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Alzheimer disease - new drugs, markets and companies

Notes

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.

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 205 clinical trials are listed, of which 144 are still in progress and 61 were discontinued for various reasons.

Alzheimer's disease market in the seven major markets is analyzed for the year 2013. 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 2023. 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 143 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 92 collaborations. The bibliography contains over 910 publications that are cited in the report.The report is supplemented with 46 tables and 18 figures.

Table of Contents

0. Executive Summary 17

1. Clinical Features, Epidemiology and Pathology 19

  • Introduction 19
  • Historical aspects 19
  • Clinical features of Alzheimer disease 20
  • Seven stages of Alzheimer disease 22
  • AD as a terminal illness 24
  • Detection of AD in the preclinical phase 24
  • Differentiation of AD from other dementias 24
  • Differentiation of AD from non-dementing disorders 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 39
  • Relation of APP mutations to CNS disorders 39
  • Relation of APP to Aβ deposits and pathogenesis of AD 40
  • 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 44
  • Role of Aβ dimers in the pathogenesis of AD 45
  • Role of dsDNA breaks in neurodegeneration due to Aβ 45
  • 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 51
  • Loss of serotonin 1A receptors in the brain 52
  • Factors in pathogenesis of AD 52
  • Astrocytes and AD 52
  • Axonal transport failure in AD 53
  • Cell-cycle hypothesis 53
  • Chronic heart failure link with AD 53
  • Creatine and AD 54
  • Disturbances in brain metabolism in early AD 54
  • Disturbances of interaction of nervous system proteins 54
  • DENN/MADD expression and enhanced pro-apoptotic signaling in AD 55
  • 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
  • Role of dopamine in AD 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 72
  • Homocysteine and AD 72
  • Hypertension and AD 72
  • Level of education/type of job and risk of AD 73
  • Metals and AD 74
  • Obesity 75
  • Proneness to psychological distress and risk of AD 76
  • Reduced muscle strength 76
  • Sleep deprivation 76
  • Traumatic brain injury and AD 77
  • Vascular risk factors for AD 78
  • Vitamin B12 and folate 79
  • AD versus non-dementing changes in the aging brain 79
  • AD and cognitive impairment with aging 80
  • Pathomechanism of memory impairment and AD 80
  • Concluding remarks on pathophysiology of AD 81
  • Genetics of AD 83
  • Familial AD 83
  • Presenilins and calcium channel leak in pathogenesis of familial AD 84
  • Late onset AD 85
  • Genomics of AD 85
  • Introduction to genomics 85
  • Genes associated with Alzheimer disease 86
  • AlzGene database 87
  • ApoE gene 87
  • ApoE genotype and nitric oxide 88
  • ApoE genotype modulates AD phenotype 89
  • APOE genotype and age-related myelin breakdown 89
  • ApoE receptor interaction with NMDA receptor 90
  • ApoE and ApoER2 90
  • ApoE receptor LR11 as regulator of Aβ 91
  • Arctic mutation 91
  • BCHE gene 91
  • CALHM1 polymorphism and AD 91
  • CLU, CRI and PICALM 92
  • CYP46 and risk for AD 92
  • DAPK1 gene variants and AD 92
  • Genetic variants associated with early-onset AD 93
  • Genetic variants associated with late-onset AD 93
  • ApoE polymorphisms associated with LOAD 93
  • Copy number variation (CNV) in LOAD 94
  • LRRTM3 as a candidate gene for AD 94
  • MTHFD1L gene variant associated with AD 94
  • Mutation in APP gene with protective effect against AD 94
  • OGG1 mutations associated with AD 95
  • SORL1 gene in AD 95
  • TOMM40 gene and risk of AD 95
  • TREM2 variants in AD 96
  • International Genomics of Alzheimer's Project 96
  • Sequencing in Alzheimer disease 96
  • Molecular neuropathology 98
  • Role of microRNAs in AD 99
  • DNA methylation in AD 99
  • AD as a polygenic disorder 100
  • Proteomics of AD 100
  • Introduction 100
  • Application of proteomic technologies to study AD 101
  • Protein misfolding in AD 103
  • Common denominators of AD and prion diseases 104
  • Amyloid fibrils as a common feature of AD and prion diseases 104
  • FE65 proteins and AD 104

2. Diagnostic Procedures for Alzheimer Disease 105

  • Importance of the diagnosis of Alzheimer disease 105
  • Methods of diagnosis of AD 105
  • Self-administered olfactory test 106
  • Neuropsychological testing 106
  • Assessment and evaluation 107
  • 7-minute screen 107
  • 15-point risk index 108
  • Activities of Daily Living 108
  • Alzheimer Disease Cooperative Study 108
  • CDR-SOB score 108
  • Clinician's Interview-Based Impression of Change 109
  • DETECT™ System 109
  • Measurement of aggregation in anterior segment of the eye 109
  • Resource Utilization in Dementia Battery 109
  • SymptomGuide™ 109
  • Electrophysiology 110
  • Quantitative EEG for investigation of early AD 110
  • EEG-based bispectral index 110
  • Event-related potentials 110
  • Correlation of electrical activity of the brain with cognition 111
  • Early detection of cataract associated with AD 111
  • Retinal imaging to detect Aβ deposits 111
  • Laboratory methods for diagnosis of AD 112
  • Monitoring of synthesis and clearance rates of Aβ in the CSF 113
  • Molecular diagnostics for AD 113
  • Genetic tests for AD 114
  • ApoE genotyping 115
  • Gene expression patterns in AD 115
  • Molecular fingerprinting of the immune system in AD 115
  • Microarray-based tests for AD 116
  • Monoclonal antibody-based in vitro diagnosis of AD from brain tissues 116
  • Biomarkers of AD 116
  • The ideal biomarker for AD 118
  • CSF biomarkers of AD 118
  • CSF sulfatide as a biomarker for AD 118
  • Glycerophosphocholine as CSF biomarker in AD 119
  • Protein biomarkers of AD in CSF 119
  • Tau proteins in CSF 120
  • Tests for the detection of Aβ in CSF 121
  • Tests combining CSF tau and Aβ 122
  • Concluding remarks abut CSF biomarkers of AD 122
  • Urine tests for AD 123
  • Blood tests for AD 123
  • Blood Aβ levels 123
  • Blood test for AD based on heme oxygenase-1 124
  • Blood test for AD based on RNA hybridization 124
  • GSK-3 elevation in white blood cells 124
  • Lipid biomarkers for preclinical detection of AD 125
  • Lymphocyte Proliferation Test 125
  • Metabolomic biomarker profiling 125
  • MGAT3 as biomarker for prognosis of AD 125
  • MicroRNA-based test for AD 126
  • Protein kinase C in red blood cells 126
  • Sphingolipids 126
  • Tests based on protein biomarkers in blood 126
  • A skin test for early detection of AD 127
  • Saliva-based tests for AD 127
  • Saliva Aβ42 level as a biomarker of AD 128
  • Nanotechnology to measure Aβ-derived diffusible ligands 128
  • Simultaneous measurement of several biomarkers for AD 128
  • Nutritional biomarkers in plasma of AD patients 129
  • Plasma biomarkers of drug response in AD 129
  • A serum protein-based algorithm for the detection of AD 130
  • Concluding remarks about biomarkers for AD 130
  • Imaging in AD 130
  • Computed tomography 131
  • Magnetic resonance imaging 131
  • Arterial spin labeling with MRI 132
  • Magnetic resonance microscopy 132
  • Magnetic resonance spectroscopy 132
  • Single photon emission computed tomography and modifications 133
  • Positron emission tomography 133
  • In vivo imaging of Aβ deposits by PET 135
  • Pittsburgh compound B and PET 135
  • Florbetapir-PET 136
  • Florbetaben-PET 137
  • Flutemetamol-PET 138
  • Future prospects of the PET imaging in AD 138
  • In vivo detection of Aβ plaques by MRI 138
  • Imaging agents for Aβ and neurofibrillary tangles 139
  • Targeting of a chemokine receptor as biomarker for brain imaging 140
  • Radioiodinated clioquinol as a biomarker for Aβ 140
  • Imaging neuroinflammation in AD 140
  • Preclinical diagnosis of AD 140
  • Correlation of imaging with CSF biomarkers for early detection of AD 141
  • Meta-analysis of literature on imaging in AD 142
  • Alzheimer Disease Neuroimaging Initiative 142
  • Computer aided diagnosis systems for AD based on imaging data 143
  • Concluding remarks on imaging for diagnosis of AD 143
  • Diagnosis of MCI and prediction of AD 144
  • Diagnosis of MCI 144
  • Computer-Administered Neurophychological screen for MCI 144
  • Infrared eye-tracking technology to detect MCI 144
  • MRI for detection of MCI 144
  • PET for detection of MCI 145
  • Role of APOE genotype in early MCI 145
  • Presymptomatic detection of AD 145
  • Biomarker changes in autosomal dominantly inherited AD 146
  • PredictAD project 146
  • Prediction of AD in patients with MCI 147
  • Combination of MMSE and a memory test for prediction of AD 147
  • Biochemical biomarkers in CSF for prediction of AD 147
  • Structural MRI biomarkers for prediction of AD 147
  • Magnetoencephalography for detection of MCI and AD 148
  • MRI-based index to measure the severity of AD in MCI 149
  • Concluding remarks about prediction of AD in MCI 149
  • Criteria for diagnosis of AD 149
  • Role of biomarkers in diagnosis of AD dementia 149
  • Ethical aspects of diagnostics for AD 150
  • Genetic testing for AD 150
  • Ethical issues of brain imaging in AD 151
  • Monitoring of treatment of AD 151
  • Monitoring treatment of mixed AD and vascular dementia 151
  • Companies involved in diagnosis of AD 151

3. Management of Alzheimer Disease 153

  • Introduction 153
  • Cholinergic approaches 153
  • Mechanism of action of cholinesterase inhibitors 154
  • Choline and lecithin 155
  • Donepezil 156
  • Rivastigmine 157
  • Galantamine 158
  • Duration of treatment with ChE inhibitors 159
  • Comparative studies of ChE inhibitors 159
  • Donepezil versus rivastigmine 160
  • Donepezil versus galantamine 160
  • Combination of cholinesterase inhibitors and a cholinergic precursor 160
  • An assessment and future prospects of anticholinergic therapies 161
  • Neuroprotection in Alzheimer's disease 162
  • Memantine 162
  • Combination of memantine with ChE inhibitors 165
  • Monoamine oxidase inhibitors 166
  • Selegiline 166
  • Synaptoprotection in AD 166
  • Drugs for noncognitive symptoms in AD 166
  • Antidepressants 167
  • Antipsychotics 167
  • ChE inhibitors for behavioral and psychological disorders in AD 168
  • Concluding remarks and other drugs for agitation in AD 168
  • Sensory stimulation 169
  • Non-pharmacological treatments of AD 169
  • Management of memory loss in AD 169
  • Exposure to electromagnetic fields for treatment of AD 170
  • Application of electrical fields for improvement of cerebral function 170
  • High-frequency electromagnetic field treatment of AD 170
  • Vagal nerve stimulation 171
  • Cerebrospinal fluid shunting 171
  • Omental transposition 172
  • Microchip-based hippocampal prosthesis for AD 172
  • Nutritional therapies for AD 172
  • Axona 172
  • Cocktail of dietary supplements for AD 173
  • Docosahexaenoic acid 173
  • Magnesium 175
  • Nicotinamide for the treatment of AD 175
  • Omega-3 fatty acids 175
  • Preventing decline of mental function with aging and dementia 176
  • Prevention of Alzheimer disease 177
  • Mental training 178
  • Physical exercise 178
  • Higher level of conscientiousness and decreased risk of AD 179
  • Nutritional factors in prevention of AD and MCI 179
  • Black and green teas 179
  • Caffeine 180
  • Caloric restriction 180
  • Cinnamon 181
  • Cocoa flavonol consumption 181
  • Grapes and red wine 181
  • Drugs to prevent Alzheimer disease 182
  • Preimplantation genetic diagnosis of inherited Alzheimer disease 182
  • Presymptomatic detection of AD 183
  • Management of mild cognitive impairment 183
  • Slowing the progression of MCI to AD 183
  • Management of Down syndrome 184
  • Guidelines for use of anti-dementia drugs in clinical practice 185
  • Donepezil and/or memantine 186
  • General care of the Alzheimer disease patients 186
  • Strategies for the management of Alzheimer disease 186

4. Research in Alzheimer Disease 189

  • Introduction 189
  • Animal models of Alzheimer disease 189
  • Lesional models 189
  • Cerebroventricular injection of Aβ in rats 189
  • Lentiviral vector-based models of amyloid pathology 190
  • AAV-mediated gene transfer to increase hippocampal Aβ 190
  • Transgenic mouse models 190
  • Quantitative assessment of amyloid load in transgenic models 191
  • In vivo magnetic resonance microimaging in transgenic models of AD 192
  • Transgenic model of AD with suppression of Aβ production 192
  • Transgenic AD11 anti-NGF mice 192
  • Genetically altered mice with deficiency of vesicular ACh transporter 193
  • Limitations of mouse models of Alzheimer disease 193
  • Improved mouse models of AD expressing human genes 194
  • Cholesterol-fed rabbits as models for AD 194
  • Canine dementia as model for AD 194
  • Zebrafish model for AD 195
  • Transgenic invertebrate models of Alzheimer disease 196
  • Drosophila model of AD 196
  • Caenorhabditis elegans Alzheimer disease model 196
  • Correlation of studies in animal models and human clinical trials 197
  • Cell systems for AD research 198
  • In vitro neuronal cell Lines 198
  • Single-gene expression system for use in cell culture 198
  • Stem cells for testing efficacy of AD drugs 198
  • Transgenic cells 199
  • In silico models 199
  • Estimation of progression rates of Alzheimer disease 200
  • Clinical trial methods in Alzheimer disease 200
  • Molecular imaging as a guide to drug development 201
  • Use of MRI and PET in clinical trials 201
  • Cognitive-function assessment in clinical trials 202
  • Clinical trials in mild cognitive impairment 202
  • Research in AD as a basis for future therapies 203
  • Use of microarrays for studying pathogenesis of AD 203
  • Computational brain mapping in AD 203
  • Study of neurogenesis in AD 203
  • Study of 3D structure of Aβ 203
  • Solid-state NMR to study precursors of Aβ 204
  • Research in Alzheimer disease at academic centers 204
  • Role of NIH in AD research 204
  • NIH Clinical Trials Database for AD 204
  • Alzheimer Research Consortium 204
  • The National Institute on Aging and AD research 205

5. Drug Discovery & Development for Alzheimer Disease 207

  • Introduction 207
  • Categories of drugs in development for AD 207
  • Memory-enhancing drugs 209
  • Enhancing memory by drugs that block eIF2α phosphorylation 209
  • Drugs based on cholinergic approaches 209
  • AP2238 210
  • Butyrylcholinesterase inhibitors 210
  • Donepezil-tacrine hybrids 210
  • Drugs modulating gamma-aminobutyric acid receptors 211
  • Ganstigmina 211
  • Methanesulfonyl fluoride 211
  • Muscarinic receptor modulators 212
  • Muscarinic M1 agonists 212
  • Muscarinic M2 antagonists 213
  • Nicotine and nicotinic receptor modulators 213
  • Nicotine 213
  • Nicotinic receptor modulators 214
  • GTS21 216
  • Ispronicline 217
  • JWB1-84-1 217
  • Neuropeptide/neurotransmitters 217
  • Somatostatin release enhancers 217
  • Glutamate receptor modulators 218
  • Physiology and pharmacology of glutamate receptors 218
  • NMDA receptor ion channel complex 218
  • Metabotropic glutamate receptors 219
  • Glutamate receptor modulators as potential therapeutics for AD 220
  • N20C 221
  • AMPA modulators 221
  • Glutamate release inhibitors 222
  • INI-0602 222
  • Drugs affecting multiple neurotransmitters 222
  • Ensaculin 222
  • NS2330 222
  • RS-1259 222
  • Lecozotan 223
  • Vaccines for AD 223
  • Active immunization with Aβ 224
  • AN-1792 vaccine 224
  • Complications in clinical trials with AN-1792 224
  • Effects of Aβ vaccine on the brain 224
  • Strategies to avoid undesirable effect of Aβ vaccination 225
  • Passive immunization in AD 226
  • Passive immunization with MAbs 226
  • Clinical trials of MAbs in AD 227
  • Delivery of the passive antibody directly to the brain 228
  • Systemic injection of MAbs to treat AD 229
  • Combination of Aβ immunotherapy and CD40-CD40L blockade 229
  • Shaping the immune responses elicited against Aβ 230
  • Delivery of AD vaccines 230
  • Gene vaccination 230
  • Modified Aβ nasal vaccine 231
  • Transdermal Aβ vaccination 231
  • Other vaccines for AD 231
  • Nasal vaccination with Proteosome™ adjuvant 232
  • T-cell vaccination with glatiramer acetate adjuvant 232
  • Early start of immunotherapy to clear Aβ plaques 232
  • Reversal of cholinergic dysfunction by anti-Aβ antibody 233
  • Immune modulation via Toll-like receptors to reduce Aβ 233
  • Mechanisms by which Aβ antibodies reduce amyloid accumulation in the brain 233
  • Perspectives on vaccines for AD 234
  • Companies involved in AD vaccines 236
  • Inhibition of amyloid precursor protein aggregation 236
  • Secretase modulators 237
  • Neuroprotection by α-secretase cleaved APP 237
  • Inhibitors of β-secretase 238
  • Inhibitors of γ-secretase 239
  • Amyloid-derived diffusible ligands 240
  • GABA receptor modulation by etazolate and APP processing 240
  • Depletion of serum amyloid P 241
  • Trojan-horse approach to prevent build-up of Aβ aggregates 241
  • Drugs that inhibit the formation of Aβ 241
  • 22R-hydroxycholesterol 242
  • Acylaminopyrazole 242
  • Cadmium telluride nanoparticles prevent Aβ fibril formation 242
  • Cannabinoids 243
  • Chelation therapy for AD 243
  • Clioquinol and PBT2 244
  • Copper chelation by FKBP52 246
  • Zinc chelation from amyloid plaques 246
  • Next generation multifunctional chelating agents for AD 246
  • Heparin and its derivatives 247
  • A reassessment of the role of heparin in AD 247
  • Enoxaparin 247
  • Heparan sulfate 248
  • Imatinib mesylate 248
  • Laminin 248
  • NSAIDs 248
  • Flurbiprofen analogs with Aβ42-lowering action 249
  • Nitric oxide-donating NSAIDs 250
  • In vivo demonstration of the effects of NSAIDs on brain in AD 250
  • Paclitaxel 251
  • Phenserine 251
  • Tolserine 252
  • Platinum-based inhibitors of Aβ 252
  • Retro-inverso peptide inhibitor 252
  • Scyllo-cyclohexanehexol 252
  • Selective serotonin reuptake inhibitor 253
  • Ubiquitin C-terminal hydrolase L1 253
  • Drugs to prevent the formation of NFTs 253
  • Tau suppression 254
  • ApoE4 as a therapeutic target in AD 255
  • Strategies to prevent deposits and enhance clearance of Aβ 255
  • 4,5-dianilinophthalimide for disruption of Aβ1-42 fibrils 256
  • ABCA1 overexpression to lower amyloid deposits 257
  • ANAVEX 2-73 257
  • Beta-sheet breakers 258
  • Bexarotene 258
  • Blocking ApoE/Aβ interaction to reduce Aβ plaques 259
  • CD33 inhibitors 259
  • Clearance of Aβ across the blood-brain barrier 259
  • Enhanced PKCε activity promotes clearance of Aβ 260
  • Galantamine-induced Aβ clearance 260
  • Hemopheresis 260
  • Inhibitors of Aβ dehydrogenase 260
  • Intravenous immune globulin 261
  • Monoclonal antibodies for removal of Aβ 262
  • Crenezumab 262
  • Gantenerumab 262
  • Solanezumab 262
  • Nanotechnology for removal of Aβ deposits 263
  • Role of matrix metalloproteinases in clearance of Aβ 263
  • SAN-61 for cleavage of fibril and soluble amyloid 263
  • Serum amyloid P component depletion 264
  • Small molecule DAPH for clearance of amyloid 264
  • Companies developing Aβ-directed therapeutics for AD 264
  • Nootropics 265
  • Acetyl-L-carnitine 266
  • Cerebrolysin 266
  • Ergot derivatives 267
  • Lisuride 267
  • Dihydroergocryptine 267
  • Neuroprotective effect drugs not primarily developed for AD 267
  • Antiinflammatory and antimicrobial drugs 268
  • Dapsone 268
  • Antimicrobial drugs against C. pneumoniae 269
  • PPAR-gamma agonists 269
  • Antidiabetic drugs 269
  • Rosiglitazone 270
  • Pioglitazone 270
  • Antihypertensive drugs 270
  • Angiotensin-converting enzyme inhibitors 270
  • Angiotensin receptor blockers 271
  • Dimebon 271
  • Drugs acting on estrogen receptors 272
  • Estrogen 272
  • Raloxifene 273
  • Inhibitors of neuroinflammation 273
  • Ceramide 273
  • Cyclophosphamide 274
  • Etanercept 274
  • Fingolimod 274
  • MW01-5-188WH 275
  • Neurosteroids 275
  • Pregnenolone sulfate 275
  • Dehydroepiandrosterone 275
  • Levetiracetam 276
  • Lithium 276
  • MAO-B inhibitors 277
  • Ladostigil tartrate 277
  • Memoquin 277
  • Methylene blue 278
  • Nimodipine 278
  • Rapamycin 278
  • Statins 279
  • Testosterone 280
  • Valproic acid 281
  • Future prospects of neuroprotection in AD 281
  • Targeting Cdk5 pathway 281
  • Antioxidants 282
  • Colostrinin 282
  • Curcumin 283
  • Dehydroascorbic acid 283
  • Melatonin 284
  • Reservatrol 284
  • Synthetic catalytic scavengers 285
  • Vitamins 285
  • Vitamin E as antioxidant 285
  • Vitamin B for lowering homocysteine 285
  • Folic acid 286
  • Aminopyridazines 286
  • Nanobody-based drugs for AD 287
  • Nitric oxide based therapeutics for AD 287
  • Nitric oxide mimetics 287
  • iNOS inhibitors for AD 287
  • Novel drugs for AD from natural resources 288
  • Berberine chloride 289
  • Centella asiatica 289
  • Ginko biloba 289
  • Huperzine-A 290
  • Hyperforin 291
  • Melissa officinalis 291
  • Nostocarboline derived from cyanobacteria 292
  • PTI-00703 292
  • Salvia 292
  • Securinega suffruticosa 292
  • Withania somnifera 293
  • ZT-1 293
  • Cholesterol and AD 293
  • ACAT inhibitors 294
  • Role of gene for cholesterol ester transfer protein 295
  • Cholesterol 24S-hydroxylase as a drug target for AD 295
  • Selectively increase of ApoA-I production 295
  • Neurotrophic factors 296
  • Brain derived neurotrophic factor 296
  • Insulin-like growth factor-1 296
  • Nerve growth factor 297
  • Neotrofin (AIT-082) 298
  • Limitations of the use of NTFs for AD 298
  • Role of serotonin modulators in AD 298
  • Xaliproden 299
  • 5-HT1A receptor antagonists 299
  • 5-HT6 antagonists 299
  • 5-HT4 receptor agonists 300
  • PRX-03140 300
  • Donecopride 300
  • Restoration of factors deficient in the aging brain 301
  • Reversal of cognitive impairment in aging by activation of creb protein 301
  • Reversal of cognitive impairment in aging by GDF11 protein 301
  • Restoration of repressor element 1-silencing transcription factor 301
  • Cell therapy for AD 302
  • Stem cell transplantation for AD 302
  • Potential benefits of grafting NSCs in AD 302
  • NSCs improve cognition in AD via BDNF 303
  • Drugs for enhancing neuronal differentiation of implanted NSCs 303
  • Choroid plexus epithelial cells for AD 303
  • Implantation of encapsulated cells for delivering NGF 304
  • Gene therapy for AD 304
  • ApoE gene therapy 304
  • FGF2 gene transfer in AD 304
  • Humanin gene therapy 305
  • Neprilysin gene therapy 305
  • NGF gene therapy 306
  • Targeting plasminogen activator inhibitor type-1 gene 306
  • Antisense approaches to AD 307
  • RNAi approaches to AD 307
  • Combined therapeutic approaches to AD 308
  • Drug delivery for Alzheimer disease 308
  • Delivery of biologicals across the BBB 309
  • Delivery of thyrotropin-releasing hormone analogs by molecular packaging 309
  • Nanoparticle-based drug delivery for Alzheimer's disease 310
  • Transdermal drug delivery in Alzheimer's disease 311
  • Transdermal rivastigmine 311
  • Intranasal delivery of therapeutics for AD 311
  • Intranasal delivery of tacrine 311
  • Intranasal delivery of nerve growth factor to the brain 312
  • Circadian rhythms and timing of cholinesterase inhibitor therapy 312
  • Clinical trials for AD 312
  • Drugs for AD that were discontinued in clinical trials 317
  • Monitoring of cognitive function during clinical trials 320
  • Concluding remarks on clinical trials of AD 320
  • Drug discovery for AD 321
  • Drugs acting on signaling pathways 321
  • Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 321
  • Drugs to reverse inhibition of the PKA/CREB pathway in AD 321
  • Inhibition of the CD40 signaling pathway 322
  • JNK pathway as a target 322
  • Mitogen-activated protein kinase pathway as target 323
  • Protein kinase C activators 323
  • Electrophysiological detection of drug target for neuroprotection in early AD 323
  • Genomics-based drug discovery 324
  • High through screening for AD drug candidates 324
  • Proteomics and drug discovery for AD 324
  • Small molecule compounds binding to neurotrophin receptor p75NTR 325
  • Targeting Vav in tyrosine kinase signaling pathway 326
  • New chemical entities for AD by combining galantamine and memantine 326
  • Novels targets/receptors for AD drug discovery 327
  • Activation of cerebral Rho GTPases 327
  • Activators of insulin-degrading enzyme 327
  • Blockade of TGF-β-Smad2/3 signaling in peripheral macrophages 327
  • Calcium channel blockers 328
  • Calpain inhibitors 328
  • Casein kinase 1 329
  • Cyclin-dependent kinase-5 329
  • Heat shock protein 90 inhibitors 329
  • Histone deacetylase 1 330
  • Inhibition of PDK1 to slow progression of both AD and prion disease 330
  • NF-κB inhibitors 330
  • Kinases and phosphatases as targets for AD therapeutics 330
  • Neutral sphingomyelinase inhibitors 331
  • Phosphodiesterase inhibitors 331
  • Pin 1 as a target in AD 332
  • Protein phosphatase 5 as a neuroprotective in AD 332
  • Src homology-containing protein-1 inhibitors 333
  • Targeting GABAergic system 333
  • TSPO ligands 333
  • Pharmacogenomics of Alzheimer disease 334
  • Personalized therapy of AD 334
  • Genotyping and AD therapeutics 334
  • Biomarkers and companion diagnostics for AD 335
  • Regulatory aspects of drug development for AD 336
  • EMEA guidelines for drug development for AD 336
  • FDA guidelines for drug development for AD 336
  • Concluding remarks and future prospects of drugs for AD 337

6. Markets & Finances of AD Care 339

  • Introduction 339
  • Pharmacoeconomics of treatment of AD 339
  • Quality of Life in relation to economics of AD 339
  • Costs associated with Alzheimer disease 339
  • Pharmacoeconomics of donepezil 340
  • Pharmacoeconomics studies using rivastigmine 341
  • Pharmacoenonomics studies using galantamine 341
  • Pharmacoenonomics studies using memantine 342
  • Patterns of AD care in major markets 342
  • Care of AD patients in the US 342
  • Cost of care 342
  • Medicare and AD 343
  • Patterns of practice in AD care 344
  • Opinions of physicians' organizations on drugs for dementia 344
  • Care of AD patients in the UK 345
  • Cost of care 345
  • Patterns of practice in AD care 345
  • Retraction of NICE recommendations to NHS 346
  • Care of AD patients in Germany 347
  • Care of AD patients in France 348
  • Care of AD patients in Italy 348
  • Care of AD patients in Spain 349
  • Care of AD patients in Japan 349
  • Markets for AD diagnostics 349
  • Markets for AD therapeutics 350
  • Geographical markets for AD 350
  • Markets for currently approved drugs for AD 351
  • Markets for generic AD drugs 351
  • Statins 351
  • Future growth of AD market 351
  • Limitations of AD drug development by the biotechnology industry 352
  • Unmet needs in the management of AD 353
  • Drivers of AD markets 354
  • Increase of the aged populations 354
  • Increase in the number of approved drugs for AD 354
  • Limitations of the current therapies 355
  • Improvements in diagnosis 355
  • Increasing awareness of the disease 355

7. Companies 357

  • Introduction 357
  • Profiles of companies 357
  • Collaborations 506

8. References 511

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 86
  • Table 1-10: Abnormalities of expression of brain proteins in Down's syndrome and AD 102
  • Table 2-1: Classification of methods of diagnosis of Alzheimer disease 105
  • Table 2-2: Neuropsychological test batteries and scales for Alzheimer's disease 106
  • Table 2-3: Available molecular diagnostic tests for Alzheimer disease 114
  • Table 2-4: Classification of biomarkers of AD in blood and CSF 116
  • Table 2-5: Characteristics of an ideal biomarker for Alzheimer disease 118
  • Table 2-6: Role of biomarkers in diagnosis of AD dementia 149
  • Table 2-7: Companies involved in the diagnosis/monitoring of Alzheimer disease 152
  • Table 3-1: Classification of treatments for Alzheimer disease 153
  • Table 3-2: Cholinergic approaches used in the treatment of Alzheimer disease 154
  • Table 3-3: Categories of neuroprotective agents for Alzheimer disease 162
  • Table 3-4: Strategies for prevention of Alzheimer disease 177
  • Table 3-5: Guidelines for the treatment of dementia 185
  • Table 4-1: Transgenic mouse models of Alzheimer disease 190
  • Table 4-2: Correlation of studies in animal models with human clinical trials 197
  • Table 5-1: Classification of therapies in development for Alzheimer disease 207
  • Table 5-2: Drugs for AD targeting nACh receptors 216
  • Table 5-3: Ionotropic glutamate receptors 218
  • Table 5-4: Classification of mGluRs 218
  • Table 5-5: Glutamate receptor modulators as potential therapeutic agents in AD 220
  • Table 5-6: Companies involved in developing vaccines for AD 236
  • Table 5-7: Secretase modulators in clinical trials 237
  • Table 5-8: Companies developing Aβ-directed therapeutics for AD 264
  • Table 5-9: Innovative neuroprotective approaches for Alzheimer disease 267
  • Table 5-10: Herbal therapies for AD 288
  • Table 5-11: Novel drug delivery methods for Alzheimer disease therapies 309
  • Table 5-12: Clinical trials in Alzheimer disease 312
  • Table 5-13: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 317
  • Table 6-1: Direct and indirect costs associated with Alzheimer disease 340
  • Table 6-2: Prevalence of AD in major markets 2013-2023 350
  • Table 6-3: AD market values from 2013-2023 in major world markets 350
  • Table 6-4: Markets for currently approved AD drugs 2013-2023 351
  • Table 6-5: Potential markets for drugs in development 2013-2023 352
  • Table 6-6: Limitations of AD drug development by the biotechnology industry 352
  • Table 6-7: Factors that drive AD markets 354
  • Table 7-1: Major players in Alzheimer's disease therapeutics 357
  • Table 7-2: Collaborations relevant to Alzheimer disease 506

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 46
  • Figure 1-5: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease 62
  • 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: Cholesterol-related pathways to AD 71
  • Figure 1-9: Pathomechanism of AD 83
  • Figure 3-1: Metabolism of acetylcholine 155
  • Figure 3-2: Neuroprotective effective of galantamine in AD 159
  • Figure 3-3: Strategies for the management of Alzheimer disease 188
  • Figure 5-1: Activation of α7 nicotinic acetylcholine receptors 215
  • Figure 5-2: NMDA receptor ion channel complex. 219
  • Figure 5-3: Neurotoxicity due to misfolding of Aβ1-42 257
  • Figure 5-4: Role of proteomics in drug discovery/development for Alzheimer disease 325
  • Figure 5-5: FDA industry interaction during drug development for AD 337
  • Figure 5-6: FDA's accelerated approval pathway in early Alzheimer disease 338
  • Figure 6-1: Unmet needs in the management of Alzheimer disease 353
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