Alzheimer Disease

New Drugs, Markets & Companies

by
Prof. K. K. Jain
MD, FRACS, FFPM

Jain PharmaBiotech
Basel, Switzerland

July 2012

A Jain PharmaBiotech Report

AUTHOR'S

BIOGRAPHY

Professor K. K. Jain is a neurologist/neurosurgeon by training and has been working in
the biotechnology/biopharmaceuticals industry for several years. He received graduate
training in both Europe and US, held academic positions in several countries and is a
Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of
UK. Currently he is CEO and consultant at Jain PharmaBiotech. Prof. Jain is the author of
440 publications including 21 books (4 as editor) and 50 special reports, which have
covered important areas in biotechnology, gene therapy and biopharmaceuticals. Recent
books relevant to the nervous system include “Handbook of Neuroprotection” (Springer,
2011) and “Application of Biotechnology in Neurology” (Springer, 2012).

July 2012
Copyright  2012 by
Jain PharmaBiotech
Bläsiring 7
CH-4057 Basel
Switzerland
Tel & Fax:
Email:
Web site:

+4161-6924461
info@pharmabiotech.ch
http://pharmabiotech.ch/

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, or otherwise without the prior written
permission of the Publisher. This report may not be lent, resold or otherwise traded in any manner without the
consent of the Publisher. While all reasonable steps have been taken to ensure the accuracy of the information
presented, the Publisher cannot accept responsibility for inadvertent errors or omissions.

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TABLE

OF

CONTENTS

0. Executive Summary .............................................................................. 17
1. Clinical Features, Epidemiology and Pathology ..................................... 19
Introduction....................................................................................................................... 19
Historical aspects............................................................................................................... 19
Clinical features of Alzheimer disease ................................................................................ 20
Seven stages of Alzheimer disease ..................................................................................... 22
AD as a terminal illness .................................................................................................... 24
Detection of AD in the preclinical phase .............................................................................. 24
Differentiation of AD from other dementias ......................................................................... 24
Differentiation of AD from non-dementing disorders ............................................................. 25
Cerebral insufficiency and AD ............................................................................................ 26
Memory deficits and preclinical AD ..................................................................................... 26
Mild cognitive impairment ................................................................................................. 27
Evolution of diagnostic criteria of AD .................................................................................. 29
Revised criteria for the clinical diagnosis of AD .................................................................... 30
Epidemiology ..................................................................................................................... 31
Epidemiology of aging ...................................................................................................... 31
Epidemiology of dementia ................................................................................................. 34
Epidemiology of AD .......................................................................................................... 34
Prevalence of AD according to age ................................................................................ 35
Mortality in AD ............................................................................................................ 35
Pathophysiology of AD ....................................................................................................... 36
Cerebral atrophy and neuronal loss .................................................................................... 36
Neuritic plaques and neurofibrillary tangles ......................................................................... 36
Sp proteins as markers of neuronal death in AD................................................................... 37
Role of tau in the pathogenesis of AD ................................................................................. 37
RNA-binding proteins and AD ............................................................................................ 38
Amyloid precursor protein ................................................................................................. 39
Relation of APP mutations to CNS disorders .................................................................... 39
Relation of APP to Aβ deposits and pathogenesis of AD .................................................... 40
APP intracellular domain .............................................................................................. 41
Role of secretases in amyloid cascade............................................................................ 41
Role of exosomal proteins ............................................................................................ 43
Role of nicastrin .......................................................................................................... 43
Neurotixicity of Aβ deposits ............................................................................................... 44
Relation of Aβ deposits to synaptic activity ..................................................................... 44
Dysfunction of TGF-β signaling accelerates Aβ deposition ................................................. 44
Role of TMP21 in presenilin complexes and Aβ formation .................................................. 45
Role of Aβ dimers in the pathogenesis of AD ................................................................... 45
Structure–neurotoxicity relationships of Aβ oligomers ...................................................... 46
Aβ deposit and clearance .................................................................................................. 46
Impairment of mitochondrial energy metabolism ................................................................. 47
Aβ-binding alcohol dehydrogenase links AD to mitochondrial toxicity ................................. 47
Neural thread protein ....................................................................................................... 48
Loss of synaptic proteins ................................................................................................... 48
AD and Down syndrome ............................................................................................... 48
Overlapping pathologies of AD and Parkinson disease ...................................................... 49
AD and age-related macular degeneration ...................................................................... 49
Myelin hypothesis of AD ............................................................................................... 50
Blood-brain barrier in AD ............................................................................................. 50
Blood vessel damage in AD .......................................................................................... 51
Loss of serotonin 1A receptors in the brain ..................................................................... 51
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 .................................................................................. 53
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 ............................................................................................... 54
Glutamate transport dysfunction in AD .......................................................................... 55
Innate immune system and AD ..................................................................................... 56
Insulin, diabetes and AD .............................................................................................. 56
Mechanisms underlying cognitive deficits in AD ............................................................... 57
Monoamine oxidase and AD .......................................................................................... 57

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Neuroinflammation and AD ........................................................................................... 58
Neurotransmitter deficits.............................................................................................. 59
Neurotrophic factors .................................................................................................... 59
NF-B signaling and the pathogenesis of neurodegeneration ............................................. 60
Nitric oxide and AD ..................................................................................................... 60
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
Spread of neurodegeneration ............................................................................................ 66
Synaptic failure in AD .................................................................................................. 67
Transmission of AD ..................................................................................................... 67
Ubiquitin-proteasome system in pathogenesis of AD ........................................................ 68
Risk factors in the etiology of AD ....................................................................................... 69
Aging and developmental abnormalities of the cholinergic system ..................................... 69
Cholesterol, dietary lipids, and Aβ ................................................................................. 70
Exposure to magnetic fields .......................................................................................... 70
Family history of AD .................................................................................................... 71
Homocysteine and AD .................................................................................................. 71
Level of education/type of job and risk of AD .................................................................. 71
Metals and AD ............................................................................................................ 72
Obesity ...................................................................................................................... 74
Proneness to psychological distress and risk of AD .......................................................... 74
Reduced muscle strength ............................................................................................. 75
Sleep deprivation ........................................................................................................ 75
Traumatic brain injury and AD ...................................................................................... 75
Vascular risk factors for AD .......................................................................................... 76
Vitamin B12 and folate ................................................................................................ 78
AD versus non-dementing changes in the aging brain ........................................................... 78
AD and cognitive impairment with aging ............................................................................. 79
Pathomechanism of memory impairment and AD ................................................................. 79
Concluding remarks on pathophysiology of AD ..................................................................... 80
Genetics of AD ................................................................................................................... 81
Familial AD ...................................................................................................................... 81
Presenilins and calcium channel leak in pathogenesis of familial AD ................................... 82
Late onset AD .................................................................................................................. 83
Genomics of AD .................................................................................................................. 83
Introduction to genomics .................................................................................................. 83
Genes associated with Alzheimer disease ............................................................................ 83
AlzGene database ....................................................................................................... 85
ApoE gene.................................................................................................................. 85
ApoE genotype and nitric oxide ..................................................................................... 86
ApoE genotype modulates AD phenotype ....................................................................... 87
APOE genotype and age-related myelin breakdown ......................................................... 87
ApoE receptor interaction with NMDA receptor ................................................................ 88
ApoE and ApoER2 ....................................................................................................... 88
ApoE receptor LR11 as regulator of A  ........................................................................... 88
Arctic mutation ........................................................................................................... 89
CALHM1 polymorphism and AD ..................................................................................... 89
CLU, CRI and PICALM .................................................................................................. 89
CYP46 and risk for AD.................................................................................................. 90
DAPK1 gene variants and AD ........................................................................................ 90
Genetic variants associated with late-onset AD .................................................................... 90
Copy number variation (CNV) in LOAD ........................................................................... 91
LRRTM3 as a candidate gene for AD .............................................................................. 91
MTHFD1L gene variant associated with AD ..................................................................... 91
OGG1 mutations associated with AD .............................................................................. 92
SORL1 gene in AD ....................................................................................................... 92
TOMM40 gene and risk of AD ........................................................................................ 92
International Genomics of Alzheimer's Project ..................................................................... 92
Sequencing in Alzheimer disease ....................................................................................... 93
Molecular neuropathology ................................................................................................. 93
Role of microRNAs in AD ................................................................................................... 93
AD as a polygenic disorder ................................................................................................ 94
Proteomics of AD ............................................................................................................... 94
Introduction .................................................................................................................... 94
Application of proteomic technologies to study AD ................................................................ 95
Protein misfolding in AD .................................................................................................... 97

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Common denominators of AD and prion diseases ................................................................. 98
Amyloid fibrils as a common feature of AD and prion diseases .......................................... 98
FE65 proteins and AD ....................................................................................................... 99

2. Diagnostic Procedures for Alzheimer Disease ..................................... 101
Importance of the diagnosis of Alzheimer disease ........................................................... 101
Methods of diagnosis of AD .............................................................................................. 101
Self-administered olfactory test ....................................................................................... 102
Neuropsychological testing .............................................................................................. 102
Assessment and evaluation ............................................................................................. 103
7-minute screen ....................................................................................................... 103
15-point risk index .................................................................................................... 104
Measurement of aggregation in anterior segment of the eye ........................................... 104
Activities of Daily Living ............................................................................................. 104
Alzheimer Disease Cooperative Study .......................................................................... 105
CDR-SOB score ......................................................................................................... 105
Clinician's Interview-Based Impression of Change ......................................................... 105
Resource Utilization in Dementia Battery ...................................................................... 105
DETECT System ...................................................................................................... 105
Electrophysiology ........................................................................................................... 106
EEG-based bispectral index ........................................................................................ 106
Event-related potentials ............................................................................................. 106
Correlation of electrical activity of the brain with cognition ............................................. 106
Early detection of cataract associated with AD ................................................................... 107
Retinal imaging to detect Aβ deposits ............................................................................... 107
Laboratory methods for diagnosis of AD ............................................................................ 107
Monitoring of synthesis and clearance rates of Aβ in the CSF ............................................... 107
Molecular diagnostics for AD ............................................................................................ 108
Genetic tests for AD .................................................................................................. 109
ApoE genotyping ....................................................................................................... 109
Gene expression patterns in AD .................................................................................. 110
Molecular fingerprinting of the immune system in AD .................................................... 110
Microarray-based tests for AD..................................................................................... 110
Monoclonal antibody-based in vitro diagnosis of AD from brain tissues ............................. 111
Biomarkers of AD ........................................................................................................... 111
The ideal biomarker for AD.............................................................................................. 113
CSF biomarkers of AD..................................................................................................... 113
CSF sulfatide as a biomarker for AD ............................................................................ 113
Glycerophosphocholine as CSF biomarker in AD ............................................................ 114
Protein biomarkers of AD in CSF ................................................................................. 114
Amyloid precursor protein .......................................................................................... 116
Tau proteins in CSF ................................................................................................... 116
Tests for the detection of A  in CSF ............................................................................. 116
Tests combining CSF tau and A  ................................................................................. 117
Urine tests for AD .......................................................................................................... 117
Blood tests for AD .......................................................................................................... 118
Blood Aβ levels ......................................................................................................... 118
Blood test for AD based on heme oxygenase-1 ............................................................. 119
Blood test for AD based on RNA hybridization ............................................................... 119
GSK-3 elevation in white blood cells ............................................................................ 119
Lymphocyte Proliferation Test ..................................................................................... 120
MGAT3 as biomarker for prognosis of AD ..................................................................... 120
Protein kinase C in red blood cells ............................................................................... 120
Sphingolipids ............................................................................................................ 120
Tests based on protein biomarkers in blood .................................................................. 121
A skin test for early detection of AD ................................................................................. 121
Saliva-based tests for AD ................................................................................................ 122
Saliva Aβ42 level as a biomarker of AD ........................................................................ 122
Nanotechnology to measure Aβ-derived diffusible ligands ................................................... 122
Simultaneous measurement of several biomarkers for AD ................................................... 123
Plasma biomarkers of drug response in AD ........................................................................ 123
A serum protein-based algorithm for the detection of AD .................................................... 123
Concluding remarks about biomarkers for AD .................................................................... 124
Imaging in AD .................................................................................................................. 124
Computed tomography ................................................................................................... 124
Magnetic resonance imaging............................................................................................ 125
Arterial spin labeling with MRI .................................................................................... 125
Magnetic resonance microscopy .................................................................................. 126
Magnetic resonance spectroscopy................................................................................ 126
Single photon emission computed tomography and modifications ......................................... 127
Positron emission tomography ......................................................................................... 127

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In vivo imaging of A deposits by PET............................................................................... 129
Pittsburgh compound B and PET.................................................................................. 129
Florbetapir-PET ......................................................................................................... 130
Florbetaben-PET ....................................................................................................... 131
In vivo detection of Aβ plaques by MRI ............................................................................. 131
Imaging agents for Aβ and neurofibrillary tangles .............................................................. 132
Targeting of a chemokine receptor as biomarker for brain imaging ....................................... 132
Radioiodinated clioquinol as a biomarker for Aβ ................................................................. 133
Imaging neuroinflammation in AD .................................................................................... 133
Preclinical diagnosis of AD ............................................................................................... 133
Meta-analysis of literature on imaging in AD ...................................................................... 134
Alzheimer Disease Neuroimaging Initiative ........................................................................ 134
Concluding remarks on imaging for diagnosis of AD............................................................ 135
Diagnosis of MCI and prediction of AD ............................................................................. 135
Diagnosis of MCI ............................................................................................................ 135
Computer-Administered Neurophychological screen for MCI ........................................... 136
Infrared eye-tracking technology to detect MCI............................................................. 136
PET for detection of MCI ............................................................................................ 136
MRI for detection of MCI ............................................................................................ 137
Presymptomatic detection of AD ...................................................................................... 137
PredictAD project ........................................................................................................... 137
Prediction of AD in patients with MCI ................................................................................ 138
Combination of MMSE and a memory test for prediction of AD ........................................ 138
Biochemical biomarkers in CSF for prediction of AD ....................................................... 138
Structural MRI biomarkers for prediction of AD ............................................................. 138
Magnetoencephalography for detection of MCI and AD ................................................... 139
Concluding remarks about prediction of AD in MCI ........................................................ 140
Criteria for diagnosis of AD .............................................................................................. 140
Role of biomarkers in diagnosis of AD dementia ................................................................. 140
Ethical aspects of diagnostics for AD ............................................................................... 141
Genetic testing for AD .................................................................................................... 141
Ethical issues of brain imaging in AD ................................................................................ 141
Companies involved in diagnosis of AD ............................................................................ 142

3. Management of Alzheimer Disease ..................................................... 145
Introduction..................................................................................................................... 145
Cholinergic approaches .................................................................................................... 145
Mechanism of action of cholinesterase inhibitors ................................................................ 146
Choline and lecithin ........................................................................................................ 147
Donepezil ...................................................................................................................... 148
Rivastigmine ................................................................................................................. 149
Galantamine .................................................................................................................. 150
Duration of treatment with ChE inhibitors.......................................................................... 151
Comparative studies of ChE inhibitors ............................................................................. 151
Donepezil versus rivastigmine ......................................................................................... 152
Donepezil versus galantamine ......................................................................................... 152
An assessment and future prospects of anticholinergic therapies .......................................... 152
Neuroprotection in Alzheimer's disease ........................................................................... 153
Memantine .................................................................................................................... 154
Combination of memantine with ChE inhibitors ............................................................. 157
Monoamine oxidase inhibitors .......................................................................................... 158
Selegiline ................................................................................................................. 158
Synaptoprotection in AD ................................................................................................. 158
Drugs for noncognitive symptoms in AD .......................................................................... 158
Antidepressants ............................................................................................................. 159
Antipsychotics ............................................................................................................... 159
ChE inhibitors for behavioral and psychological disorders in AD ............................................ 159
Concluding remarks and other drugs for agitation in AD ...................................................... 160
Sensory stimulation........................................................................................................ 161
Non-pharmacological treatments of AD ........................................................................... 161
Management of memory loss in AD .................................................................................. 161
Exposure to electromagnetic fields for treatment of AD ....................................................... 162
Application of electrical fields for improvement of cerebral function ................................. 162
High-frequency electromagnetic field treatment of AD ................................................... 162
Vagal nerve stimulation .................................................................................................. 163
Cerebrospinal fluid shunting ............................................................................................ 163
Omental transposition .................................................................................................... 164
Microchip-based hippocampal prosthesis for AD ................................................................. 164
Nutritional therapies for AD ............................................................................................. 164
Axona ...................................................................................................................... 164
Cocktail of dietary supplements for AD ........................................................................ 164

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Docosahexaenoic acid ................................................................................................ 165
Magnesium............................................................................................................... 166
Nicotinamide for the treatment of AD .......................................................................... 167
Omega-3 fatty acids .................................................................................................. 167
Preventing decline of mental function with aging and dementia ...................................... 168
Prevention of Alzheimer disease ...................................................................................... 168
Mental training ......................................................................................................... 169
Physical exercise ....................................................................................................... 170
Higher level of conscientiousness and decreased risk of AD ............................................ 170
Caloric restriction ...................................................................................................... 171
Nutritional factors in prevention of AD ......................................................................... 171
Grapes and red wine ................................................................................................. 171
Black and green teas ................................................................................................. 173
Caffeine ................................................................................................................... 173
Drugs to prevent Alzheimer disease ................................................................................. 173
Preimplantation genetic diagnosis of inherited Alzheimer disease ......................................... 173
Presymptomatic detection of AD ...................................................................................... 174
Management of mild cognitive impairment ...................................................................... 174
Management of Down syndrome ...................................................................................... 175
Guidelines for use of anti-dementia drugs in clinical practice .......................................... 176
Donepezil and/or memantine ........................................................................................... 177
General care of the Alzheimer disease patients ............................................................... 177
Strategies for the management of Alzheimer disease ...................................................... 177

4. Research in Alzheimer Disease ........................................................... 180
Introduction..................................................................................................................... 180
Animal models of Alzheimer disease ................................................................................ 180
Lesional models ............................................................................................................. 180
Cerebroventricular injection of Aβ in rats ..................................................................... 180
Lentiviral vector-based models of amyloid pathology ..................................................... 181
AAV-mediated gene transfer to increase hippocampal A  ............................................... 181
Transgenic mouse models ............................................................................................... 181
Quantitative assessment of amyloid load in transgenic models........................................ 183
In vivo magnetic resonance microimaging in transgenic models of AD ............................. 183
Transgenic model of AD with suppression of Aβ production ............................................. 183
Transgenic AD11 anti-NGF mice .................................................................................. 184
Genetically altered mice with deficiency of vesicular ACh transporter ............................... 184
Limitations of mouse models of Alzheimer disease ........................................................ 184
Cholesterol-fed rabbits as models for AD........................................................................... 185
Zebrafish model for AD ................................................................................................... 185
Transgenic invertebrate models of Alzheimer disease ......................................................... 186
Drosophila model of AD ............................................................................................. 186
Caenorhabditis elegans Alzheimer disease model .......................................................... 187
Cell systems for AD research ........................................................................................... 187
In vitro neuronal cell Lines .............................................................................................. 187
Single-gene expression system for use in cell culture ......................................................... 188
Transgenic cells ............................................................................................................. 188
In silico models.............................................................................................................. 189
Estimation of progression rates of Alzheimer disease ...................................................... 189
Clinical trial methods in Alzheimer disease ...................................................................... 190
Molecular imaging as a guide to drug development ............................................................ 190
Use of MRI and PET in clinical trials ............................................................................. 191
Cognitive-function assessment in clinical trials ................................................................... 191
Clinical trials in mild cognitive impairment ......................................................................... 192
Research in AD as a basis for future therapies ................................................................. 192
Use of microarrays for studying pathogenesis of AD ........................................................... 192
Computational brain mapping in AD ................................................................................. 192
Study of neurogenesis in AD............................................................................................ 193
Study of 3D structure of Aβ ............................................................................................. 193
Solid-state NMR to study precursors of Aβ......................................................................... 193
Research in Alzheimer disease at academic centers ........................................................ 193
Role of NIH in AD research .............................................................................................. 194
NIH Clinical Trials Database for AD ................................................................................... 194
Alzheimer Research Consortium ....................................................................................... 194
The National Institute on Aging and AD research................................................................ 194

5. Drug Discovery & Development for Alzheimer Disease ....................... 196
Introduction..................................................................................................................... 196
Categories of drugs in development for AD ...................................................................... 196
Memory-enhancing drugs ................................................................................................ 198
Enhancing memory by drugs that block eIF2α phosphorylation ............................................ 198

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Drugs based on cholinergic approaches ........................................................................... 198
AP2238 ......................................................................................................................... 199
Butyrylcholinesterase inhibitors ....................................................................................... 199
Donepezil-tacrine hybrids ................................................................................................ 199
Drugs modulating gamma-aminobutyric acid receptors ....................................................... 200
Ganstigmina .................................................................................................................. 200
Methanesulfonyl fluoride ................................................................................................. 200
Muscarinic receptor modulators ....................................................................................... 201
Muscarinic M1 agonists .............................................................................................. 201
Muscarinic M2 antagonists .......................................................................................... 202
Nicotine and nicotinic receptor modulators ........................................................................ 202
Nicotine ................................................................................................................... 202
Nicotinic receptor modulators ..................................................................................... 203
GTS21 ..................................................................................................................... 204
Ispronicline .............................................................................................................. 204
JWB1-84-1 ............................................................................................................... 205
Neuropeptide/neurotransmitters ..................................................................................... 205
Somatostatin release enhancers ...................................................................................... 205
Glutamate receptor modulators ....................................................................................... 205
Physiology and pharmacology of glutamate receptors ......................................................... 206
NMDA receptor ion channel complex ................................................................................. 206
Metabotropic glutamate receptors .................................................................................... 208
Glutamate receptor modulators as potential therapeutics for AD .......................................... 209
Non-competitive NMDA modulators ............................................................................. 210
AMPA modulators ...................................................................................................... 210
Drugs affecting multiple neurotransmitters ..................................................................... 211
Ensaculin ...................................................................................................................... 211
NS2330 ........................................................................................................................ 211
RS-1259 ....................................................................................................................... 211
Lecozotan ..................................................................................................................... 212
Vaccines for AD ................................................................................................................ 212
Active immunization with A ............................................................................................ 213
AN-1792 vaccine ....................................................................................................... 213
Complications in clinical trials with AN-1792 ................................................................. 213
Effects of Aβ vaccine on the brain ............................................................................... 213
Strategies to avoid undesirable effect of Aβ vaccination ...................................................... 214
Passive immunization in AD ............................................................................................. 215
Passive immunization with MAbs ................................................................................. 215
Delivery of the passive antibody directly to the brain ..................................................... 217
Systemic injection of MAbs to treat AD ........................................................................ 218
Combination of A immunotherapy and CD40-CD40L blockade ............................................ 218
Shaping the immune responses elicited against A ............................................................. 218
Delivery of AD vaccines .................................................................................................. 219
Gene vaccination ...................................................................................................... 219
Modified Aβ nasal vaccine........................................................................................... 219
Transdermal Aβ vaccination ........................................................................................ 219
Other vaccines for AD ..................................................................................................... 220
Nasal vaccination with Proteosome  adjuvant .............................................................. 220
T-cell vaccination with glatiramer acetate adjuvant ....................................................... 221
Early start of immunotherapy to clear A plaques............................................................... 221
Reversal of cholinergic dysfunction by anti-A antibody ...................................................... 221
Immune modulation via TRL9 to reduce Aβ ....................................................................... 221
Mechanisms by which A antibodies reduce amyloid accumulation in the brain ...................... 222
Perspectives on vaccines for AD ....................................................................................... 222
Companies involved in AD vaccines .................................................................................. 224
Inhibition of amyloid precursor protein aggregation ....................................................... 225
Secretase modulators ..................................................................................................... 225
Neuroprotection by α-secretase cleaved APP................................................................. 226
Inhibitors of β-secretase ............................................................................................ 226
Inhibitors of γ-secretase ............................................................................................ 227
Amyloid-derived diffusible ligands .................................................................................... 228
GABA receptor modulation by etazolate and APP processing ................................................ 229
Depletion of serum amyloid P .......................................................................................... 229
Trojan-horse approach to prevent build-up of Aβ aggregates ............................................... 229
Drugs that inhibit the formation of Aβ ............................................................................. 230
22R-hydroxycholesterol .................................................................................................. 230
Acylaminopyrazole ......................................................................................................... 231
Cadmium telluride nanoparticles prevent Aβ fibril formation ................................................ 231
Cannabinoids ................................................................................................................. 231
Chelation therapy for AD ................................................................................................. 232
Clioquinol and PBT2 ................................................................................................... 232

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Copper chelation by FKBP52 ....................................................................................... 233
Zinc chelation from amyloid plaques ............................................................................ 234
Next generation multifunctional chelating agents for AD................................................. 234
Heparin and its derivatives .............................................................................................. 234
A reassessment of the role of heparin in AD ................................................................. 234
Enoxaparin ............................................................................................................... 235
Heparan sulfate ........................................................................................................ 235
Imatinib mesylate .......................................................................................................... 235
Laminin ........................................................................................................................ 236
NSAIDs ......................................................................................................................... 236
Flurbiprofen analogs with A 42-lowering action ............................................................. 237
Nitric oxide-donating NSAIDs...................................................................................... 238
In vivo demonstration of the effects of NSAIDs on brain in AD ........................................ 238
Paclitaxel ...................................................................................................................... 238
Phenserine .................................................................................................................... 239
Tolserine .................................................................................................................. 239
Platinum-based inhibitors of A ........................................................................................ 240
Scyllo-cyclohexanehexol ................................................................................................. 240
Ubiquitin C-terminal hydrolase L1 .................................................................................... 240
Drugs to prevent the formation of NFTs ........................................................................... 240
Tau suppression ............................................................................................................... 241
ApoE4 as a therapeutic target in AD ................................................................................ 242
Strategies to prevent deposits and enhance clearance of Aβ ........................................... 242
4,5-dianilinophthalimide for disruption of Aβ1-42 fibrils ......................................................... 243
ABCA1 overexpression to lower amyloid deposits ............................................................... 244
ANAVEX 2-73 ................................................................................................................ 244
Beta-sheet breakers ....................................................................................................... 244
Blocking ApoE/A interaction to reduce Aβ plaques............................................................. 245
Clearance of Aβ across the blood-brain barrier ................................................................... 245
Enhanced PKCє activity promotes clearance of Aβ .............................................................. 245
Galantamine-induced Aβ clearance ................................................................................... 246
Inhibitors of Aβ dehydrogenase ....................................................................................... 246
Intravenous immune globulin .......................................................................................... 246
Meptides ....................................................................................................................... 247
Monoclonal antibodies for removal of Aβ ........................................................................... 248
Crenezumab ............................................................................................................. 248
Gantenerumab .......................................................................................................... 248
Solanezumab ............................................................................................................ 248
Nanotechnology for removal of Aβ deposits ....................................................................... 249
Role of matrix metalloproteinases in clearance of Aβ .......................................................... 249
SAN-61 for cleavage of fibril and soluble amyloid ............................................................... 249
Serum amyloid P component depletion ............................................................................. 249
Small molecule DAPH for clearance of amyloid ................................................................... 250
Companies developing Aβ-directed therapeutics for AD .................................................. 250
Antiinflammatory and antimicrobial drugs ....................................................................... 251
Dapsone ....................................................................................................................... 251
Antimicrobial drugs against C. pneumoniae ....................................................................... 252
PPAR-gamma agonists .................................................................................................... 252
Inhibitors of neuroinflammation ....................................................................................... 253
Cyclophosphamide .................................................................................................... 253
Etanercept ............................................................................................................... 253
MW01-5-188WH ....................................................................................................... 254
Antidiabetic drugs ............................................................................................................ 254
Rosiglitazone ................................................................................................................. 254
Pioglitazone ................................................................................................................... 255
Nootropics ....................................................................................................................... 255
Acetyl-L-carnitine ........................................................................................................... 255
Cerebrolysin .................................................................................................................. 256
Ergot derivatives ............................................................................................................ 256
Lisuride.................................................................................................................... 256
Dihydroergocryptine .................................................................................................. 256
Neuroprotective effect drugs not primarily developed for AD .......................................... 257
Antihypertensive drugs ................................................................................................... 258
Angiotensin-converting enzyme inhibitors .................................................................... 258
Angiotensin receptor blockers ..................................................................................... 258
Dimebon ....................................................................................................................... 258
Drugs acting on estrogen receptors .................................................................................. 259
Estrogen .................................................................................................................. 259
Raloxifene ................................................................................................................ 260
Neurosteroids ................................................................................................................ 260
Pregnenolone sulfate ................................................................................................. 261

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Dehydroepiandrosterone ............................................................................................ 261
Lithium ......................................................................................................................... 261
MAO-B inhibitors ............................................................................................................ 262
Ladostigil tartrate...................................................................................................... 262
Memoquin ................................................................................................................ 262
Methylene blue .............................................................................................................. 263
Nimodipine .................................................................................................................... 263
Rapamycin .................................................................................................................... 264
Statins.......................................................................................................................... 264
Testosterone ................................................................................................................. 265
Valproic acid.................................................................................................................. 266
Future prospects of neuroprotection in AD ......................................................................... 266
Targeting Cdk5 pathway ............................................................................................ 267
Antioxidants .................................................................................................................... 267
Colostrinin .................................................................................................................... 268
Curcumin ...................................................................................................................... 268
Dehydroascorbic acid...................................................................................................... 269
Melatonin ...................................................................................................................... 269
Omega-3 fatty acids ....................................................................................................... 269
Reservatrol ................................................................................................................... 270
Synthetic catalytic scavengers ......................................................................................... 270
Vitamins........................................................................................................................... 271
Vitamin E as antioxidant ................................................................................................. 271
Vitamins to lower homocysteine ....................................................................................... 271
Folic acid ...................................................................................................................... 271
Aminopyridazines ............................................................................................................ 271
Nanobody-based drugs for AD ......................................................................................... 272
Nitric oxide based therapeutics for AD ............................................................................. 272
Nitric oxide mimetics ...................................................................................................... 272
iNOS inhibitors for AD ..................................................................................................... 273
Novel drugs for AD from natural resources ...................................................................... 273
Berberine chloride .......................................................................................................... 274
Centella asiatica............................................................................................................. 274
Ginko biloba .................................................................................................................. 275
Huperzine-A .................................................................................................................. 276
Hyperforin ..................................................................................................................... 276
Melissa officinalis ........................................................................................................... 276
Nostocarboline derived from cyanobacteria ....................................................................... 277
PTI-00703 ..................................................................................................................... 277
Salvia ........................................................................................................................... 277
Securinega suffruticosa ................................................................................................... 278
Withania somnifera ........................................................................................................ 278
ZT-1 ............................................................................................................................. 278
Cholesterol and AD .......................................................................................................... 279
ACAT inhibitors .............................................................................................................. 280
Role of gene for cholesterol ester transfer protein .............................................................. 280
Cholesterol 24S-hydroxylase as a drug target for AD .......................................................... 280
Selectively increase of ApoA-I production .......................................................................... 281
Neurotrophic factors ........................................................................................................ 281
Activity-dependent neuroprotective protein ....................................................................... 281
Brain derived neurotrophic factor ..................................................................................... 282
Insulin-like growth factor-1 ............................................................................................. 282
Nerve growth factor ....................................................................................................... 283
Neotrofin (AIT-082)........................................................................................................ 284
Limitations of the use of NTFs for AD ................................................................................ 284
Role of serotonin modulators in AD ................................................................................. 284
Xaliproden .................................................................................................................... 284
5-HT1A receptor antagonists ............................................................................................ 285
5-HT6 antagonists .......................................................................................................... 285
5-HT4 receptor agonists................................................................................................... 285
PRX-03140 ............................................................................................................... 286
Cell therapy for AD ........................................................................................................... 286
Stem cell transplantation for AD ...................................................................................... 287
Potential benefits of grafting NSCs in AD ...................................................................... 287
NSCs improve cognition in AD via BDNF ....................................................................... 287
Drugs for enhancing neuronal differentiation of implanted NSCs...................................... 287
Implantation of encapsulated cells for delivering NGF ......................................................... 288
Gene therapy for AD ........................................................................................................ 288
ApoE gene therapy ......................................................................................................... 288
FGF2 gene transfer in AD ................................................................................................ 288
Humanin gene therapy ................................................................................................... 289

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Neprilysin gene therapy .................................................................................................. 289
NGF gene therapy .......................................................................................................... 289
Targeting plasminogen activator inhibitor type-1 gene ........................................................ 290
Antisense approaches to AD ............................................................................................ 290
RNAi approaches to AD .................................................................................................... 291
Combined therapeutic approaches to AD ......................................................................... 292
Drug delivery for Alzheimer disease ................................................................................ 292
Delivery of thyrotropin-releasing hormone analogs by molecular packaging ........................... 293
Nanoparticle-based drug delivery for Alzheimer’s disease .................................................... 293
Transdermal drug delivery in Alzheimer's disease ............................................................... 294
Transdermal rivastigmine ........................................................................................... 294
Intranasal delivery of therapeutics for AD ......................................................................... 295
Intranasal delivery of tacrine ...................................................................................... 295
Intranasal delivery of nerve growth factor to the brain ................................................... 295
Circadian rhythms and timing of cholinesterase inhibitor therapy ......................................... 295
Clinical trials for AD ......................................................................................................... 296
Drugs for AD that were discontinued in clinical trials........................................................... 300
Evaluation of clinical trials of AD ...................................................................................... 303
Monitoring of cognitive function during clinical trials ........................................................... 303
Drug discovery for AD ...................................................................................................... 304
Drugs acting on signaling pathways.................................................................................. 304
Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 ..................................... 304
Drugs to reverse inhibition of the PKA/CREB pathway in AD ........................................... 304
Inhibition of the CD40 signaling pathway ..................................................................... 305
JNK pathway as a target ............................................................................................ 305
Mitogen-activated protein kinase pathway as target ...................................................... 305
Protein kinase C activators ......................................................................................... 306
Electrophysiological detection of drug target for neuroprotection in early AD ......................... 306
Genomics-based drug discovery ....................................................................................... 306
High through screening for AD drug candidates ................................................................. 307
Proteomics and drug discovery for AD .............................................................................. 307
Small molecule compounds binding to neurotrophin receptor p75NTR ................................... 308
Targeting Vav in tyrosine kinase signaling pathway ....................................................... 309
Novels targets/receptors for AD drug discovery ................................................................. 309
Activation of cerebral Rho GTPases.............................................................................. 310
Activators of insulin-degrading enzyme ........................................................................ 310
Blockade of TGF--Smad2/3 signaling in peripheral macrophages ................................... 310
Calcium channel blockers ........................................................................................... 311
Casein kinase 1......................................................................................................... 311
Cyclin-dependent kinase-5 ......................................................................................... 311
Heat shock protein 90 inhibitors .................................................................................. 312
Histone deacetylase 1 ................................................................................................ 312
Inactivation of aph-1 and pen-2 reduces APP cleavage................................................... 312
NF-B inhibitors ........................................................................................................ 313
Kinases and phosphatases as targets for AD therapeutics............................................... 313
Neutral sphingomyelinase inhibitors ............................................................................ 313
Phosphodiesterase inhibitors ...................................................................................... 314
Pin 1 as a target in AD ............................................................................................... 314
Protein phosphatase 5 as a neuroprotective in AD ......................................................... 315
Src homology-containing protein-1 inhibitors ................................................................ 315
Targeting GABAergic system....................................................................................... 315
Pharmacogenomics of Alzheimer disease ........................................................................ 315
Personalized therapy of AD ............................................................................................. 316
Genotyping and AD therapeutics ...................................................................................... 316
Biomarkers and companion diagnostics for AD ................................................................... 317
Regulatory aspects of drug development for AD .............................................................. 318
EMEA guidelines for drug development for AD ................................................................... 318
Concluding remarks and future prospects of drugs for AD ............................................... 318

6. Markets & Finances of AD Care ........................................................... 321
Introduction..................................................................................................................... 321
Pharmacoeconomics of treatment of AD .......................................................................... 321
Quality of Life in relation to economics of AD ..................................................................... 321
Costs associated with Alzheimer disease ........................................................................... 321
Pharmacoeconomics of donepezil ..................................................................................... 322
Pharmacoeconomics studies using rivastigmine ................................................................. 322
Pharmacoenonomics studies using galantamine ................................................................. 323
A comparison of pharmacoenonomics outcomes with different ChE inhibitors ......................... 323
Pharmacoenonomics studies using memantine................................................................... 324
Patterns of AD care in major markets .............................................................................. 324
Care of AD patients in the US .......................................................................................... 324

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Cost of care .............................................................................................................. 324
Medicare and AD ....................................................................................................... 325
Patterns of practice in AD care .................................................................................... 326
Opinions of physicians’ organizations on drugs for dementia ........................................... 326
Care of AD patients in the UK .......................................................................................... 327
Cost of care .............................................................................................................. 327
Patterns of practice in AD care .................................................................................... 327
Retraction of NICE recommendations to NHS ................................................................ 328
Care of AD patients in Germany ....................................................................................... 329
Care of AD patients in France .......................................................................................... 329
Care of AD patients in Italy ............................................................................................. 330
Care of AD patients in Spain ............................................................................................ 330
Care of AD patients in Japan ........................................................................................... 330
Markets for AD diagnostics .............................................................................................. 331
Markets for AD therapeutics ............................................................................................ 331
Geographical markets for AD ........................................................................................... 331
Markets for currently approved drugs for AD ..................................................................... 332
Markets for generic AD drugs .......................................................................................... 332
Future growth of AD market ............................................................................................ 333
Statins.......................................................................................................................... 333
Limitations of AD drug development by the biotechnology industry ................................ 334
Unmet needs in the management of AD ........................................................................... 334
Drivers of AD markets ...................................................................................................... 335
Increase of the aged populations ..................................................................................... 336
Increase in the number of approved drugs for AD .............................................................. 336
Limitations of the current therapies .................................................................................. 336
Improvements in diagnosis ............................................................................................. 336
Increasing awareness of the disease................................................................................. 337

7. Companies .......................................................................................... 339
Introduction..................................................................................................................... 339
Profiles of companies ....................................................................................................... 339
Collaborations .................................................................................................................. 488

8. References .......................................................................................... 493
Tables
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1-1: Historical landmarks relevant to Alzheimer disease ......................................................... 19
1-2: Clinical features of Alzheimer disease............................................................................ 20
1-3: Non-Alzheimer dementias............................................................................................ 25
1-4: A guide to evaluation for MCI due to AD ........................................................................ 28
1-5: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease ............................................. 29
1-6: 2011 Revised criteria for diagnosis of dementia due to Alzheimer Disease ......................... 31
1-7: Relation of mutations in amyloid precursor protein to CNS disorders ................................. 39
1-8: Risk factors for Alzheimer's disease .............................................................................. 69
1-9: Genes linked to AD ..................................................................................................... 84
1-10: Abnormalities of expression of brain proteins in Down's syndrome and AD ....................... 96
2-1: Classification of methods of diagnosis of Alzheimer disease ........................................... 101
2-2: Neuropsychological test batteries and scales for Alzheimer's disease .............................. 102
2-3: Available molecular diagnostic tests for Alzheimer disease ............................................. 108
2-4: Classification of biomarkers of AD in blood and CSF ...................................................... 111
2-5: Characteristics of an ideal biomarker for Alzheimer disease ........................................... 113
2-6: Role of biomarkers in diagnosis of AD dementia ........................................................... 140
2-7: Companies involved in the diagnosis of Alzheimer disease ............................................. 142
3-1: Classification of treatments for Alzheimer disease ........................................................ 145
3-2: Cholinergic approaches used in the treatment of Alzheimer disease ................................ 146
3-3: Categories of neuroprotective agents for Alzheimer disease ........................................... 154
3-4: Strategies for prevention of Alzheimer disease ............................................................. 169
3-5: Guidelines for the treatment of dementia .................................................................... 176
4-1: Transgenic mouse models of Alzheimer disease............................................................ 181
5-1: Classification of therapies in development for Alzheimer disease .................................... 196
5-2: Drugs for AD targeting nACh receptors ....................................................................... 204
5-3: Ionotropic glutamate receptors .................................................................................. 206
5-4: Classification of mGluRs ............................................................................................ 206
5-5: Glutamate receptor modulators as potential therapeutic agents in AD ............................. 209
5-6: Companies involved in developing vaccines for AD ....................................................... 224
5-7: Secretase modulators in clinical trials ......................................................................... 225
5-8: Companies developing Aβ-directed therapeutics for AD ................................................. 250

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5-9: Innovative neuroprotective approaches for Alzheimer disease ........................................ 257
5-10: Herbal therapies for AD ........................................................................................... 273
5-11: Novel drug delivery methods for Alzheimer disease therapies ....................................... 292
5-12: Clinical trials in Alzheimer disease ............................................................................ 296
5-13: Discontinued, failed or inconclusive clinical trials of Alzheimer disease ........................... 300
6-1: Direct and indirect costs associated with Alzheimer disease ........................................... 322
6-2: Prevalence of AD in major markets 2011-2021 ............................................................ 331
6-3: AD market values from 2011-2021 in major world markets ........................................... 332
6-4: Markets for currently approved AD drugs 2011-2021 .................................................... 332
6-5: Potential markets for drugs in development 2011-2021................................................. 333
6-6: Limitations of AD drug discovery and development by the biotechnology industry ............ 334
6-7: Factors that drive AD markets.................................................................................... 335
7-1: Major players in Alzheimer's disease therapeutics ......................................................... 339
7-2: Collaborations relevant to Alzheimer disease ............................................................... 488

Figures
Figure 1-1: Percentages of world population of people over the age of 65 according to more
developed and less developed portions  2000 to 2050. ......................................................... 32
Figure 1-2: Correlation between aging and AD in the US from 2000 to 2020 ..................................... 33
Figure 1-3: Prevalence of different types of dementia ..................................................................... 34
Figure 1-4: Mechanisms of Aβ clearance ....................................................................................... 46
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 Aβ generation and neurodegeneration ............................ 69
Figure 1-8: Pathomechanism of AD .............................................................................................. 81
Figure 3-1: Metabolism of acetylcholine ...................................................................................... 147
Figure 3-2: Neuroprotective effective of galantamine in AD ........................................................... 151
Figure 3-3: Strategies for the management of Alzheimer disease ................................................... 179
Figure 5-1: NMDA receptor ion channel complex. ......................................................................... 208
Figure 5-2: Neurotoxicity due to misfolding of A1-42 .................................................................. 243
Figure 5-3: Role of proteomics in drug discovery/development for Alzheimer disease ....................... 308
Figure 6-1: Unmet needs in the management of Alzheimer disease ................................................ 335

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