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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 19 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
  • Neurotoxicity 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
  • Sequence of events in neurotoxicity of AΒ 46
  • AΒ production and clearance 47
  • Impairment of mitochondrial energy metabolism 48
  • AΒ-binding alcohol dehydrogenase links AD to mitochondrial toxicity 48
  • Neural thread protein 48
  • Loss of synaptic proteins 49
  • AD and Down syndrome 49
  • Overlapping pathologies of AD and Parkinson disease 50
  • AD and age-related macular degeneration 50
  • Myelin hypothesis of AD 50
  • Blood-brain barrier in AD 51
  • Blood vessel damage in AD 52
  • Loss of serotonin 1A receptors in the brain 52
  • Factors in pathogenesis of AD 52
  • Astrocytes and AD 53
  • Axonal transport failure in AD 53
  • Cell-cycle hypothesis 54
  • Chronic heart failure link with AD 54
  • Creatine and AD 54
  • Disturbances in brain metabolism in early AD 54
  • Disturbances of interaction of nervous system proteins 55
  • DENN/MADD expression and enhanced pro-apoptotic signaling in AD 55
  • Gonadotrophins and AD 55
  • Glutamate transport dysfunction in AD 56
  • Innate immune system and AD 57
  • Insulin, diabetes and AD 57
  • Mechanisms underlying cognitive deficits in AD 58
  • Monoamine oxidase and AD 58
  • Neuroinflammation and AD 59
  • Neurotransmitter deficits 60
  • Role of dopamine in AD 61
  • Neurotrophic factors 61
  • NF-κB signaling and the pathogenesis of neurodegeneration 62
  • Nitric oxide and AD 62
  • 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 71
  • Exposure to magnetic fields 72
  • Family history of AD 72
  • Homocysteine and AD 72
  • Hypertension and AD 73
  • 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
  • Blood test for preclinical diagnosis of AD 146
  • PredictAD project 147
  • Prediction of AD in patients with MCI 147
  • Biochemical biomarkers in CSF for prediction of AD 147
  • Combination of MMSE and a memory test for prediction of AD 148
  • Plasma protein biomarkers of conversion of MCI to AD 148
  • Structural MRI biomarkers for prediction of AD 148
  • 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 150
  • Role of biomarkers in diagnosis of AD dementia 151
  • Ethical aspects of diagnostics for AD 152
  • Genetic testing for AD 152
  • Ethical issues of brain imaging in AD 153
  • Monitoring of treatment of AD 153
  • Monitoring treatment of mixed AD and vascular dementia 153
  • Companies involved in diagnosis of AD 154

3. Management of Alzheimer Disease 157

  • Introduction 157
  • Cholinergic approaches 157
  • Mechanism of action of cholinesterase inhibitors 158
  • Choline and lecithin 159
  • Donepezil 160
  • Rivastigmine 161
  • Galantamine 162
  • Duration of treatment with ChE inhibitors 163
  • Comparative studies of ChE inhibitors 163
  • Donepezil versus rivastigmine 164
  • Donepezil versus galantamine 164
  • Combination of cholinesterase inhibitors and a cholinergic precursor 164
  • An assessment and future prospects of anticholinergic therapies 165
  • Neuroprotection in Alzheimer's disease 166
  • Memantine 166
  • Combination of memantine with ChE inhibitors 169
  • Monoamine oxidase inhibitors 170
  • Selegiline 170
  • Synaptoprotection in AD 170
  • Drugs for noncognitive symptoms in AD 170
  • Antidepressants 171
  • Antipsychotics 171
  • ChE inhibitors for behavioral and psychological disorders in AD 172
  • Concluding remarks and other drugs for agitation in AD 172
  • Sensory stimulation 173
  • Non-pharmacological treatments of AD 173
  • Management of memory loss in AD 173
  • Exposure to electromagnetic fields for treatment of AD 174
  • Application of electrical fields for improvement of cerebral function 174
  • High-frequency electromagnetic field treatment of AD 174
  • Vagal nerve stimulation 175
  • Cerebrospinal fluid shunting 175
  • Omental transposition 176
  • Microchip-based hippocampal prosthesis for AD 176
  • Nutritional therapies for AD 176
  • Axona 176
  • Cocktail of dietary supplements for AD 177
  • Docosahexaenoic acid 177
  • Magnesium 179
  • Nicotinamide for the treatment of AD 179
  • Omega-3 fatty acids 179
  • Preventing decline of mental function with aging and dementia 180
  • Prevention of Alzheimer disease 181
  • Mental training 182
  • Physical exercise 182
  • Higher level of conscientiousness and decreased risk of AD 183
  • Nutritional factors in prevention of AD and MCI 183
  • Black and green teas 183
  • Caffeine 184
  • Caloric restriction 184
  • Cinnamon 185
  • Cocoa flavonol consumption 185
  • Grapes and red wine 185
  • Drugs to prevent Alzheimer disease 186
  • Preimplantation genetic diagnosis of inherited Alzheimer disease 186
  • Presymptomatic detection of AD 187
  • Management of mild cognitive impairment 187
  • Slowing the progression of MCI to AD 187
  • Management of Down syndrome 188
  • Guidelines for use of anti-dementia drugs in clinical practice 189
  • Donepezil and/or memantine 190
  • General care of the Alzheimer disease patients 190
  • Strategies for the management of Alzheimer disease 190

4. Research in Alzheimer Disease 193

  • Introduction 193
  • Animal models of Alzheimer disease 193
  • Lesional models 193
  • Cerebroventricular injection of AΒ in rats 193
  • Lentiviral vector-based models of amyloid pathology 194
  • AAV-mediated gene transfer to increase hippocampal Aβ 194
  • Transgenic mouse models 194
  • Quantitative assessment of amyloid load in transgenic models 195
  • In vivo magnetic resonance microimaging in transgenic models of AD 196
  • Transgenic model of AD with suppression of AΒ production 196
  • Transgenic AD11 anti-NGF mice 196
  • Genetically altered mice with deficiency of vesicular ACh transporter 197
  • Limitations of mouse models of Alzheimer disease 197
  • Improved mouse models of AD expressing human genes 198
  • Cholesterol-fed rabbits as models for AD 198
  • Canine dementia as model for AD 198
  • Zebrafish model for AD 199
  • Transgenic invertebrate models of Alzheimer disease 200
  • Drosophila model of AD 200
  • Caenorhabditis elegans Alzheimer disease model 200
  • Correlation of studies in animal models and human clinical trials 201
  • Cell systems for AD research 202
  • In vitro neuronal cell Lines 202
  • Single-gene expression system for use in cell culture 202
  • Stem cells for testing efficacy of AD drugs 202
  • Transgenic cells 203
  • In silico models 203
  • Estimation of progression rates of Alzheimer disease 204
  • Clinical trial methods in Alzheimer disease 204
  • Molecular imaging as a guide to drug development 205
  • Use of MRI and PET in clinical trials 205
  • Cognitive-function assessment in clinical trials 206
  • Clinical trials in mild cognitive impairment 206
  • Research in AD as a basis for future therapies 207
  • Use of microarrays for studying pathogenesis of AD 207
  • Computational brain mapping in AD 207
  • Study of neurogenesis in AD 207
  • Study of 3D structure of AΒ 207
  • Solid-state NMR to study precursors of AΒ 208
  • Research in Alzheimer disease at academic centers 208
  • Role of NIH in AD research 208
  • NIH Clinical Trials Database for AD 208
  • Alzheimer Research Consortium 208
  • The National Institute on Aging and AD research 209

5. Drug Discovery & Development for Alzheimer Disease 211

  • Introduction 211
  • Categories of drugs in development for AD 211
  • Memory-enhancing drugs 213
  • Enhancing memory by drugs that block eIF2α phosphorylation 213
  • Drugs based on cholinergic approaches 213
  • AP2238 214
  • Butyrylcholinesterase inhibitors 214
  • Donepezil-tacrine hybrids 214
  • Drugs modulating gamma-aminobutyric acid receptors 215
  • Ganstigmina 215
  • Methanesulfonyl fluoride 215
  • Muscarinic receptor modulators 216
  • Muscarinic M1 agonists 216
  • Muscarinic M2 antagonists 217
  • Nicotine and nicotinic receptor modulators 217
  • Nicotine 217
  • Nicotinic receptor modulators 218
  • GTS21 220
  • Ispronicline 221
  • JWB1-84-1 221
  • Neuropeptide/neurotransmitters 221
  • Somatostatin release enhancers 221
  • Glutamate receptor modulators 222
  • Physiology and pharmacology of glutamate receptors 222
  • NMDA receptor ion channel complex 222
  • Metabotropic glutamate receptors 223
  • Glutamate receptor modulators as potential therapeutics for AD 224
  • N20C 225
  • AMPA modulators 225
  • Glutamate release inhibitors 226
  • INI-0602 226
  • Drugs affecting multiple neurotransmitters 226
  • Ensaculin 226
  • NS2330 226
  • RS-1259 226
  • Lecozotan 227
  • Vaccines for AD 227
  • Active immunization with Aβ 228
  • AN-1792 vaccine 228
  • Complications in clinical trials with AN-1792 228
  • Effects of AΒ vaccine on the brain 228
  • Strategies to avoid undesirable effect of AΒ vaccination 229
  • Passive immunization in AD 230
  • Passive immunization with MAbs 230
  • Clinical trials of MAbs in AD 231
  • Delivery of the passive antibody directly to the brain 232
  • Systemic injection of MAbs to treat AD 233
  • Combination of AΒ immunotherapy and CD40-CD40L blockade 233
  • Shaping the immune responses elicited against AΒ 234
  • Delivery of AD vaccines 234
  • Gene vaccination 234
  • Modified AΒ nasal vaccine 235
  • Transdermal AΒ vaccination 235
  • Other vaccines for AD 235
  • Nasal vaccination with Proteosome™ adjuvant 236
  • T-cell vaccination with glatiramer acetate adjuvant 236
  • Early start of immunotherapy to clear AΒ plaques 236
  • Reversal of cholinergic dysfunction by anti-AΒ antibody 237
  • Immune modulation via Toll-like receptors to reduce AΒ 237
  • Mechanisms by which AΒ antibodies reduce amyloid accumulation in the brain 237
  • Perspectives on vaccines for AD 238
  • Companies involved in AD vaccines 240
  • Inhibition of amyloid precursor protein aggregation 240
  • Secretase modulators 241
  • Neuroprotection by α-secretase cleaved APP 241
  • Inhibitors of Β-secretase 242
  • Inhibitors of γ-secretase 243
  • Amyloid-derived diffusible ligands 244
  • GABA receptor modulation by etazolate and APP processing 244
  • Depletion of serum amyloid P 245
  • Trojan-horse approach to prevent build-up of AΒ aggregates 245
  • Drugs that inhibit the formation of AΒ 245
  • 22R-hydroxycholesterol 246
  • Acylaminopyrazole 246
  • Cadmium telluride nanoparticles prevent AΒ fibril formation 246
  • Cannabinoids 247
  • Chelation therapy for AD 247
  • Clioquinol and PBT2 248
  • Copper chelation by FKBP52 250
  • Zinc chelation from amyloid plaques 250
  • Next generation multifunctional chelating agents for AD 250
  • Heparin and its derivatives 251
  • A reassessment of the role of heparin in AD 251
  • Enoxaparin 251
  • Heparan sulfate 252
  • Imatinib mesylate 252
  • Laminin 252
  • NSAIDs 252
  • Flurbiprofen analogs with AΒ42-lowering action 253
  • Nitric oxide-donating NSAIDs 254
  • In vivo demonstration of the effects of NSAIDs on brain in AD 254
  • Paclitaxel 255
  • Phenserine 255
  • Tolserine 256
  • Platinum-based inhibitors of AΒ 256
  • Retro-inverso peptide inhibitor 256
  • Scyllo-cyclohexanehexol 256
  • Selective serotonin reuptake inhibitor 257
  • Ubiquitin C-terminal hydrolase L1 257
  • Drugs to prevent the formation of NFTs 257
  • Tau suppression 258
  • ApoE4 as a therapeutic target in AD 259
  • Strategies to prevent deposits and enhance clearance of AΒ 259
  • 4,5-dianilinophthalimide for disruption of AΒ1-42 fibrils 260
  • ABCA1 overexpression to lower amyloid deposits 261
  • ANAVEX 2-73 261
  • Beta-sheet breakers 262
  • Bexarotene 262
  • Blocking ApoE/AΒ interaction to reduce AΒ plaques 263
  • CD33 inhibitors 263
  • Clearance of AΒ across the blood-brain barrier 263
  • Enhanced PKCε activity promotes clearance of AΒ 264
  • Galantamine-induced AΒ clearance 264
  • Hemopheresis 264
  • Inhibitors of AΒ dehydrogenase 264
  • Intravenous immune globulin 265
  • Monoclonal antibodies for removal of AΒ 266
  • Crenezumab 266
  • Gantenerumab 266
  • Solanezumab 266
  • Nanotechnology for removal of AΒ deposits 267
  • Role of matrix metalloproteinases in clearance of AΒ 267
  • SAN-61 for cleavage of fibril and soluble amyloid 267
  • Serum amyloid P component depletion 268
  • Small molecule DAPH for clearance of amyloid 268
  • Companies developing AΒ-directed therapeutics for AD 268
  • Nootropics 269
  • Acetyl-L-carnitine 270
  • Cerebrolysin 270
  • Ergot derivatives 271
  • Lisuride 271
  • Dihydroergocryptine 271
  • Neuroprotective effect drugs not primarily developed for AD 271
  • Antiinflammatory and antimicrobial drugs 272
  • Dapsone 272
  • Antimicrobial drugs against C. pneumoniae 273
  • PPAR-gamma agonists 273
  • Antidiabetic drugs 273
  • Rosiglitazone 274
  • Pioglitazone 274
  • Antihypertensive drugs 274
  • Angiotensin-converting enzyme inhibitors 274
  • Angiotensin receptor blockers 275
  • Dimebon 275
  • Drugs acting on estrogen receptors 276
  • Estrogen 276
  • Raloxifene 277
  • Inhibitors of neuroinflammation 277
  • Ceramide 277
  • Cyclophosphamide 278
  • Etanercept 278
  • Fingolimod 278
  • MW01-5-188WH 279
  • Neurosteroids 279
  • Pregnenolone sulfate 279
  • Dehydroepiandrosterone 279
  • Levetiracetam 280
  • Lithium 280
  • MAO-B inhibitors 281
  • Ladostigil tartrate 281
  • Memoquin 281
  • Methylene blue 282
  • Nimodipine 282
  • Rapamycin 282
  • Statins 283
  • Testosterone 284
  • Valproic acid 285
  • Future prospects of neuroprotection in AD 285
  • Targeting Cdk5 pathway 285
  • Antioxidants 286
  • Colostrinin 286
  • Curcumin 287
  • Dehydroascorbic acid 287
  • Melatonin 288
  • Reservatrol 288
  • Synthetic catalytic scavengers 289
  • Vitamins 289
  • Vitamin E as antioxidant 289
  • Vitamin B for lowering homocysteine 289
  • Folic acid 290
  • Aminopyridazines 290
  • Nanobody-based drugs for AD 291
  • Nitric oxide based therapeutics for AD 291
  • Nitric oxide mimetics 291
  • iNOS inhibitors for AD 291
  • Novel drugs for AD from natural resources 292
  • Berberine chloride 293
  • Centella asiatica 293
  • Ginko biloba 293
  • Huperzine-A 294
  • Hyperforin 295
  • Melissa officinalis 295
  • Nostocarboline derived from cyanobacteria 296
  • PTI-00703 296
  • Salvia 296
  • Securinega suffruticosa 296
  • Withania somnifera 297
  • ZT-1 297
  • Cholesterol and AD 297
  • ACAT inhibitors 298
  • Role of gene for cholesterol ester transfer protein 299
  • Cholesterol 24S-hydroxylase as a drug target for AD 299
  • Selectively increase of ApoA-I production 299
  • Neurotrophic factors 300
  • Brain derived neurotrophic factor 300
  • Insulin-like growth factor-1 300
  • Nerve growth factor 301
  • Neotrofin (AIT-082) 302
  • Limitations of the use of NTFs for AD 302
  • Role of serotonin modulators in AD 302
  • Xaliproden 303
  • 5-HT1A receptor antagonists 303
  • 5-HT6 antagonists 303
  • 5-HT4 receptor agonists 304
  • PRX-03140 304
  • Donecopride 304
  • Restoration of factors deficient in the aging brain 305
  • Reversal of cognitive impairment in aging by activation of creb protein 305
  • Reversal of cognitive impairment in aging by GDF11 protein 305
  • Restoration of repressor element 1-silencing transcription factor 305
  • Cell therapy for AD 306
  • Stem cell transplantation for AD 306
  • Potential benefits of grafting NSCs in AD 306
  • NSCs improve cognition in AD via BDNF 307
  • Drugs for enhancing neuronal differentiation of implanted NSCs 307
  • Choroid plexus epithelial cells for AD 307
  • Implantation of encapsulated cells for delivering NGF 308
  • Gene therapy for AD 308
  • ApoE gene therapy 308
  • FGF2 gene transfer in AD 308
  • Humanin gene therapy 309
  • Neprilysin gene therapy 309
  • NGF gene therapy 310
  • Targeting plasminogen activator inhibitor type-1 gene 310
  • Antisense approaches to AD 311
  • RNAi approaches to AD 311
  • Combined therapeutic approaches to AD 312
  • Drug delivery for Alzheimer disease 312
  • Delivery of biologicals across the BBB 313
  • Delivery of thyrotropin-releasing hormone analogs by molecular packaging 313
  • Nanoparticle-based drug delivery for Alzheimer's disease 314
  • Transdermal drug delivery in Alzheimer's disease 315
  • Transdermal rivastigmine 315
  • Intranasal delivery of therapeutics for AD 315
  • Intranasal delivery of tacrine 315
  • Intranasal delivery of nerve growth factor to the brain 316
  • Circadian rhythms and timing of cholinesterase inhibitor therapy 316
  • Clinical trials for AD 316
  • Drugs for AD that were discontinued in clinical trials 321
  • Monitoring of cognitive function during clinical trials 324
  • Concluding remarks on clinical trials of AD 324
  • Drug discovery for AD 325
  • Drugs acting on signaling pathways 325
  • Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 325
  • Drugs to reverse inhibition of the PKA/CREB pathway in AD 325
  • Inhibition of the CD40 signaling pathway 326
  • JNK pathway as a target 326
  • Mitogen-activated protein kinase pathway as target 327
  • Protein kinase C activators 327
  • Electrophysiological detection of drug target for neuroprotection in early AD 327
  • Genomics-based drug discovery 328
  • High through screening for AD drug candidates 328
  • Proteomics and drug discovery for AD 328
  • Small molecule compounds binding to neurotrophin receptor p75NTR 329
  • Targeting Vav in tyrosine kinase signaling pathway 330
  • New chemical entities for AD by combining galantamine and memantine 330
  • Novels targets/receptors for AD drug discovery 331
  • Activation of cerebral Rho GTPases 331
  • Activators of insulin-degrading enzyme 331
  • Blockade of TGF-β-Smad2/3 signaling in peripheral macrophages 331
  • Calcium channel blockers 332
  • Calpain inhibitors 332
  • Casein kinase 1 333
  • Cyclin-dependent kinase-5 333
  • Heat shock protein 90 inhibitors 333
  • Histone deacetylase 1 334
  • Inhibition of PDK1 to slow progression of both AD and prion disease 334
  • NF-κB inhibitors 334
  • Kinases and phosphatases as targets for AD therapeutics 334
  • Neutral sphingomyelinase inhibitors 335
  • Phosphodiesterase inhibitors 335
  • Pin 1 as a target in AD 336
  • Protein phosphatase 5 as a neuroprotective in AD 336
  • Src homology-containing protein-1 inhibitors 337
  • Targeting GABAergic system 337
  • TSPO ligands 337
  • Pharmacogenomics of Alzheimer disease 338
  • Personalized therapy of AD 338
  • Genotyping and AD therapeutics 338
  • Biomarkers and companion diagnostics for AD 339
  • Regulatory aspects of drug development for AD 340
  • EMEA guidelines for drug development for AD 340
  • FDA guidelines for drug development for AD 340
  • Concluding remarks and future prospects of drugs for AD 341

6. Markets & Finances of AD Care 343

  • Introduction 343
  • Pharmacoeconomics of treatment of AD 343
  • Quality of Life in relation to economics of AD 343
  • Costs associated with Alzheimer disease 343
  • Pharmacoeconomics of donepezil 344
  • Pharmacoeconomics studies using rivastigmine 345
  • Pharmacoenonomics studies using galantamine 345
  • Pharmacoenonomics studies using memantine 346
  • Patterns of AD care in major markets 346
  • Care of AD patients in the US 346
  • Cost of care 346
  • Medicare and AD 347
  • Patterns of practice in AD care 348
  • Opinions of physicians' organizations on drugs for dementia 348
  • Care of AD patients in the UK 349
  • Cost of care 349
  • Patterns of practice in AD care 349
  • Retraction of NICE recommendations to NHS 350
  • Care of AD patients in Germany 351
  • Care of AD patients in France 352
  • Care of AD patients in Italy 352
  • Care of AD patients in Spain 353
  • Care of AD patients in Japan 353
  • Markets for AD diagnostics 353
  • Markets for AD therapeutics 354
  • Geographical markets for AD 354
  • Markets for currently approved drugs for AD 355
  • Markets for generic AD drugs 355
  • Statins 355
  • Future growth of AD market 355
  • Limitations of AD drug development by the biotechnology industry 356
  • Unmet needs in the management of AD 357
  • Drivers of AD markets 358
  • Increase of the aged populations 358
  • Increase in the number of approved drugs for AD 358
  • Limitations of the current therapies 359
  • Improvements in diagnosis 359
  • Increasing awareness of the disease 359

7. Companies 361

  • Introduction 361
  • Profiles of companies 361
  • Collaborations 510

8. References 515

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 152
  • Table 2-7: Companies involved in the diagnosis/monitoring of Alzheimer disease 154
  • Table 3-1: Classification of treatments for Alzheimer disease 157
  • Table 3-2: Cholinergic approaches used in the treatment of Alzheimer disease 158
  • Table 3-3: Categories of neuroprotective agents for Alzheimer disease 166
  • Table 3-4: Strategies for prevention of Alzheimer disease 181
  • Table 3-5: Guidelines for the treatment of dementia 189
  • Table 4-1: Transgenic mouse models of Alzheimer disease 194
  • Table 4-2: Correlation of studies in animal models with human clinical trials 201
  • Table 5-1: Classification of therapies in development for Alzheimer disease 211
  • Table 5-2: Drugs for AD targeting nACh receptors 220
  • Table 5-3: Ionotropic glutamate receptors 222
  • Table 5-4: Classification of mGluRs 222
  • Table 5-5: Glutamate receptor modulators as potential therapeutic agents in AD 224
  • Table 5-6: Companies involved in developing vaccines for AD 240
  • Table 5-7: Secretase modulators in clinical trials 241
  • Table 5-8: Companies developing AΒ-directed therapeutics for AD 268
  • Table 5-9: Innovative neuroprotective approaches for Alzheimer disease 271
  • Table 5-10: Herbal therapies for AD 292
  • Table 5-11: Novel drug delivery methods for Alzheimer disease therapies 313
  • Table 5-12: Clinical trials in Alzheimer disease 316
  • Table 5-13: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 321
  • Table 6-1: Direct and indirect costs associated with Alzheimer disease 344
  • Table 6-2: Prevalence of AD in major markets 2013-2023 354
  • Table 6-3: AD market values from 2013-2023 in major world markets 354
  • Table 6-4: Markets for currently approved AD drugs 2013-2023 355
  • Table 6-5: Potential markets for drugs in development 2013-2023 356
  • Table 6-6: Limitations of AD drug development by the biotechnology industry 356
  • Table 6-7: Factors that drive AD markets 358
  • Table 7-1: Major players in Alzheimer's disease therapeutics 361
  • Table 7-2: Collaborations relevant to Alzheimer disease 510

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: Cholesterol-related pathways to AD 71
  • Figure 1-9: Pathomechanism of AD 83
  • Figure 3-1: Metabolism of acetylcholine 159
  • Figure 3-2: Neuroprotective effective of galantamine in AD 163
  • Figure 3-3: Strategies for the management of Alzheimer disease 192
  • Figure 5-1: Activation of α7 nicotinic acetylcholine receptors 219
  • Figure 5-2: NMDA receptor ion channel complex. 223
  • Figure 5-3: Neurotoxicity due to misfolding of Aβ1-42 261
  • Figure 5-4: Role of proteomics in drug discovery/development for Alzheimer disease 329
  • Figure 5-5: FDA industry interaction during drug development for AD 341
  • Figure 5-6: FDA's accelerated approval pathway in early Alzheimer disease 342
  • Figure 6-1: Unmet needs in the management of Alzheimer disease 357
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