Reportlinker Adds Alzheimer Disease - New Drugs, Markets and Companies

Jun 03, 2010, 11:38 ET from Reportlinker

NEW YORK, June 3 /PRNewswire/ -- announces that a new market research report is available in its catalogue:

Alzheimer disease - new drugs, markets and companies


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. Over 171 clinical trials are listed, of which 127 are still in progress and 44 were discontinued for various reasons.

Alzheimer's disease market in the seven major markets is analyzed for the year 2008. 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 2018. 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 139 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 104 collaborations. The bibliography contains over 600 publications that are cited in the report. The report is supplemented with 42 tables and 14 figures.


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 25

Cerebral insufficiency and AD 26

Memory deficits and preclinical AD 26

Mild cognitive impairment 27

Diagnostic criteria of AD 28

Epidemiology 30

Epidemiology of aging 30

Epidemiology of dementia 31

Epidemiology of AD 31

Prevalence of AD according to age 32

Mortality in AD 32

Pathophysiology of AD 33

Cerebral atrophy and neuronal loss 33

Neuritic plaques and neurofibrillary tangles 33

Sp proteins as markers of neuronal death in AD 34

Role of tau in the pathogenesis of AD 34

Amyloid precursor protein 35

Relation of APP mutations to CNS disorders 35

Relation of APP to A? deposits and pathogenesis of AD 36

APP intracellular domain 37

Role of secretases in amyloid cascade 38

Role of exosomal proteins 40

Role of nicastrin 40

Neurotixicity of A? deposits 40

Relation of A? deposits to synaptic activity 40

Dysfunction of TGF-? signaling accelerates A? deposition 41

Role of TMP21 in presenilin complexes and A? formation 41

Role of A? dimers in the pathogenesis of AD 42

Structure–neurotoxicity relationships of A? oligomers 42

A? deposit and clearance 42

Impairment of mitochondrial energy metabolism 43

A?-binding alcohol dehydrogenase links AD to mitochondrial toxicity 44

Neural thread protein 44

Loss of synaptic proteins 44

AD and Down syndrome 45

Overlapping pathologies of AD and Parkinson disease 45

AD and age-related macular degeneration 46

Myelin hypothesis of AD 46

Blood-brain barrier in AD 46

Blood vessel damage in AD 48

Loss of serotonin 1A receptors in the brain 48

Factors in pathogenesis of AD 48

Astrocytes and AD 48

Axonal transport failure in AD 49

Cell-cycle hypothesis 49

Chronic heart failure link with AD 49

Creatine and AD 50

Disturbances of interaction of nervous system proteins 50

DENN/MADD expression and enhanced pro-apoptotic signaling in AD 50

Gonadotrophins and AD 50

Glutamate transport dysfunction in AD 51

Innate immune system and AD 52

Insulin, diabetes and AD 52

Mechanisms underlying cognitive deficits in AD 53

Monoamine oxidase and AD 54

Neuroinflammation and AD 54

Neurotransmitter deficits 55

Neurotrophic factors 55

NF-?B signaling and the pathogenesis of neurodegeneration 56

Nitric oxide and AD 56

Nogo receptor pathway 59

Oxidative stress and AD 59

Prostaglandins and AD 61

Quinolinic acid and AD 61

Retromer deficiency 61

Serotonin and AD 62

Spherotoxin 62

Synaptic failure in AD 62

Transmission of AD 63

Ubiquitin-proteasome system in pathogenesis of AD 63

Risk factors in the etiology of AD 64

Aging and developmental abnormalities of the cholinergic system 65

Cholesterol, dietary lipids, and A? 65

Exposure to magnetic fields 66

Family history of AD 66

Homocysteine and AD 66

Level of education/type of job and risk of AD 67

Metals and AD 68

Obesity 69

Proneness to psychological distress and risk of AD 70

Reduced muscle strength 70

Sleep deprivation 70

Traumatic brain injury and AD 71

Vascular risk factors for AD 72

Vitamin B12 and folate 73

AD versus non-dementing changes in the aging brain 73

AD and cognitive impairment with aging 74

Pathomechanism of memory impairment and AD 74

Concluding remarks on pathophysiology of AD 75

Genetics of AD 76

Familial AD 76

Presenilins and calcium channel leak in pathogenesis of familial AD 78

Late onset AD 78

Genomics of AD 78

Introduction to genomics 78

Genes associated with Alzheimer disease 79

AlzGene database 80

ApoE gene 81

ApoE genotype and nitric oxide 82

ApoE genotype modulates AD phenotype 82

APOE genotype and age-related myelin breakdown 83

ApoE receptor interaction with NMDA receptor 83

ApoE and ApoER2 83

ApoE receptor LR11 as regulator of A? 84

Arctic mutation 84

CALHM1 polymorphism and AD 84


CYP46 and risk for AD 85

DAPK1 gene variants and AD 85

Genetic variants associated with late-onset AD 86

LRRTM3 as a candidate gene for AD 86

OGG1 mutations associated with AD 86

SORL1 gene in AD 87

TOMM40 gene and risk of AD 87

Copy number variation (CNV) in LOAD 87

Molecular neuropathology 87

AD as a polygenic disorder 88

Proteomics of AD 88

Introduction 88

Application of proteomic technologies to study AD 88

Protein misfolding in AD 90

Common denominators of AD and prion diseases 91

Amyloid fibrils as a common feature of AD and prion diseases 91

FE65 proteins and AD 92

2. Diagnostic Procedures for Alzheimer Disease 93

Importance of the diagnosis of Alzheimer disease 93

Methods of diagnosis of AD 93

Self-administered olfactory test 94

Neuropsychological testing 94

Assessment and evaluation 95

7-minute screen 95

15-point risk index 96

Measurement of aggregation in anterior segment of the eye 96

Activities of Daily Living 96

Alzheimer Disease Cooperative Study 97

CDR-SOB score 97

Clinician's Interview-Based Impression of Change 97

Resource Utilization in Dementia Battery 97

DETECT? System 97

Electrophysiology 98

EEG-based bispectral index 98

Event-related potentials 98

Early detection of cataract associated with AD 98

Retinal imaging to detect A? deposits 99

Laboratory methods for diagnosis of AD 99

Monitoring of synthesis and clearance rates of A? in the CSF 99

Molecular diagnostics for AD 100

Genetic tests for AD 101

ApoE genotyping 101

Gene expression patterns in AD 101

Molecular fingerprinting of the immune system in AD 102

Microarray-based tests for AD 102

Monoclonal antibody-based in vitro diagnosis of AD from brain tissues 102

Biomarkers of AD 102

The ideal biomarker for AD 104

CSF biomarkers of AD 105

CSF sulfatide as a biomarker for AD 105

Glycerophosphocholine as CSF biomarker in AD 105

Protein biomarkers of AD in CSF 105

Amyloid precursor protein 107

Tau proteins in CSF 107

Tests for the detection of A? in CSF 108

Tests combining CSF tau and A? 108

Urine tests for AD 109

Blood tests for AD 109

Blood A? levels 109

Blood test for AD based on heme oxygenase-1 110

Blood test for AD based on RNA hybridization 110

GSK-3 elevation in white blood cells 111

Lymphocyte Proliferation Test 111

Protein kinase C in red blood cells 111

Tests based on protein biomarkers in blood 111

A skin test for early detection of AD 112

Nanotechnology to measure A?-derived diffusible ligands 112

Simultaneous measurement of several biomarkers for AD 113

Plasma biomarkers of drug response in AD 113

Concluding remarks about biomarkers for AD 114

Imaging in AD 114

Computed tomography 114

Magnetic resonance imaging 114

Arterial spin labeling with MRI 115

Magnetic resonance microscopy 115

Magnetic resonance spectroscopy 116

Single photon emission computed tomography and modifications 116

Positron emission tomography 117

In vivo imaging of A? deposits by PET 119

Pittsburgh compound B and PET 119

18F-AV-45 and PET 120

Florbetaben (BAY 94-9172) and PET 120

In vivo detection of A? plaques by MRI 121

Imaging agents for A? and neurofibrillary tangles 121

Targeting of a chemokine receptor as biomarker for brain imaging 122

Radioiodinated clioquinol as a biomarker for A? 122

Imaging neuroinflammation in AD 123

Preclinical diagnosis of AD 123

Meta-analysis of literature on imaging in AD 124

Alzheimer Disease Neuroimaging Initiative 124

Concluding remarks on imaging for diagnosis of AD 125

Diagnosis of MCI and prediction of AD 125

Diagnosis of MCI 125

Computer-Administered Neurophychological screen for MCI 125

Infrared eye-tracking technology to detect MCI 125

PET for detection of MCI 126

MRI for detection of MCI 126

Presymptomatic detection of AD 126

PredictAD project 127

Use of biomarkers to predict AD in patients with MCI 127

Biochemical biomarkers in CSF for prediction of AD 127

Structural MRI biomarkers for prediction of AD 128

Magnetoencephalography for detection of MCI and AD 128

Concluding remarks about prediction of AD in MCI 129

Ethical aspects of diagnostics for AD 129

Genetic testing for AD 129

Ethical issues of brain imaging in AD 130

Companies involved in diagnosis of AD 131

3. Management of Alzheimer Disease 133

Introduction 133

Cholinergic approaches 133

Mechanism of action of cholinesterase inhibitors 134

Choline and lecithin 135

Donepezil 136

Rivastigmine 137

Galantamine 138

Duration of treatment with ChE inhibitors 139

Comparative studies of ChE inhibitors 139

Donepezil versus rivastigmine 139

Donepezil versus galantamine 140

An assessment and future prospects of anticholinergic therapies 140

Neuroprotection in Alzheimer's disease 141

Memantine 142

Combination of memantine with ChE inhibitors 144

Monoamine oxidase inhibitors 145

Selegiline 145

Synaptoprotection in AD 146

Drugs for noncognitive symptoms in AD 146

Antidepressants 146

Antipsychotics 146

ChE inhibitors for behavioral and psychological disorders in AD 147

Concluding remarks and other drugs for agitation in AD 148

Sensory stimulation 148

Non-pharmacological treatments of AD 148

Management of memory loss in AD 149

Exposure to electromagnetic fields for treatment of AD 149

Application of electrical fields for improvement of cerebral function 149

High-frequency electromagnetic field treatment of AD 150

Vagal nerve stimulation 150

Cerebrospinal fluid shunting 151

Omental transposition 151

Microchip-based hippocampal prosthesis for AD 151

Nutritional therapies for AD 152

Cocktail of dietary supplements for AD 152

Docosahexaenoic acid 152

Magnesium 154

Nicotinamide for the treatment of AD 154

Omega-3 fatty acids 154

Preventing decline of mental function with aging and dementia 155

Prevention of Alzheimer disease 156

Mental training 157

Physical exercise 157

Higher level of conscientiousness and decreased risk of AD 157

Caloric restriction 158

Nutritional factors in prevention of AD 158

Grapes and red wine 158

Black and green teas 159

Caffeine 160

Drugs to prevent Alzheimer disease 160

Preimplantation genetic diagnosis of inherited Alzheimer disease 160

Presymptomatic detection of AD 161

Management of mild cognitive impairment 161

Management of Down syndrome 162

Guidelines for use of anti-dementia drugs in clinical practice 163

General care of the Alzheimer disease patients 164

Strategies for the management of Alzheimer disease 164

4. Research in Alzheimer Disease 165

Introduction 165

Animal models of Alzheimer disease 165

Lesional models 165

Cerebroventricular injection of A? in rats 165

Lentiviral vector-based models of amyloid pathology 166

AAV-mediated gene transfer to increase hippocampal A? 166

Transgenic mouse models 166

Quantitative assessment of amyloid load in transgenic models 168

In vivo magnetic resonance microimaging in transgenic models of AD 168

Transgenic model of AD with suppression of A? production 168

Transgenic AD11 anti-NGF mice 169

Genetically altered mice with deficiency of vesicular ACh transporter 169

Limitations of mouse models of Alzheimer disease 169

Cholesterol-fed rabbits as models for AD 170

Zebrafish model for AD 170

Transgenic invertebrate models of Alzheimer disease 171

Drosophila model of AD 171

Caenorhabditis elegans Alzheimer disease model 172

Cell systems for AD research 172

In vitro neuronal cell Lines 172

Single-gene expression system for use in cell culture 173

Transgenic cells 173

In silico models 174

Estimation of progression rates of Alzheimer disease 174

Clinical trial methods in Alzheimer disease 175

Molecular imaging as a guide to drug development 175

Use of MRI and PET in clinical trials 176

Cognitive-function assessment in clinical trials 176

Clinical trials in mild cognitive impairment 177

Research in AD as a basis for future therapies 177

Use of microarrays for studying pathogenesis of AD 177

Computational brain mapping in AD 177

Study of neurogenesis in AD 178

Study of 3D structure of A? 178

Solid-state NMR to study precursors of A? 178

Research in Alzheimer disease at academic centers 178

Role of NIH in AD research 179

NIH Clinical Trials Database for AD 179

Alzheimer Research Consortium 179

The National Institute on Aging and AD research 179

5. Drug Discovery & Development for Alzheimer Disease 181

Introduction 181

Categories of drugs in development for AD 181

Memory-enhancing drugs 183

Enhancing memory by drugs that block eIF2? phosphorylation 183

Drugs based on cholinergic approaches 183

AP2238 184

Butyrylcholinesterase inhibitors 184

Donepezil-tacrine hybrids 184

Drugs modulating gamma-aminobutyric acid receptors 185

Ganstigmina 185

Methanesulfonyl fluoride 185

Muscarinic receptor modulators 186

Muscarinic M1 agonists 186

Muscarinic M2 antagonists 187

Nicotine and nicotinic receptor modulators 187

Nicotine 187

Nicotinic receptor modulators 188

GTS21 189

Ispronicline 189

JWB1-84-1 190

Neuropeptide/neurotransmitters 190

Somatostatin release enhancers 190

Glutamate receptor modulators 190

Physiology and pharmacology of glutamate receptors 191

NMDA receptor ion channel complex 191

Metabotropic glutamate receptors 192

Glutamate receptor modulators as potential therapeutics for AD 193

Non-competitive NMDA modulators 194

AMPA modulators 194

Drugs affecting multiple neurotransmitters 195

Ensaculin 195

NS2330 195

RS-1259 195

Lecozotan 196

Vaccines for AD 196

Active immunization with A? 196

AN-1792 vaccine 196

Complications in clinical trials with AN-1792 197

Effects of A? vaccine on the brain 197

Strategies to avoid undesirable effect of A? vaccination 198

Passive immunization in AD with monoclonal antibodies 199

Delivery of the passive antibody directly to the brain 201

Systemic injection of MAbs to treat AD 201

Combination of A? immunotherapy and CD40-CD40L blockade 202

Shaping the immune responses elicited against A? 202

Gene vaccination 202

Modified A? nasal vaccine 203

Transdermal A? vaccination 203

Other vaccines for AD 203

Nasal vaccination with Proteosome? adjuvant 204

T-cell vaccination with glatiramer acetate adjuvant 204

Early start of immunotherapy to clear A? plaques 204

Reversal of cholinergic dysfunction by anti-A? antibody 205

Immune modulation via TRL9 to reduce A? 205

Mechanisms by which A? antibodies reduce amyloid accumulation in the brain 205

Perspectives on vaccines for AD 206

Companies involved in AD vaccines 208

Inhibition of amyloid precursor protein aggregation 208

Secretase inhibitors 208

Neuroprotection by ?-secretase cleaved APP 209

-secretase inhibitors 209

-secretase inhibitors 210

Substrate-targeting by ?-secretase modulators 211

Amyloid-derived diffusible ligands 211

GABA receptor modulation by etazolate and APP processing 211

Depletion of serum amyloid P 212

Trojan-horse approach to prevent build-up of A? aggregates 212

Drugs that inhibit the formation of A? 213

22R-hydroxycholesterol 213

Acylaminopyrazole 213

Chelation therapy for AD 214

Clioquinol and PBT2 214

Copper chelation by FKBP52 215

Zinc chelation from amyloid plaques 215

Next generation multifunctional chelating agents for AD 216

Tetrahydrocannabinol 216

NSAIDs 217

Flurbiprofen analogs with A?42-lowering action 218

Nitric oxide-donating NSAIDs 218

In vivo demonstration of the effects of NSAIDs on brain in AD 219

Imatinib mesylate 219

Laminin 219

Paclitaxel 220

Phenserine 220

Tolserine 221

Platinum-based inhibitors of A? 221

Heparin and its derivatives 221

A reassessment of the role of heparin in AD 221

Enoxaparin 222

Heparan sulfate 222

Scyllo-cyclohexanehexol 222

Ubiquitin C-terminal hydrolase L1 222

Drugs to prevent the formation of NFTs 223

Tau suppression 223

ApoE4 as a therapeutic target in AD 224

Strategies to enhance clearance of A? 224

Removal of A? deposits by nanotechnology 225

Enhanced PKC? activity promotes clearance of A? 225

Role of matrix metalloproteinases in clearance of A? 226

Small molecule DAPH for clearance of amyloid 226

Clearance of A? across the blood-brain barrier 226

Therapeutics to reverse cerebral A? deposits 227

4,5-dianilinophthalimide for disruption of A?1-42 fibrils 227

ABCA1 overexpression to lower amyloid deposits 227

-sheet breakers 228

Blocking ApoE/A? interaction to reduce A? plaques 228

Inhibitors of A? dehydrogenase 228

Intravenous immune globulin 229

Meptides 230

SAN-61 for cleavage of fibril and soluble amyloid 230

Serum amyloid P component depletion 231

Companies developing A?-directed therapeutics for AD 231

Antiinflammatory and antimicrobial drugs 232

Dapsone 232

Antimicrobial drugs against C. pneumoniae 233

PPAR-gamma agonists 233

Inhibitors of neuroinflammation 234

Cyclophosphamide 234

Etanercept 234

MW01-5-188WH 235

VP015 235

Antidiabetic drugs 235

Rosiglitazone 236

Pioglitazone 236

Nootropics 236

Acetyl-L-carnitine 237

Cerebrolysin 237

Ergot derivatives 237

Lisuride 238

Dihydroergocryptine 238

Neuroprotective effect drugs not primarily developed for AD 238

Antihypertensive drugs 239

Angiotensin-converting enzyme inhibitors 239

Angiotensin receptor blockers 239

Dimebolin 240

Drugs acting on estrogen receptors 240

Estrogen 241

Raloxifene 241

Neurosteroids 242

Pregnenolone sulfate 242

Dehydroepiandrosterone 242

Lithium 243

MAO-B inhibitors 243

Ladostigil tartrate 243

Memoquin 244

Methylene blue 244

Nimodipine 245

Rapamycin 245

Testosterone 245

Valproic acid 246

Future prospects of neuroprotection in AD 247

Targeting Cdk5 pathway 247

Antioxidants 248

Colostrinin 248

Curcumin 248

Melatonin 249

Synthetic catalytic scavengers 249

Dehydroascorbic acid 250

Omega-3 fatty acids 250

Vitamins 250

Vitamin E as antioxidant 251

Vitamins to lower homocysteine 251

Folic acid 251

Aminopyridazines 251

Nanobody-based drugs for AD 252

Nitric oxide based therapeutics for AD 252

Nitric oxide mimetics 252

iNOS inhibitors for AD 253

Novel drugs for AD from natural resources 253

Berberine chloride 254

Centella asiatica 254

Ginko biloba 255

Huperzine-A 256

Hyperforin 256

Melissa officinalis 256

Nostocarboline derived from cyanobacteria 257

PTI-00703 257

Salvia 257

Securinega suffruticosa 257

Withania somnifera 258

ZT-1 258

Cholesterol and AD 258

Role of statins in reducing the risk of Alzheimer disease 259

Neuroprotective effect of statins unrelated to cholesterol lowering 260

ACAT inhibitors 260

Role of gene for cholesterol ester transfer protein 261

Cholesterol 24S-hydroxylase as a drug target for AD 261

Selectively increase of ApoA-I production 261

Neurotrophic factors 262

Activity-dependent neuroprotective protein 262

Brain derived neurotrophic factor 262

Insulin-like growth factor-1 262

Nerve growth factor 263

Neotrofin (AIT-082) 264

Limitations of the use of NTFs for AD 264

Role of serotonin modulators in AD 265

Xaliproden 265

5-HT1A receptor antagonists 265

5-HT6 antagonists 265

5-HT4 receptor agonists 266

PRX-03140 266

Cell therapy for AD 266

Stem cell transplantation for AD 267

Potential benefits of grafting NSCs in AD 267

NSCs improve cognition in AD via BDNF 267

Drugs for enhancing neuronal differentiation of implanted NSCs 268

Implantation of encapsulated cells for delivering NGF 268

Gene therapy for AD 268

ApoE gene therapy 268

Humanin gene therapy 268

Neprilysin gene therapy 269

NGF gene therapy 269

Targeting plasminogen activator inhibitor type-1 gene 270

Antisense approaches to AD 270

RNAi approaches to AD 271

Combined therapeutic approaches to AD 272

Drug delivery for Alzheimer disease 272

Delivery of thyrotropin-releasing hormone analogs by molecular packaging 273

Nanoparticle-based drug delivery for Alzheimer's disease 273

Transdermal drug delivery in Alzheimer's disease 274

Transdermal rivastigmine 274

Intranasal delivery of therapeutics for AD 274

Intranasal delivery of tacrine 274

Intranasal delivery of nerve growth factor to the brain 275

Circadian rhythms and timing of cholinesterase inhibitor therapy 275

Clinical trials for AD 275

Drugs for AD that were discontinued in clinical trials 280

Evaluation of clinical trials of AD 282

Monitoring of cognitive function during clinical trials 282

Drug discovery for AD 282

Drugs acting on signaling pathways 282

Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 282

Drugs to reverse inhibition of the PKA/CREB pathway in AD 283

Inhibition of the CD40 signaling pathway 283

JNK pathway as a target 284

Mitogen-activated protein kinase pathway as target 284

Protein kinase C activators 285

Electrophysiological detection of drug target for neuroprotection in early AD 285

Genomics-based drug discovery 285

High through screening for AD drug candidates 285

Proteomics and drug discovery for AD 286

Small molecule compounds binding to neurotrophin receptor p75NTR 287

Targeting Vav in tyrosine kinase signaling pathway 288

Novels targets/receptors for AD drug discovery 288

Activation of cerebral Rho GTPases 288

Activators of insulin-degrading enzyme 288

Blockade of TGF-?-Smad2/3 signaling in peripheral macrophages 289

Blockers of A? calcium channel 289

Casein kinase 1 289

Cyclin-dependent kinase-5 290

Heat shock protein 90 inhibitors 290

Histone deacetylase 1 290

Inactivation of aph-1 and pen-2 reduces APP cleavage 291

NF-?B inhibitors 291

Kinases and phosphatases as targets for AD therapeutics 291

Phosphodiesterase inhibitors 292

Pin 1 as a target in AD 292

Protein phosphatase 5 as a neuroprotective in AD 293

Src homology-containing protein-1 inhibitors 293

Targeting GABAergic system 293

Pharmacogenomics of Alzheimer disease 294

Personalized therapy of AD 294

Genotyping and AD therapeutics 294

Biomarkers of AD/companion diagnostics for cholinesterase inhibitors 295

Regulatory aspects of drug development for AD 296

EMEA guidelines for drug development for AD 296

Concluding remarks and future prospects of drugs for AD 296

6. Markets & Finances of AD Care 299

Introduction 299

Pharmacoeconomics of treatment of AD 299

Quality of Life in relation to economics of AD 299

Costs associated with Alzheimer disease 299

Pharmacoeconomics of donepezil 300

Pharmacoeconomics studies using rivastigmine 300

Pharmacoenonomics studies using galantamine 301

A comparison of pharmacoenonomics outcomes with different ChE inhibitors 301

Pharmacoenonomics studies using memantine 302

Patterns of AD care in major markets 302

Care of AD patients in the US 302

Cost of care 302

Medicare and AD 303

Patterns of practice in AD care 304

Opinions of physicians' organizations on drugs for dementia 304

Care of AD patients in the UK 305

Cost of care 305

Patterns of practice in AD care 305

Retraction of NICE recommendations to NHS 306

Care of AD patients in Germany 307

Care of AD patients in France 307

Care of AD patients in Italy 308

Care of AD patients in Spain 308

Care of AD patients in Japan 308

Markets for AD diagnostics 309

Markets for AD therapeutics 309

Geographical markets for AD 309

Markets for currently approved drugs for AD 310

Markets for generic AD drugs 310

Future growth of AD market 311

Statins 311

Limitations of AD drug development by the biotechnology industry 311

Unmet needs in the management of AD 312

Drivers of AD markets 313

Increase of the aged populations 314

Increase in the number of approved drugs for AD 314

Limitations of the current therapies 314

Improvements in diagnosis 314

Increasing awareness of the disease 315

7. Companies 317

Introduction 317

Profiles of companies 317

Collaborations 462

8. References 467


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 24

Table 1 4: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease 29

Table 1 5: Relation of mutations in amyloid precursor protein to CNS disorders 36

Table 1 6: Risk factors for Alzheimer's disease 64

Table 1 7: Genes linked to AD 79

Table 1 8: Abnormalities of expression of brain proteins in Down's syndrome and AD 89

Table 2 1: Classification of methods of diagnosis of Alzheimer disease 93

Table 2 2: Neuropsychological test batteries and scales for Alzheimer's disease 94

Table 2 3: Available molecular diagnostic tests for Alzheimer disease 100

Table 2 4: Classification of biomarkers of AD in blood and CSF 103

Table 2 5: Characteristics of an ideal biomarker for Alzheimer disease 104

Table 2 6: Companies involved in the diagnosis of Alzheimer disease 131

Table 3 1: Classification of treatments for Alzheimer disease 133

Table 3 2: Cholinergic approaches used in the treatment of Alzheimer disease 134

Table 3 3: Categories of neuroprotective agents for Alzheimer disease 141

Table 3 4: Strategies for prevention of Alzheimer disease 156

Table 3 5: Guidelines for the treatment of dementia 163

Table 4 1: Transgenic mouse models of Alzheimer disease 166

Table 5 1: Classification of therapies in development for Alzheimer disease 181

Table 5 2: Drugs for AD targeting nACh receptors 188

Table 5 3: Ionotropic glutamate receptors 191

Table 5 4: Classification of mGluRs 191

Table 5 5: Glutamate receptor modulators as potential therapeutic agents in AD 193

Table 5 6: Companies involved in developing vaccines for AD 208

Table 5 7: Companies developing A?-directed therapeutics for AD 231

Table 5 8: Innovative neuroprotective approaches for Alzheimer disease 238

Table 5 9: Herbal therapies for AD 253

Table 5 10: Novel drug delivery methods for Alzheimer disease therapies 272

Table 5 11: Clinical trials in Alzheimer disease 275

Table 5 12: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 280

Table 6 1: Direct and indirect costs associated with Alzheimer disease 300

Table 6 2: Prevalence of AD in major markets 2009-2019 309

Table 6 3: AD market values from 2009-2019 in the seven major world markets 310

Table 6 4: Markets for currently approved AD drugs 2009-2019 310

Table 6 5: Potential markets for drugs in development 2009-2019 311

Table 6 6: Limitations of AD drug discovery and development by the biotechnology industry 312

Table 6 7: Factors that drive AD markets 313

Table 7 1: Major players in Alzheimer's disease therapeutics 317

Table 7 2: Collaborations relevant to Alzheimer disease 462


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. 30

Figure 1 2: Prevalence of different types of dementia 31

Figure 1 3: Mechanisms of A? clearance 43

Figure 1 4: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease 58

Figure 1 5: Oxidative stress and Alzheimer disease 60

Figure 1 6: Role of proteosome inhibition in A? generation and neurodegeneration 64

Figure 1 7: Pathomechanism of AD 76

Figure 3 1: Metabolism of acetylcholine 135

Figure 3 2: Neuroprotective effective of galantamine in AD 139

Figure 3 3: Strategies for the management of Alzheimer disease 164

Figure 5 1: NMDA receptor ion channel complex. 192

Figure 5 2: Neurotoxicity due to misfolding of A?1-42 227

Figure 5 3: Role of proteomics in drug discovery and development for Alzheimer disease 286

Figure 6 1: Unmet needs in the management of Alzheimer disease 313

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Nicolas Bombourg



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