Alzheimer Disease – New Drugs, Markets and Companies

NEW YORK , Jan. 3, 2012 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:

Alzheimer disease - New drugs, markets and companies

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Summary

Alzheimer's disease remains a challenge in management. With nearly 8 million sufferers from this condition in the seven major markets of the world and anticipated increases in the future. Considerable research is in progress to understand the pathomechanism of the disease and find a cure. The only drugs approved currently are acetylcholinesterase inhibitors but they do not correct the basic pathology of the disease, beta amyloid deposits and neurofibrillary tangles. Several new approaches emphasize neuroprotection as well.

Early diagnosis of Alzheimer's disease is an important first step in management. Several biomarkers in cerebrospinal fluid, blood and urine can detect the disease. They provide a valuable aid to the clinical examination and neuropsychological testing which are the main diagnostic methods supplemented by brain imaging. Genotyping, particularly of ApoE gene alleles is also useful in the evaluation of cases and planning management.

The current management of Alzheimer's disease is reviewed and it involves a multidisciplinary approach. Acetylcholinesterase inhibitors are mostly a symptomatic treatment but some claims are made about a neuroprotective effect. Currently the only approved neuroprotective therapy in is memantine. Management of these patients also require neuroleptics for aggressive behavior and antidepressants. There is an emphasis on early detection at the stage of mild cognitive impairment and early institution of neuroprotective measures. The value of mental exercise in delaying the onset of Alzheimer's disease is being recognized.

Research in Alzheimer's disease still aims at elucidating the basic pathomechanisms. Animal models are important for research, particularly in testing some of the potential therapeutic approaches. There is considerable research in progress at the various centers, some of which is funded by the National Institute of Aging of the National Institutes of Health.

Over 300 different compounds are at various stages of development for the treatment of Alzheimer's disease. These are classified and described. There are non-pharmacological approaches such as vagal nerve stimulation and cerebrospinal fluid shunting, which are in clinical trials. Approximately 180 clinical trials are listed, of which 127 are still in progress and 53 were discontinued for various reasons.

Alzheimer's disease market in the seven major markets is analyzed for the year 2010. 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 2020. 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.

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-kB 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 Ab 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

DETECTä 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 Ab in CSF 114

Tests combining CSF tau and Ab 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 Ab 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 166

Grapes and red wine 167

Black and green teas 168

Caffeine 168

Drugs to prevent Alzheimer disease 169

Preimplantation genetic diagnosis of inherited Alzheimer disease 169

Presymptomatic detection of AD 169

Management of mild cognitive impairment 169

Management of Down syndrome 171

Guidelines for use of anti-dementia drugs in clinical practice 171

Donepezil and/or memantine 172

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 Ab 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 Ab 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 Ab immunotherapy and CD40-CD40L blockade 213

Shaping the immune responses elicited against Ab 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 ProteosomeÔ adjuvant 215

T-cell vaccination with glatiramer acetate adjuvant 216

Early start of immunotherapy to clear Ab plaques 216

Reversal of cholinergic dysfunction by anti-Ab antibody 216

Immune modulation via TRL9 to reduce A? 216

Mechanisms by which Ab 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 Ab42-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 Ab 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/Ab 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

Dimebolin 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 298

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-b-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-kB 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

Collaborations 480

8. References 485

Tables

Table 1-1: Historical landmarks relevant to Alzheimer disease 21

Table 1-2: Clinical features of Alzheimer disease 22

Table 1-3: Non-Alzheimer dementias 27

Table 1-4: A guide to evaluation for MCI due to AD 30

Table 1-5: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease 31

Table 1-6: Relation of mutations in amyloid precursor protein to CNS disorders 40

Table 1-7: Risk factors for Alzheimer's disease 68

Table 1-8: Genes linked to AD 83

Table 1-9: Abnormalities of expression of brain proteins in Down's syndrome and AD 94

Table 2-1: Classification of methods of diagnosis of Alzheimer disease 99

Table 2-2: Neuropsychological test batteries and scales for Alzheimer's disease 100

Table 2-3: Available molecular diagnostic tests for Alzheimer disease 106

Table 2-4: Classification of biomarkers of AD in blood and CSF 109

Table 2-5: Characteristics of an ideal biomarker for Alzheimer disease 111

Table 2-6: Role of biomarkers in diagnosis of AD dementia 138

Table 2-7: Companies involved in the diagnosis of Alzheimer disease 139

Table 3-1: Classification of treatments for Alzheimer disease 141

Table 3-2: Cholinergic approaches used in the treatment of Alzheimer disease 142

Table 3-3: Categories of neuroprotective agents for Alzheimer disease 150

Table 3-4: Strategies for prevention of Alzheimer disease 164

Table 3-5: Guidelines for the treatment of dementia 171

Table 4-1: Transgenic mouse models of Alzheimer disease 176

Table 5-1: Classification of therapies in development for Alzheimer disease 191

Table 5-2: Drugs for AD targeting nACh receptors 199

Table 5-3: Ionotropic glutamate receptors 201

Table 5-4: Classification of mGluRs 201

Table 5-5: Glutamate receptor modulators as potential therapeutic agents in AD 204

Table 5-6: Companies involved in developing vaccines for AD 219

Table 5-7: Secretase modulators in clinical trials 220

Table 5-8: Companies developing A--directed therapeutics for AD 244

Table 5-9: Innovative neuroprotective approaches for Alzheimer disease 251

Table 5-10: Herbal therapies for AD 267

Table 5-11: Novel drug delivery methods for Alzheimer disease therapies 286

Table 5-12: Clinical trials in Alzheimer disease 289

Table 5-13: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 294

Table 6-1: Direct and indirect costs associated with Alzheimer disease 316

Table 6-2: Prevalence of AD in major markets 2011-2021 325

Table 6-3: AD market values from 2011-2021 in major world markets 326

Table 6-4: Markets for currently approved AD drugs 2011-2021 326

Table 6-5: Potential markets for drugs in development 2011-2021 327

Table 6-6: Limitations of AD drug discovery and development by the biotechnology industry 328

Table 6-7: Factors that drive AD markets 329

Table 7-1: Major players in Alzheimer's disease therapeutics 333

Table 7-2: Collaborations relevant to Alzheimer disease 480

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. 33

Figure 1-2: Correlation between aging and AD in the US from 2000 to 2020 34

Figure 1-3: Prevalence of different types of dementia 35

Figure 1-4: Mechanisms of A- clearance 47

Figure 1-5: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease 62

Figure 1-6: Oxidative stress and Alzheimer disease 64

Figure 1-7: Role of proteosome inhibition in A- generation and neurodegeneration 68

Figure 1-8: Pathomechanism of AD 80

Figure 3-1: Metabolism of acetylcholine 143

Figure 3-2: Neuroprotective effective of galantamine in AD 147

Figure 3-3: Strategies for the management of Alzheimer disease 173

Figure 5-1: NMDA receptor ion channel complex. 203

Figure 5-2: Neurotoxicity due to misfolding of Ab1-42 238

Figure 5-3: Role of proteomics in drug discovery and development for Alzheimer disease 302

Figure 6-1: Unmet needs in the management of Alzheimer disease 329

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Nicolas Bombourg
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