Alzheimer disease - New drugs, markets and companies

• Publication date: February 2012

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 neur...

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. Approximately 180 clinical trials are listed, of which 126 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 2011. 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 2021. 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 140 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 110 collaborations. The bibliography contains over 850 publications that are cited in the report.The report is supplemented with 44 tables and 15 figures.

Drug And Medication Industry

TABLE OF CONTENTS

0. Executive Summary 19
1. Clinical Features, Epidemiology and Pathology 21
Introduction 21
Historical aspects 21
Clinical features of Alzheimer disease 22
Seven stages of Alzheimer disease 24
AD as a terminal illness 26
Detection of AD in the preclinical phase 26
Differentiation of AD from other dementias 26
Differentiation of AD from non-dementing disorders 27
Cerebral insufficiency and AD 28
Memory deficits and preclinical AD 28
Mild cognitive impairment 29
Evolution of diagnostic criteria of AD 31
Revised criteria for the clinical diagnosis of AD 32
Epidemiology 33
Epidemiology of aging 33
Epidemiology of dementia 35
Epidemiology of AD 35
Prevalence of AD according to age 36
Mortality in AD 36
Pathophysiology of AD 37
Cerebral atrophy and neuronal loss 37
Neuritic plaques and neurofibrillary tangles 37
Sp proteins as markers of neuronal death in AD 38
Role of tau in the pathogenesis of AD 38
Amyloid precursor protein 39
Relation of APP mutations to CNS disorders 40
Relation of APP to A? deposits and pathogenesis of AD 40
APP intracellular domain 42
Role of secretases in amyloid cascade 42
Role of exosomal proteins 44
Role of nicastrin 44
Neurotixicity of A? deposits 44
Relation of A? deposits to synaptic activity 45
Dysfunction of TGF-? signaling accelerates A? deposition 45
Role of TMP21 in presenilin complexes and A? formation 45
Role of A? dimers in the pathogenesis of AD 46
Structure–neurotoxicity relationships of A? oligomers 46
A? deposit and clearance 46
Impairment of mitochondrial energy metabolism 47
A?-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 59
Neurotrophic factors 60
NF-?B signaling and the pathogenesis of neurodegeneration 60
Nitric oxide and AD 61
Nogo receptor pathway 63
Oxidative stress and AD 63
Prostaglandins and AD 65
Quinolinic acid and AD 65
Retromer deficiency 65
Serotonin and AD 66
Spherotoxin 66
Synaptic failure in AD 66
Transmission of AD 67
Ubiquitin-proteasome system in pathogenesis of AD 67
Risk factors in the etiology of AD 68
Aging and developmental abnormalities of the cholinergic system 69
Cholesterol, dietary lipids, and A? 69
Exposure to magnetic fields 70
Family history of AD 70
Homocysteine and AD 70
Level of education/type of job and risk of AD 71
Metals and AD 72
Obesity 73
Proneness to psychological distress and risk of AD 74
Reduced muscle strength 74
Sleep deprivation 74
Traumatic brain injury and AD 75
Vascular risk factors for AD 76
Vitamin B12 and folate 77
AD versus non-dementing changes in the aging brain 77
AD and cognitive impairment with aging 78
Pathomechanism of memory impairment and AD 78
Concluding remarks on pathophysiology of AD 79
Genetics of AD 80
Familial AD 80
Presenilins and calcium channel leak in pathogenesis of familial AD 82
Late onset AD 82
Genomics of AD 82
Introduction to genomics 82
Genes associated with Alzheimer disease 83
AlzGene database 84
ApoE gene 84
ApoE genotype and nitric oxide 85
ApoE genotype modulates AD phenotype 86
APOE genotype and age-related myelin breakdown 86
ApoE receptor interaction with NMDA receptor 87
ApoE and ApoER2 87
ApoE receptor LR11 as regulator of A? 88
Arctic mutation 88
CALHM1 polymorphism and AD 88
CLU, CRI and PICALM 88
CYP46 and risk for AD 89
DAPK1 gene variants and AD 89
Genetic variants associated with late-onset AD 89
Copy number variation (CNV) in LOAD 90
LRRTM3 as a candidate gene for AD 90
MTHFD1L gene variant associated with AD 90
OGG1 mutations associated with AD 91
SORL1 gene in AD 91
TOMM40 gene and risk of AD 91
International Genomics of Alzheimer's Project 91
Molecular neuropathology 92
Role of microRNAs in AD 92
AD as a polygenic disorder 93
Proteomics of AD 93
Introduction 93
Application of proteomic technologies to study AD 93
Protein misfolding in AD 95
Common denominators of AD and prion diseases 96
Amyloid fibrils as a common feature of AD and prion diseases 97
FE65 proteins and AD 97
2. Diagnostic Procedures for Alzheimer Disease 99
Importance of the diagnosis of Alzheimer disease 99
Methods of diagnosis of AD 99
Self-administered olfactory test 100
Neuropsychological testing 100
Assessment and evaluation 101
7-minute screen 101
15-point risk index 102
Measurement of aggregation in anterior segment of the eye 102
Activities of Daily Living 102
Alzheimer Disease Cooperative Study 103
CDR-SOB score 103
Clinician's Interview-Based Impression of Change 103
Resource Utilization in Dementia Battery 103
DETECT? System 103
Electrophysiology 104
EEG-based bispectral index 104
Event-related potentials 104
Correlation of electrical activity of the brain with cognition 104
Early detection of cataract associated with AD 105
Retinal imaging to detect A? deposits 105
Laboratory methods for diagnosis of AD 105
Monitoring of synthesis and clearance rates of A? in the CSF 105
Molecular diagnostics for AD 106
Genetic tests for AD 107
ApoE genotyping 107
Gene expression patterns in AD 108
Molecular fingerprinting of the immune system in AD 108
Microarray-based tests for AD 108
Monoclonal antibody-based in vitro diagnosis of AD from brain tissues 109
Biomarkers of AD 109
The ideal biomarker for AD 111
CSF biomarkers of AD 111
CSF sulfatide as a biomarker for AD 111
Glycerophosphocholine as CSF biomarker in AD 112
Protein biomarkers of AD in CSF 112
Amyloid precursor protein 114
Tau proteins in CSF 114
Tests for the detection of A? in CSF 114
Tests combining CSF tau and A? 115
Urine tests for AD 115
Blood tests for AD 116
Blood A? levels 116
Blood test for AD based on heme oxygenase-1 117
Blood test for AD based on RNA hybridization 117
GSK-3 elevation in white blood cells 117
Lymphocyte Proliferation Test 118
Protein kinase C in red blood cells 118
Sphingolipids 118
Tests based on protein biomarkers in blood 118
A skin test for early detection of AD 119
Saliva-based tests for AD 119
Saliva A?42 level as a biomarker of AD 119
Nanotechnology to measure A?-derived diffusible ligands 120
Simultaneous measurement of several biomarkers for AD 120
Plasma biomarkers of drug response in AD 121
A serum protein-based algorithm for the detection of AD 121
Concluding remarks about biomarkers for AD 121
Imaging in AD 122
Computed tomography 122
Magnetic resonance imaging 122
Arterial spin labeling with MRI 123
Magnetic resonance microscopy 123
Magnetic resonance spectroscopy 123
Single photon emission computed tomography and modifications 124
Positron emission tomography 125
In vivo imaging of A? deposits by PET 126
Pittsburgh compound B and PET 127
Florbetapir-PET 128
Florbetaben-PET 128
In vivo detection of A? plaques by MRI 129
Imaging agents for A? and neurofibrillary tangles 129
Targeting of a chemokine receptor as biomarker for brain imaging 130
Radioiodinated clioquinol as a biomarker for A? 130
Imaging neuroinflammation in AD 130
Preclinical diagnosis of AD 131
Meta-analysis of literature on imaging in AD 132
Alzheimer Disease Neuroimaging Initiative 132
Concluding remarks on imaging for diagnosis of AD 133
Diagnosis of MCI and prediction of AD 133
Diagnosis of MCI 133
Computer-Administered Neurophychological screen for MCI 133
Infrared eye-tracking technology to detect MCI 133
PET for detection of MCI 134
MRI for detection of MCI 134
Presymptomatic detection of AD 134
PredictAD project 135
Prediction of AD in patients with MCI 135
Combination of MMSE and a memory test for prediction of AD 135
Biochemical biomarkers in CSF for prediction of AD 135
Structural MRI biomarkers for prediction of AD 136
Magnetoencephalography for detection of MCI and AD 136
Concluding remarks about prediction of AD in MCI 137
Criteria for diagnosis of AD 137
Role of biomarkers in diagnosis of AD dementia 138
Ethical aspects of diagnostics for AD 138
Genetic testing for AD 138
Ethical issues of brain imaging in AD 139
Companies involved in diagnosis of AD 139
3. Management of Alzheimer Disease 141
Introduction 141
Cholinergic approaches 141
Mechanism of action of cholinesterase inhibitors 142
Choline and lecithin 143
Donepezil 144
Rivastigmine 145
Galantamine 146
Duration of treatment with ChE inhibitors 147
Comparative studies of ChE inhibitors 147
Donepezil versus rivastigmine 148
Donepezil versus galantamine 148
An assessment and future prospects of anticholinergic therapies 148
Neuroprotection in Alzheimer's disease 149
Memantine 150
Combination of memantine with ChE inhibitors 153
Monoamine oxidase inhibitors 153
Selegiline 154
Synaptoprotection in AD 154
Drugs for noncognitive symptoms in AD 154
Antidepressants 154
Antipsychotics 155
ChE inhibitors for behavioral and psychological disorders in AD 155
Concluding remarks and other drugs for agitation in AD 156
Sensory stimulation 156
Non-pharmacological treatments of AD 157
Management of memory loss in AD 157
Exposure to electromagnetic fields for treatment of AD 158
Application of electrical fields for improvement of cerebral function 158
High-frequency electromagnetic field treatment of AD 158
Vagal nerve stimulation 158
Cerebrospinal fluid shunting 159
Omental transposition 160
Microchip-based hippocampal prosthesis for AD 160
Nutritional therapies for AD 160
Axona 160
Cocktail of dietary supplements for AD 160
Docosahexaenoic acid 161
Magnesium 162
Nicotinamide for the treatment of AD 163
Omega-3 fatty acids 163
Preventing decline of mental function with aging and dementia 164
Prevention of Alzheimer disease 164
Mental training 165
Physical exercise 165
Higher level of conscientiousness and decreased risk of AD 166
Caloric restriction 166
Nutritional factors in prevention of AD 167
Grapes and red wine 167
Black and green teas 168
Caffeine 169
Drugs to prevent Alzheimer disease 169
Preimplantation genetic diagnosis of inherited Alzheimer disease 169
Presymptomatic detection of AD 170
Management of mild cognitive impairment 170
Management of Down syndrome 171
Guidelines for use of anti-dementia drugs in clinical practice 172
Donepezil and/or memantine 173
General care of the Alzheimer disease patients 173
Strategies for the management of Alzheimer disease 173
4. Research in Alzheimer Disease 175
Introduction 175
Animal models of Alzheimer disease 175
Lesional models 175
Cerebroventricular injection of A? in rats 175
Lentiviral vector-based models of amyloid pathology 176
AAV-mediated gene transfer to increase hippocampal A? 176
Transgenic mouse models 176
Quantitative assessment of amyloid load in transgenic models 178
In vivo magnetic resonance microimaging in transgenic models of AD 178
Transgenic model of AD with suppression of A? production 178
Transgenic AD11 anti-NGF mice 179
Genetically altered mice with deficiency of vesicular ACh transporter 179
Limitations of mouse models of Alzheimer disease 179
Cholesterol-fed rabbits as models for AD 180
Zebrafish model for AD 180
Transgenic invertebrate models of Alzheimer disease 181
Drosophila model of AD 181
Caenorhabditis elegans Alzheimer disease model 182
Cell systems for AD research 182
In vitro neuronal cell Lines 182
Single-gene expression system for use in cell culture 183
Transgenic cells 183
In silico models 184
Estimation of progression rates of Alzheimer disease 184
Clinical trial methods in Alzheimer disease 185
Molecular imaging as a guide to drug development 185
Use of MRI and PET in clinical trials 186
Cognitive-function assessment in clinical trials 186
Clinical trials in mild cognitive impairment 187
Research in AD as a basis for future therapies 187
Use of microarrays for studying pathogenesis of AD 187
Computational brain mapping in AD 187
Study of neurogenesis in AD 188
Study of 3D structure of A? 188
Solid-state NMR to study precursors of A? 188
Research in Alzheimer disease at academic centers 188
Role of NIH in AD research 189
NIH Clinical Trials Database for AD 189
Alzheimer Research Consortium 189
The National Institute on Aging and AD research 189
5. Drug Discovery & Development for Alzheimer Disease 191
Introduction 191
Categories of drugs in development for AD 191
Memory-enhancing drugs 193
Enhancing memory by drugs that block eIF2? phosphorylation 193
Drugs based on cholinergic approaches 193
AP2238 194
Butyrylcholinesterase inhibitors 194
Donepezil-tacrine hybrids 194
Drugs modulating gamma-aminobutyric acid receptors 195
Ganstigmina 195
Methanesulfonyl fluoride 195
Muscarinic receptor modulators 196
Muscarinic M1 agonists 196
Muscarinic M2 antagonists 197
Nicotine and nicotinic receptor modulators 197
Nicotine 197
Nicotinic receptor modulators 198
GTS21 199
Ispronicline 199
JWB1-84-1 200
Neuropeptide/neurotransmitters 200
Somatostatin release enhancers 200
Glutamate receptor modulators 200
Physiology and pharmacology of glutamate receptors 201
NMDA receptor ion channel complex 201
Metabotropic glutamate receptors 203
Glutamate receptor modulators as potential therapeutics for AD 204
Non-competitive NMDA modulators 205
AMPA modulators 205
Drugs affecting multiple neurotransmitters 206
Ensaculin 206
NS2330 206
RS-1259 206
Lecozotan 207
Vaccines for AD 207
Active immunization with A? 208
AN-1792 vaccine 208
Complications in clinical trials with AN-1792 208
Effects of A? vaccine on the brain 208
Strategies to avoid undesirable effect of A? vaccination 209
Passive immunization in AD 210
Passive immunization with MAbs 210
Delivery of the passive antibody directly to the brain 212
Systemic injection of MAbs to treat AD 213
Combination of A? immunotherapy and CD40-CD40L blockade 213
Shaping the immune responses elicited against A? 213
Delivery of AD vaccines 214
Gene vaccination 214
Modified A? nasal vaccine 214
Transdermal A? vaccination 214
Other vaccines for AD 215
Nasal vaccination with Proteosome? adjuvant 215
T-cell vaccination with glatiramer acetate adjuvant 216
Early start of immunotherapy to clear A? plaques 216
Reversal of cholinergic dysfunction by anti-A? antibody 216
Immune modulation via TRL9 to reduce A? 216
Mechanisms by which A? antibodies reduce amyloid accumulation in the brain 217
Perspectives on vaccines for AD 217
Companies involved in AD vaccines 219
Inhibition of amyloid precursor protein aggregation 220
Secretase modulators 220
Neuroprotection by ?-secretase cleaved APP 221
Inhibitors of ?-secretase 221
Inhibitors of ?-secretase 222
Amyloid-derived diffusible ligands 223
GABA receptor modulation by etazolate and APP processing 224
Depletion of serum amyloid P 224
Trojan-horse approach to prevent build-up of A? aggregates 224
Drugs that inhibit the formation of A? 225
22R-hydroxycholesterol 225
Acylaminopyrazole 226
Cadmium telluride nanoparticles prevent A? fibril formation 226
Cannabinoids 226
Chelation therapy for AD 227
Clioquinol and PBT2 227
Copper chelation by FKBP52 228
Zinc chelation from amyloid plaques 229
Next generation multifunctional chelating agents for AD 229
Heparin and its derivatives 229
A reassessment of the role of heparin in AD 229
Enoxaparin 230
Heparan sulfate 230
Imatinib mesylate 230
Laminin 231
NSAIDs 231
Flurbiprofen analogs with A?42-lowering action 232
Nitric oxide-donating NSAIDs 233
In vivo demonstration of the effects of NSAIDs on brain in AD 233
Paclitaxel 233
Phenserine 234
Tolserine 234
Platinum-based inhibitors of A? 235
Scyllo-cyclohexanehexol 235
Ubiquitin C-terminal hydrolase L1 235
Drugs to prevent the formation of NFTs 235
Tau suppression 236
ApoE4 as a therapeutic target in AD 237
Strategies to prevent deposits and enhance clearance of A? 237
4,5-dianilinophthalimide for disruption of A?1-42 fibrils 238
ABCA1 overexpression to lower amyloid deposits 239
Beta-sheet breakers 239
Blocking ApoE/A? interaction to reduce A? plaques 239
Clearance of A? across the blood-brain barrier 240
Enhanced PKC? activity promotes clearance of A? 240
Galantamine-induced A? clearance 240
Inhibitors of A? dehydrogenase 241
Intravenous immune globulin 241
Meptides 242
Monoclonal antibodies for removal of A? 242
Nanotechnology for removal of A? deposits 243
Role of matrix metalloproteinases in clearance of A? 243
SAN-61 for cleavage of fibril and soluble amyloid 243
Serum amyloid P component depletion 244
Small molecule DAPH for clearance of amyloid 244
Companies developing A?-directed therapeutics for AD 244
Antiinflammatory and antimicrobial drugs 246
Dapsone 246
Antimicrobial drugs against C. pneumoniae 246
PPAR-gamma agonists 246
Inhibitors of neuroinflammation 247
Cyclophosphamide 247
Etanercept 247
MW01-5-188WH 248
Antidiabetic drugs 248
Rosiglitazone 248
Pioglitazone 249
Nootropics 249
Acetyl-L-carnitine 249
Cerebrolysin 250
Ergot derivatives 250
Lisuride 250
Dihydroergocryptine 251
Neuroprotective effect drugs not primarily developed for AD 251
Antihypertensive drugs 252
Angiotensin-converting enzyme inhibitors 252
Angiotensin receptor blockers 252
Dimebon 252
Drugs acting on estrogen receptors 253
Estrogen 254
Raloxifene 254
Neurosteroids 255
Pregnenolone sulfate 255
Dehydroepiandrosterone 255
Lithium 256
MAO-B inhibitors 256
Ladostigil tartrate 256
Memoquin 257
Methylene blue 257
Nimodipine 257
Rapamycin 258
Statins 258
Testosterone 259
Valproic acid 260
Future prospects of neuroprotection in AD 260
Targeting Cdk5 pathway 261
Antioxidants 261
Colostrinin 262
Curcumin 262
Melatonin 263
Synthetic catalytic scavengers 263
Dehydroascorbic acid 263
Omega-3 fatty acids 264
Vitamins 264
Vitamin E as antioxidant 264
Vitamins to lower homocysteine 264
Folic acid 265
Aminopyridazines 265
Nanobody-based drugs for AD 265
Nitric oxide based therapeutics for AD 266
Nitric oxide mimetics 266
iNOS inhibitors for AD 266
Novel drugs for AD from natural resources 267
Berberine chloride 267
Centella asiatica 268
Ginko biloba 268
Huperzine-A 269
Hyperforin 270
Melissa officinalis 270
Nostocarboline derived from cyanobacteria 270
PTI-00703 271
Salvia 271
Securinega suffruticosa 271
Withania somnifera 271
ZT-1 272
Cholesterol and AD 272
ACAT inhibitors 273
Role of gene for cholesterol ester transfer protein 274
Cholesterol 24S-hydroxylase as a drug target for AD 274
Selectively increase of ApoA-I production 274
Neurotrophic factors 275
Activity-dependent neuroprotective protein 275
Brain derived neurotrophic factor 275
Insulin-like growth factor-1 275
Nerve growth factor 276
Neotrofin (AIT-082) 277
Limitations of the use of NTFs for AD 277
Role of serotonin modulators in AD 278
Xaliproden 278
5-HT1A receptor antagonists 278
5-HT6 antagonists 278
5-HT4 receptor agonists 279
PRX-03140 279
Cell therapy for AD 280
Stem cell transplantation for AD 280
Potential benefits of grafting NSCs in AD 280
NSCs improve cognition in AD via BDNF 281
Drugs for enhancing neuronal differentiation of implanted NSCs 281
Implantation of encapsulated cells for delivering NGF 281
Gene therapy for AD 281
ApoE gene therapy 282
FGF2 gene transfer in AD 282
Humanin gene therapy 282
Neprilysin gene therapy 282
NGF gene therapy 283
Targeting plasminogen activator inhibitor type-1 gene 284
Antisense approaches to AD 284
RNAi approaches to AD 285
Combined therapeutic approaches to AD 286
Drug delivery for Alzheimer disease 286
Delivery of thyrotropin-releasing hormone analogs by molecular packaging 286
Nanoparticle-based drug delivery for Alzheimer’s disease 287
Transdermal drug delivery in Alzheimer's disease 288
Transdermal rivastigmine 288
Intranasal delivery of therapeutics for AD 288
Intranasal delivery of tacrine 288
Intranasal delivery of nerve growth factor to the brain 289
Circadian rhythms and timing of cholinesterase inhibitor therapy 289
Clinical trials for AD 289
Drugs for AD that were discontinued in clinical trials 294
Evaluation of clinical trials of AD 296
Monitoring of cognitive function during clinical trials 297
Drug discovery for AD 297
Drugs acting on signaling pathways 297
Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 297
Drugs to reverse inhibition of the PKA/CREB pathway in AD 297
Inhibition of the CD40 signaling pathway 298
JNK pathway as a target 299
Mitogen-activated protein kinase pathway as target 299
Protein kinase C activators 299
Electrophysiological detection of drug target for neuroprotection in early AD 299
Genomics-based drug discovery 300
High through screening for AD drug candidates 300
Proteomics and drug discovery for AD 301
Small molecule compounds binding to neurotrophin receptor p75NTR 302
Targeting Vav in tyrosine kinase signaling pathway 303
Novels targets/receptors for AD drug discovery 303
Activation of cerebral Rho GTPases 304
Activators of insulin-degrading enzyme 304
Blockade of TGF-?-Smad2/3 signaling in peripheral macrophages 304
Calcium channel blockers 305
Casein kinase 1 305
Cyclin-dependent kinase-5 305
Heat shock protein 90 inhibitors 306
Histone deacetylase 1 306
Inactivation of aph-1 and pen-2 reduces APP cleavage 306
NF-?B inhibitors 307
Kinases and phosphatases as targets for AD therapeutics 307
Neutral sphingomyelinase inhibitors 307
Phosphodiesterase inhibitors 308
Pin 1 as a target in AD 308
Protein phosphatase 5 as a neuroprotective in AD 309
Src homology-containing protein-1 inhibitors 309
Targeting GABAergic system 309
Pharmacogenomics of Alzheimer disease 309
Personalized therapy of AD 310
Genotyping and AD therapeutics 310
Biomarkers and companion diagnostics for AD 311
Regulatory aspects of drug development for AD 312
EMEA guidelines for drug development for AD 312
Concluding remarks and future prospects of drugs for AD 312
6. Markets & Finances of AD Care 315
Introduction 315
Pharmacoeconomics of treatment of AD 315
Quality of Life in relation to economics of AD 315
Costs associated with Alzheimer disease 315
Pharmacoeconomics of donepezil 316
Pharmacoeconomics studies using rivastigmine 316
Pharmacoenonomics studies using galantamine 317
A comparison of pharmacoenonomics outcomes with different ChE inhibitors 317
Pharmacoenonomics studies using memantine 318
Patterns of AD care in major markets 318
Care of AD patients in the US 318
Cost of care 318
Medicare and AD 319
Patterns of practice in AD care 320
Opinions of physicians’ organizations on drugs for dementia 320
Care of AD patients in the UK 321
Cost of care 321
Patterns of practice in AD care 321
Retraction of NICE recommendations to NHS 322
Care of AD patients in Germany 323
Care of AD patients in France 323
Care of AD patients in Italy 324
Care of AD patients in Spain 324
Care of AD patients in Japan 324
Markets for AD diagnostics 325
Markets for AD therapeutics 325
Geographical markets for AD 325
Markets for currently approved drugs for AD 326
Markets for generic AD drugs 326
Future growth of AD market 327
Statins 327
Limitations of AD drug development by the biotechnology industry 327
Unmet needs in the management of AD 328
Drivers of AD markets 329
Increase of the aged populations 330
Increase in the number of approved drugs for AD 330
Limitations of the current therapies 330
Improvements in diagnosis 330
Increasing awareness of the disease 331
7. Companies 333
Introduction 333
Profiles of companies 333
Abbott Laboratories 334
AC Immune SA 335
Accera Inc 337
Actelion Ltd 338
Acumen Pharmaceuticals Inc 339
Addex Pharmaceuticals 340
Adlyfe Inc 341
Advanced Life Sciences 342
Affiris GmbH 343
Allon Therapeutics Inc 344
AlzProtect 345
Amgen Inc 346
Amorfix Life Sciences Ltd 347
Applied NeuroSolutions Inc 348
Archer Pharmaceuticals Inc 349
AstraZeneca 350
Athena Diagnostics Inc 351
Avera Pharmaceuticals Inc 352
Avid Radiopharmaceuticals Inc 353
Avineuro Pharmaceuticals Inc 354
Axon Neuroscience 355
Bayer Healthcare 356
Bayer Pharma AG 357
Baxter Healthcare International Inc 358
Bellus Health Inc 359
BioArctic Neuroscience AB 360
BiOasis Technologies Inc 361
BioE Inc 362
Boehringer Ingelheim GmbH 363
Bristol-Myers Squibb Company 364
BTG International Ltd 365
CALBIOCHEM 366
Cellzome AG 367
CEPHALON Inc 368
Ceregene Inc 369
Chiesi Farmaceutici SpA 370
Circadian Technologies Ltd 371
CoMentis Inc 372
Cortex Pharmaceuticals Inc 373
Cortica Neurosciences 374
Crossbeta Biosciences BV 375
Curaxis Pharmaceutical Corporation 376
Cyberonics Inc 377
Cytos Biotechnology AG 378
D-Pharm 379
Dainippon Sumitomo Pharma 380
Debiopharm SA 381
Diamedica Inc 382
Digilab BioVisioN GmbH 383
Ebewe Pharma GmbH 384
Eisai Co Ltd 385
Eli Lilly & Co 386
ENKAM Pharmaceuticals A/S 387
EnVivo Pharmaceuticals 388
EPIX Pharmaceuticals 389
Evotec AG 390
ExonHit Therapeutics SA 391
FluoroPharma Inc 392
Forest Laboratories Inc 393
Galantos Pharma GmbH 394
Galapagos Genomics 395
GE Healthcare Ltd 396
GlaxoSmithKline 397
H. Lundbeck A/S 398
Helicon Therapeutics Inc 399
Hoffmann-La Roche Ltd 400
Humanetics Corporation 401
Innogenetics NV 402
Intellect Neurosciences Inc 403
IntelliHep Ltd 404
Interleukin Genetics Inc 405
Intra-Cellular Therapies Inc 406
ItherX 407
JANSSEN Alzheimer Immunotherapy 408
Lay Line Genomics 409
Lexicon Genetics Incorporated 411
Maas BiolAB LLC 412
Medivation Inc 413
Merck & Co 414
Merz & Co GmbH 415
MIGENIX Inc 416
MindGenix Inc 417
Mindset BioPharmaceuticals Ltd 418
Mithridion Inc 419
MorphoSys AG 420
Myriad Genetics Inc 421
Neurimmune Holding AG 422
Neuro-Hitech Inc 424
Neurologix Inc 425
NeuroMolecular Pharmaceuticals 426
Newron Pharmaceuticals SpA 427
Neuronautics Inc 428
NeuroNascent Inc 429
NeuroNova AB 430
Neuroptix Corporation 431
NeuroSearch 432
Noscira 433
Novartis AG 434
NsGene 435
Nymox Corporation 436
Ortho-McNeil Neurologics Inc 437
Osta Biotechnologies Inc 438
Panacea Pharmaceuticals Inc 439
Pfizer Pharmaceutical Group 440
Pharmexa A/S 441
Pharnext SAS 442
Phytopharm Plc 443
Prana Biotechnology Limited 444
PrimaBiomed Ltd 445
Probiodrug AG 446
Proneuron Biotechnologies Ltd 447
ProteoTech Inc 448
Provista Life Sciences 449
Raptor Pharmaceuticals Corp 450
Reata Pharmaceuticals Inc 452
ReGen Therapeutics Plc 453
reMYND NV 454
Samaritan Pharmaceuticals Inc 455
Sanomune Inc 456
Sanochemi