• Neotrofin (AIT-082) 287
• Limitations of the use of NTFs for AD 288
• Role of serotonin modulators in AD 288
• Xaliproden 288
• 5-HT1A receptor antagonists 288
• 5-HT6 antagonists 289
• 5-HT4 receptor agonists 289
• PRX-03140 290
• Cell therapy for AD 290
• Stem cell transplantation for AD 290
• Potential benefits of grafting NSCs in AD 291
• NSCs improve cognition in AD via BDNF 291
• Drugs for enhancing neuronal differentiation of implanted NSCs 291
• Choroid plexus epithelial cells for AD 291
• Implantation of encapsulated cells for delivering NGF 292
• Gene therapy for AD 292
• ApoE gene therapy 292
• FGF2 gene transfer in AD 293
• Humanin gene therapy 293
• Neprilysin gene therapy 293
• NGF gene therapy 294
• Targeting plasminogen activator inhibitor type-1 gene 295
• Antisense approaches to AD 295
• RNAi approaches to AD 295
• Combined therapeutic approaches to AD 296
• Drug delivery for Alzheimer disease 297
• Delivery of thyrotropin-releasing hormone analogs by molecular packaging 297
• Nanoparticle-based drug delivery for Alzheimer's disease 298
• Transdermal drug delivery in Alzheimer's disease 299
• Transdermal rivastigmine 299
• Intranasal delivery of therapeutics for AD 299
• Intranasal delivery of tacrine 299
• Intranasal delivery of nerve growth factor to the brain 299
• Circadian rhythms and timing of cholinesterase inhibitor therapy 300
• Clinical trials for AD 300
• Drugs for AD that were discontinued in clinical trials 305
• Evaluation of clinical trials of AD 307
• Monitoring of cognitive function during clinical trials 308
• Drug discovery for AD 308
• Drugs acting on signaling pathways 308
• Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 308
• Drugs to reverse inhibition of the PKA/CREB pathway in AD 308
• Inhibition of the CD40 signaling pathway 309
• JNK pathway as a target 310
• Mitogen-activated protein kinase pathway as target 310
• Protein kinase C activators 310
• Electrophysiological detection of drug target for neuroprotection in early AD 311
• Genomics-based drug discovery 311
• High through screening for AD drug candidates 311
• Proteomics and drug discovery for AD 312
• Small molecule compounds binding to neurotrophin receptor p75NTR 313
• Targeting Vav in tyrosine kinase signaling pathway 313
• Novels targets/receptors for AD drug discovery 314
• Activation of cerebral Rho GTPases 314
• Activators of insulin-degrading enzyme 314
• Blockade of TGF-β-Smad2/3 signaling in peripheral macrophages 314
• Calcium channel blockers 315
• Calpain inhibitors 315
• Casein kinase 1 316
• Cyclin-dependent kinase-5 316
• Heat shock protein 90 inhibitors 316
• Histone deacetylase 1 317
• Inactivation of aph-1 and pen-2 reduces APP cleavage 317
• NF-κB inhibitors 317
• Kinases and phosphatases as targets for AD therapeutics 317
• Neutral sphingomyelinase inhibitors 318
• Phosphodiesterase inhibitors 318
• Pin 1 as a target in AD 318
• Protein phosphatase 5 as a neuroprotective in AD 319
• Src homology-containing protein-1 inhibitors 319
• Targeting GABAergic system 320
• Pharmacogenomics of Alzheimer disease 320
• Personalized therapy of AD 320
• Genotyping and AD therapeutics 321
• Biomarkers and companion diagnostics for AD 321
• Regulatory aspects of drug development for AD 322
• EMEA guidelines for drug development for AD 322
• FDA guidelines for drug development for AD 322
• Concluding remarks and future prospects of drugs for AD 323

6. Markets & Finances of AD Care 325

• Introduction 325
• Pharmacoeconomics of treatment of AD 325
• Quality of Life in relation to economics of AD 325
• Costs associated with Alzheimer disease 325
• Pharmacoeconomics of donepezil 326
• Pharmacoeconomics studies using rivastigmine 326
• Pharmacoenonomics studies using galantamine 327
• A comparison of pharmacoenonomics outcomes with different ChE inhibitors 327
• Pharmacoenonomics studies using memantine 328
• Patterns of AD care in major markets 328
• Care of AD patients in the US 328
• Cost of care 328
• Medicare and AD 329
• Patterns of practice in AD care 330
• Opinions of physicians' organizations on drugs for dementia 330
• Care of AD patients in the UK 331
• Cost of care 331
• Patterns of practice in AD care 331
• Retraction of NICE recommendations to NHS 332
• Care of AD patients in Germany 333
• Care of AD patients in France 334
• Care of AD patients in Italy 334
• Care of AD patients in Spain 335
• Care of AD patients in Japan 335
• Markets for AD diagnostics 336
• Markets for AD therapeutics 336
• Geographical markets for AD 336
• Markets for currently approved drugs for AD 337
• Markets for generic AD drugs 337
• Future growth of AD market 337
• Statins 338
• Limitations of AD drug development by the biotechnology industry 338
• Unmet needs in the management of AD 339
• Drivers of AD markets 340
• Increase of the aged populations 341
• Increase in the number of approved drugs for AD 341
• Limitations of the current therapies 341
• Improvements in diagnosis 341
• Increasing awareness of the disease 342

7. Companies 343

• Introduction 343
• Profiles of companies 343
• Collaborations 494

8. References 499

Tables

• Table 1-1: Historical landmarks relevant to Alzheimer disease 19
• Table 1-2: Clinical features of Alzheimer disease 20
• Table 1-3: Non-Alzheimer dementias 25
• Table 1-4: A guide to evaluation for MCI due to AD 28
• Table 1-5: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease 29
• Table 1-6: 2011 Revised criteria for diagnosis of dementia due to Alzheimer Disease 31
• Table 1-7: Relation of mutations in amyloid precursor protein to CNS disorders 39
• Table 1-8: Risk factors for Alzheimer's disease 70
• Table 1-9: Genes linked to AD 85
• Table 1-10: Abnormalities of expression of brain proteins in Down's syndrome and AD 98
• Table 2-1: Classification of methods of diagnosis of Alzheimer disease 103
• Table 2-2: Neuropsychological test batteries and scales for Alzheimer's disease 104
• Table 2-3: Available molecular diagnostic tests for Alzheimer disease 110
• Table 2-4: Classification of biomarkers of AD in blood and CSF 113
• Table 2-5: Characteristics of an ideal biomarker for Alzheimer disease 115
• Table 2-6: Role of biomarkers in diagnosis of AD dementia 146
• Table 2-7: Companies involved in the diagnosis of Alzheimer disease 148
• Table 3-1: Classification of treatments for Alzheimer disease 149
• Table 3-2: Cholinergic approaches used in the treatment of Alzheimer disease 150
• Table 3-3: Categories of neuroprotective agents for Alzheimer disease 158
• Table 3-4: Strategies for prevention of Alzheimer disease 173
• Table 3-5: Guidelines for the treatment of dementia 180
• Table 4-1: Transgenic mouse models of Alzheimer disease 184
• Table 5-1: Classification of therapies in development for Alzheimer disease 199
• Table 5-2: Drugs for AD targeting nACh receptors 207
• Table 5-3: Ionotropic glutamate receptors 209
• Table 5-4: Classification of mGluRs 209
• Table 5-5: Glutamate receptor modulators as potential therapeutic agents in AD 211
• Table 5-6: Companies involved in developing vaccines for AD 227
• Table 5-7: Secretase modulators in clinical trials 228
• Table 5-8: Companies developing Aβ-directed therapeutics for AD 253
• Table 5-9: Innovative neuroprotective approaches for Alzheimer disease 261
• Table 5-10: Herbal therapies for AD 277
• Table 5-11: Novel drug delivery methods for Alzheimer disease therapies 297
• Table 5-12: Clinical trials in Alzheimer disease 300
• Table 5-13: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 305
• Table 6-1: Direct and indirect costs associated with Alzheimer disease 326
• Table 6-2: Prevalence of AD in major markets 2012-2022 336
• Table 6-3: AD market values from 2012-2022 in major world markets 337
• Table 6-4: Markets for currently approved AD drugs 2012-2022 337
• Table 6-5: Potential markets for drugs in development 2012-2022 338
• Table 6-6: Limitations of AD drug development by the biotechnology industry 339
• Table 6-7: Factors that drive AD markets 340
• Table 7-1: Major players in Alzheimer's disease therapeutics 343
• Table 7-2: Collaborations relevant to Alzheimer disease 494

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 32
• Figure 1-2: Correlation between aging and AD in the US from 2000 to 2020 33
• Figure 1-3: Prevalence of different types of dementia 34
• Figure 1-4: Mechanisms of Aβ clearance 47
• Figure 1-5: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease 63
• Figure 1-6: Oxidative stress and Alzheimer disease 65
• Figure 1-7: Role of proteosome inhibition in Aβ generation and neurodegeneration 69
• Figure 1-8: Pathomechanism of AD 82
• Figure 3-1: Metabolism of acetylcholine 151
• Figure 3-2: Neuroprotective effective of galantamine in AD 155
• Figure 3-3: Strategies for the management of Alzheimer disease 182
• Figure 5-1: NMDA receptor ion channel complex 210
• Figure 5-2: Neurotoxicity due to misfolding of Aβ1-42 246
• Figure 5-3: Role of proteomics in drug discovery/development for Alzheimer disease 312
• Figure 5-4: FDA's accelerated approval pathway in early Alzheimer disease 324
• Figure 6-1: Unmet needs in the management of Alzheimer disease 340

Alzheimer disease - new drugs, markets and companies published by Jain Pharmabiotech in April 1, 2013. This report price starts from US $ 3500.

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