Reportlinker Adds Alzheimer Disease - New Drugs, Markets and Companies

NEW YORK, Sept. 7 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:

Alzheimer disease - new drugs, markets and companies

http://www.reportlinker.com/p0203533/Alzheimer-disease---new-drugs-markets-and-companies.html

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. Over 174 clinical trials are listed, of which 129 are still in progress and 45 were discontinued for various reasons.

Alzheimer's disease market in the seven major markets is analyzed for the year 2009. 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 2019. 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 105 collaborations. The bibliography contains over 600 publications that are cited in the report. The report is supplemented with 43 tables and 14 figures.

TABLE OF CONTENTS

0. Executive Summary 15

1. Clinical Features, Epidemiology and Pathology . 17

Introduction .... 17

Historical aspects .. 17

Clinical features of Alzheimer disease .. 18

Seven stages of Alzheimer disease . 20

AD as a terminal illness .... 22

Detection of AD in the preclinical phase 22

Differentiation of AD from other dementias . 22

Differentiation of AD from non-dementing disorders . 23

Cerebral insufficiency and AD .. 24

Memory deficits and preclinical AD . 24

Mild cognitive impairment . 25

Diagnostic criteria of AD ... 27

Epidemiology ... 28

Epidemiology of aging 28

Epidemiology of dementia . 29

Epidemiology of AD .... 30

Prevalence of AD according to age .. 31

Mortality in AD 31

Pathophysiology of AD . 31

Cerebral atrophy and neuronal loss 31

Neuritic plaques and neurofibrillary tangles . 32

Sp proteins as markers of neuronal death in AD . 32

Role of tau in the pathogenesis of AD ... 33

Amyloid precursor protein . 34

Relation of APP mutations to CNS disorders .. 34

Relation of APP to A? deposits and pathogenesis of AD .... 35

APP intracellular domain .... 36

Role of secretases in amyloid cascade ... 36

Role of exosomal proteins .. 38

Role of nicastrin .... 38

Neurotixicity of A? deposits ..... 39

Relation of A? deposits to synaptic activity ... 39

Dysfunction of TGF-? signaling accelerates A? deposition . 39

Role of TMP21 in presenilin complexes and A? formation .. 40

Role of A? dimers in the pathogenesis of AD . 40

Structure–neurotoxicity relationships of A? oligomers 41

A? deposit and clearance .. 41

Impairment of mitochondrial energy metabolism ..... 42

A?-binding alcohol dehydrogenase links AD to mitochondrial toxicity ... 43

Neural thread protein . 43

Loss of synaptic proteins ... 43

AD and Down syndrome ..... 44

Overlapping pathologies of AD and Parkinson disease 44

AD and age-related macular degeneration .... 45

Myelin hypothesis of AD ..... 45

Blood-brain barrier in AD ... 45

Blood vessel damage in AD 47

Loss of serotonin 1A receptors in the brain ... 47

Factors in pathogenesis of AD .. 47

Astrocytes and AD . 47

Axonal transport failure in AD ... 48

Cell-cycle hypothesis ... 48

Chronic heart failure link with AD .... 48

Creatine and AD ... 49

Disturbances of interaction of nervous system proteins .... 49

DENN/MADD expression and enhanced pro-apoptotic signaling in AD .. 49

Gonadotrophins and AD ..... 49

Glutamate transport dysfunction in AD .. 50

Innate immune system and AD . 51

Insulin, diabetes and AD .... 51

Mechanisms underlying cognitive deficits in AD ... 52

Monoamine oxidase and AD 53

Neuroinflammation and AD 53

Neurotransmitter deficits ... 54

Neurotrophic factors .... 54 - 4 -

NF-?B signaling and the pathogenesis of neurodegeneration ... 55

Nitric oxide and AD ..... 55

Nogo receptor pathway 58

Oxidative stress and AD ..... 58

Prostaglandins and AD . 60

Quinolinic acid and AD . 60

Retromer deficiency .... 60

Serotonin and AD .. 61

Spherotoxin ... 61

Synaptic failure in AD .. 61

Transmission of AD ..... 62

Ubiquitin-proteasome system in pathogenesis of AD .. 62

Risk factors in the etiology of AD ... 63

Aging and developmental abnormalities of the cholinergic system . 64

Cholesterol, dietary lipids, and A? ... 64

Exposure to magnetic fields 65

Family history of AD .... 65

Homocysteine and AD .. 65

Level of education/type of job and risk of AD 66

Metals and AD 67

Obesity .... 68

Proneness to psychological distress and risk of AD .... 69

Reduced muscle strength ... 69

Sleep deprivation .. 69

Traumatic brain injury and AD .. 70

Vascular risk factors for AD 71

Vitamin B12 and folate 72

AD versus non-dementing changes in the aging brain ..... 72

AD and cognitive impairment with aging ..... 73

Pathomechanism of memory impairment and AD ..... 73

Concluding remarks on pathophysiology of AD ... 74

Genetics of AD . 75

Familial AD .... 75

Presenilins and calcium channel leak in pathogenesis of familial AD ..... 77

Late onset AD 77

Genomics of AD 77

Introduction to genomics .. 77

Genes associated with Alzheimer disease .... 78

AlzGene database . 79

ApoE gene ..... 80

ApoE genotype and nitric oxide . 81

ApoE genotype modulates AD phenotype ..... 81

APOE genotype and age-related myelin breakdown ... 82

ApoE receptor interaction with NMDA receptor .... 82

ApoE and ApoER2 . 82

ApoE receptor LR11 as regulator of A? ... 83

Arctic mutation ..... 83

CALHM1 polymorphism and AD . 83

CLU, CRI and PICALM .. 84

CYP46 and risk for AD . 84

DAPK1 gene variants and AD .... 84

Genetic variants associated with late-onset AD ... 85

LRRTM3 as a candidate gene for AD 85

OGG1 mutations associated with AD 85

SORL1 gene in AD . 86

TOMM40 gene and risk of AD .... 86

Copy number variation (CNV) in LOAD .. 86

Molecular neuropathology . 86

AD as a polygenic disorder 87

Proteomics of AD ... 87

Introduction .. 87

Application of proteomic technologies to study AD .... 87

Protein misfolding in AD .... 89

Common denominators of AD and prion diseases ..... 90

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

FE65 proteins and AD . 91

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 - 5 -

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

Correlation of electrical activity of the brain with cognition ..... 98

Early detection of cataract associated with AD ... 99

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 .... 102

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 .... 103

Biomarkers of AD ..... 103

The ideal biomarker for AD .... 105

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 ... 106

Amyloid precursor protein 107

Tau proteins in CSF ... 108

Tests for the detection of A? in CSF ..... 108

Tests combining CSF tau and A? ... 109

Urine tests for AD .... 109

Blood tests for AD .... 110

Blood A? levels ... 110

Blood test for AD based on heme oxygenase-1 . 110

Blood test for AD based on RNA hybridization ... 111

GSK-3 elevation in white blood cells .... 111

Lymphocyte Proliferation Test . 111

Protein kinase C in red blood cells . 112

Tests based on protein biomarkers in blood 112

A skin test for early detection of AD ... 112

Nanotechnology to measure A?-derived diffusible ligands .... 113

Simultaneous measurement of several biomarkers for AD ... 113

Plasma biomarkers of drug response in AD 114

Concluding remarks about biomarkers for AD .. 114

Imaging in AD 115

Computed tomography ... 115

Magnetic resonance imaging . 115

Arterial spin labeling with MRI 116

Magnetic resonance microscopy .... 116

Magnetic resonance spectroscopy . 116

Single photon emission computed tomography and modifications ..... 117

Positron emission tomography ..... 117

In vivo imaging of A? deposits by PET 119

Pittsburgh compound B and PET ... 119

18F-AV-45 and PET .... 121

Florbetaben (BAY 94-9172) and PET .... 121

In vivo detection of A? plaques by MRI ..... 121

Imaging agents for A? and neurofibrillary tangles .. 122

Targeting of a chemokine receptor as biomarker for brain imaging ... 122

Radioiodinated clioquinol as a biomarker for A? ..... 123

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 - 6 -

Diagnosis of MCI and prediction of AD ..... 125

Diagnosis of MCI 125

Computer-Administered Neurophychological screen for MCI . 126

Infrared eye-tracking technology to detect MCI 126

PET for detection of MCI .. 126

MRI for detection of MCI .. 127

Presymptomatic detection of AD .. 127

PredictAD project ..... 128

Use of biomarkers to predict AD in patients with MCI ... 128

Biochemical biomarkers in CSF for prediction of AD . 128

Structural MRI biomarkers for prediction of AD . 128

Magnetoencephalography for detection of MCI and AD .. 129

Concluding remarks about prediction of AD in MCI . 130

Ethical aspects of diagnostics for AD . 130

Genetic testing for AD .... 130

Ethical issues of brain imaging in AD .. 131

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 - 7 -

Management of mild cognitive impairment .... 161

Management of Down syndrome .. 162

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

Donepezil and/or memantine . 164

General care of the Alzheimer disease patients ... 164

Strategies for the management of Alzheimer disease 164

4. Research in Alzheimer Disease ..... 167

Introduction .. 167

Animal models of Alzheimer disease .. 167

Lesional models . 167

Cerebroventricular injection of A? in rats .... 167

Lentiviral vector-based models of amyloid pathology ..... 168

AAV-mediated gene transfer to increase hippocampal A? ..... 168

Transgenic mouse models ..... 168

Quantitative assessment of amyloid load in transgenic models .... 170

In vivo magnetic resonance microimaging in transgenic models of AD ..... 170

Transgenic model of AD with suppression of A? production ... 170

Transgenic AD11 anti-NGF mice .... 171

Genetically altered mice with deficiency of vesicular ACh transporter . 171

Limitations of mouse models of Alzheimer disease .. 171

Cholesterol-fed rabbits as models for AD ... 172

Zebrafish model for AD ... 172

Transgenic invertebrate models of Alzheimer disease ... 173

Drosophila model of AD ... 173

Caenorhabditis elegans Alzheimer disease model .... 174

Cell systems for AD research . 174

In vitro neuronal cell Lines .... 174

Single-gene expression system for use in cell culture ... 175

Transgenic cells . 175

In silico models . 176

Estimation of progression rates of Alzheimer disease 176

Clinical trial methods in Alzheimer disease .... 177

Molecular imaging as a guide to drug development 177

Use of MRI and PET in clinical trials ..... 178

Cognitive-function assessment in clinical trials . 178

Clinical trials in mild cognitive impairment . 179

Research in AD as a basis for future therapies ..... 179

Use of microarrays for studying pathogenesis of AD ..... 179

Computational brain mapping in AD ... 179

Study of neurogenesis in AD . 180

Study of 3D structure of A? ... 180

Solid-state NMR to study precursors of A? . 180

Research in Alzheimer disease at academic centers .. 180

Role of NIH in AD research .... 181

NIH Clinical Trials Database for AD ..... 181

Alzheimer Research Consortium ... 181

The National Institute on Aging and AD research ... 181

5. Drug Discovery & Development for Alzheimer Disease ..... 183

Introduction .. 183

Categories of drugs in development for AD .... 183

Memory-enhancing drugs 185

Enhancing memory by drugs that block eIF2? phosphorylation .. 185

Drugs based on cholinergic approaches ... 185

AP2238 . 186

Butyrylcholinesterase inhibitors ... 186

Donepezil-tacrine hybrids 186

Drugs modulating gamma-aminobutyric acid receptors . 187

Ganstigmina 187

Methanesulfonyl fluoride . 187

Muscarinic receptor modulators ... 188

Muscarinic M1 agonists .... 188

Muscarinic M2 antagonists 189

Nicotine and nicotinic receptor modulators 189

Nicotine . 189

Nicotinic receptor modulators . 190

GTS21 ... 191

Ispronicline .. 191

JWB1-84-1 ... 192

Neuropeptide/neurotransmitters 192 - 8 -

Somatostatin release enhancers .. 192

Glutamate receptor modulators ... 192

Physiology and pharmacology of glutamate receptors ... 193

NMDA receptor ion channel complex ... 193

Metabotropic glutamate receptors 194

Glutamate receptor modulators as potential therapeutics for AD 195

Non-competitive NMDA modulators ..... 196

AMPA modulators 196

Drugs affecting multiple neurotransmitters ... 197

Ensaculin .... 197

NS2330 197

RS-1259 ..... 197

Lecozotan ... 198

Vaccines for AD .... 198

Active immunization with A? .. 198

AN-1792 vaccine . 198

Complications in clinical trials with AN-1792 ..... 199

Effects of A? vaccine on the brain .. 199

Strategies to avoid undesirable effect of A? vaccination 200

Passive immunization in AD with monoclonal antibodies . 201

Delivery of the passive antibody directly to the brain ..... 203

Systemic injection of MAbs to treat AD 203

Combination of A? immunotherapy and CD40-CD40L blockade ... 204

Shaping the immune responses elicited against A? .. 204

Gene vaccination 204

Modified A? nasal vaccine . 205

Transdermal A? vaccination .... 205

Other vaccines for AD ..... 205

Nasal vaccination with Proteosome? adjuvant .. 206

T-cell vaccination with glatiramer acetate adjuvant . 206

Early start of immunotherapy to clear A? plaques .. 206

Reversal of cholinergic dysfunction by anti-A? antibody 207

Immune modulation via TRL9 to reduce A? ..... 207

Mechanisms by which A? antibodies reduce amyloid accumulation in the brain .... 207

Perspectives on vaccines for AD ... 208

Companies involved in AD vaccines .... 210

Inhibition of amyloid precursor protein aggregation . 210

Secretase modulators ..... 211

Neuroprotection by ?-secretase cleaved APP .... 211

Inhibitors of ?-secretase .. 212

Inhibitors of ?-secretase ... 213

Amyloid-derived diffusible ligands 214

GABA receptor modulation by etazolate and APP processing 214

Depletion of serum amyloid P 214

Trojan-horse approach to prevent build-up of A? aggregates ..... 215

Drugs that inhibit the formation of A? 215

22R-hydroxycholesterol .. 215

Acylaminopyrazole ... 216

Chelation therapy for AD . 216

Clioquinol and PBT2 .. 216

Copper chelation by FKBP52 ... 218

Zinc chelation from amyloid plaques .... 218

Next generation multifunctional chelating agents for AD 218

Tetrahydrocannabinol ..... 219

NSAIDs . 219

Flurbiprofen analogs with A?42-lowering action . 220

Nitric oxide-donating NSAIDs . 221

In vivo demonstration of the effects of NSAIDs on brain in AD .... 221

Imatinib mesylate .... 222

Laminin 222

Paclitaxel .... 222

Phenserine .. 222

Tolserine 223

Platinum-based inhibitors of A? .... 223

Heparin and its derivatives .... 224

A reassessment of the role of heparin in AD ..... 224

Enoxaparin ... 224

Heparan sulfate .. 224

Scyllo-cyclohexanehexol . 225

Ubiquitin C-terminal hydrolase L1 225

Drugs to prevent the formation of NFTs ... 225 - 9 -

Tau suppression ... 226

ApoE4 as a therapeutic target in AD .. 227

Strategies to enhance clearance of A? ..... 227

Removal of A? deposits by nanotechnology ..... 227

Enhanced PKC? activity promotes clearance of A? .. 228

Role of matrix metalloproteinases in clearance of A? .... 228

Small molecule DAPH for clearance of amyloid . 229

Clearance of A? across the blood-brain barrier . 229

Therapeutics to reverse cerebral A? deposits . 229

4,5-dianilinophthalimide for disruption of A?1-42 fibrils 229

ABCA1 overexpression to lower amyloid deposits ... 230

Beta-sheet breakers . 230

Blocking ApoE/A? interaction to reduce A? plaques . 231

Inhibitors of A? dehydrogenase .... 231

Intravenous immune globulin 231

Meptides ..... 232

SAN-61 for cleavage of fibril and soluble amyloid ... 233

Serum amyloid P component depletion ..... 233

Companies developing A?-directed therapeutics for AD ... 233

Antiinflammatory and antimicrobial drugs ..... 235

Dapsone ..... 235

Antimicrobial drugs against C. pneumoniae ..... 236

PPAR-gamma agonists .... 236

Inhibitors of neuroinflammation ... 236

Cyclophosphamide .... 236

Etanercept ... 237

MW01-5-188WH . 237

VP015 ... 238

Antidiabetic drugs 238

Rosiglitazone ..... 238

Pioglitazone . 239

Nootropics ..... 239

Acetyl-L-carnitine ..... 239

Cerebrolysin 240

Ergot derivatives 240

Lisuride . 240

Dihydroergocryptine .. 241

Neuroprotective effect drugs not primarily developed for AD 241

Antihypertensive drugs ... 242

Angiotensin-converting enzyme inhibitors .. 242

Angiotensin receptor blockers . 242

Dimebolin ... 242

Drugs acting on estrogen receptors .... 243

Estrogen 243

Raloxifene .... 244

Neurosteroids .... 244

Pregnenolone sulfate . 245

Dehydroepiandrosterone .. 245

Lithium . 245

MAO-B inhibitors 246

Ladostigil tartrate ..... 246

Memoquin .... 246

Methylene blue .. 247

Nimodipine .. 247

Rapamycin .. 248

Testosterone ..... 248

Valproic acid 249

Future prospects of neuroprotection in AD . 249

Targeting Cdk5 pathway .. 250

Antioxidants .. 250

Colostrinin .. 251

Curcumin .... 251

Melatonin .... 252

Synthetic catalytic scavengers ..... 252

Dehydroascorbic acid ..... 252

Omega-3 fatty acids . 253

Vitamins .. 253

Vitamin E as antioxidant . 253

Vitamins to lower homocysteine ... 253

Folic acid .... 254

Aminopyridazines 254 - 10 -

Nanobody-based drugs for AD ..... 254

Nitric oxide based therapeutics for AD ..... 255

Nitric oxide mimetics 255

iNOS inhibitors for AD ..... 255

Novel drugs for AD from natural resources .... 256

Berberine chloride .... 256

Centella asiatica 257

Ginko biloba 257

Huperzine-A 258

Hyperforin ... 259

Melissa officinalis ..... 259

Nostocarboline derived from cyanobacteria ..... 259

PTI-00703 ... 260

Salvia ... 260

Securinega suffruticosa ... 260

Withania somnifera .. 260

ZT-1 ..... 261

Cholesterol and AD .... 261

Role of statins in reducing the risk of Alzheimer disease ..... 261

Neuroprotective effect of statins unrelated to cholesterol lowering ... 262

ACAT inhibitors .. 263

Role of gene for cholesterol ester transfer protein .. 263

Cholesterol 24S-hydroxylase as a drug target for AD .... 264

Selectively increase of ApoA-I production .. 264

Neurotrophic factors .. 264

Activity-dependent neuroprotective protein ..... 264

Brain derived neurotrophic factor . 265

Insulin-like growth factor-1 ... 265

Nerve growth factor . 266

Neotrofin (AIT-082) .. 267

Limitations of the use of NTFs for AD .. 267

Role of serotonin modulators in AD ... 267

Xaliproden .. 268

5-HT1A receptor antagonists .. 268

5-HT6 antagonists .... 268

5-HT4 receptor agonists .. 268

PRX-03140 ... 269

Cell therapy for AD ..... 269

Stem cell transplantation for AD .. 270

Potential benefits of grafting NSCs in AD .... 270

NSCs improve cognition in AD via BDNF ..... 270

Drugs for enhancing neuronal differentiation of implanted NSCs . 270

Implantation of encapsulated cells for delivering NGF ... 271

Gene therapy for AD .. 271

ApoE gene therapy ... 271

Humanin gene therapy ... 271

Neprilysin gene therapy .. 272

NGF gene therapy .... 272

Targeting plasminogen activator inhibitor type-1 gene .. 273

Antisense approaches to AD .. 273

RNAi approaches to AD .... 274

Combined therapeutic approaches to AD . 275

Drug delivery for Alzheimer disease .. 275

Delivery of thyrotropin-releasing hormone analogs by molecular packaging ... 276

Nanoparticle-based drug delivery for Alzheimer's disease .... 276

Transdermal drug delivery in Alzheimer's disease ... 276

Transdermal rivastigmine . 277

Intranasal delivery of therapeutics for AD . 277

Intranasal delivery of tacrine .. 277

Intranasal delivery of nerve growth factor to the brain ... 277

Circadian rhythms and timing of cholinesterase inhibitor therapy ..... 278

Clinical trials for AD ... 278

Drugs for AD that were discontinued in clinical trials .... 282

Evaluation of clinical trials of AD .. 285

Monitoring of cognitive function during clinical trials ..... 285

Drug discovery for AD 286

Drugs acting on signaling pathways ... 286

Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 . 286

Drugs to reverse inhibition of the PKA/CREB pathway in AD . 286

Inhibition of the CD40 signaling pathway ... 287

JNK pathway as a target .. 287 - 11 -

Mitogen-activated protein kinase pathway as target 287

Protein kinase C activators ..... 288

Electrophysiological detection of drug target for neuroprotection in early AD . 288

Genomics-based drug discovery ... 289

High through screening for AD drug candidates ..... 289

Proteomics and drug discovery for AD 290

Small molecule compounds binding to neurotrophin receptor p75NTR ..... 290

Targeting Vav in tyrosine kinase signaling pathway . 291

Novels targets/receptors for AD drug discovery ..... 291

Activation of cerebral Rho GTPases ..... 292

Activators of insulin-degrading enzyme 292

Blockade o

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