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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
Detection of AD in the preclinical phase ......21
Differentiation of AD from other dementias..22
Differentiation of AD from non-dementing disorders ........23
Cerebral insufficiency and AD ...23
Memory deficits and preclinical AD .............24
Mild cognitive impairment ........24
Diagnostic criteria of AD...........26
Epidemiology ........ 28
Epidemiology of aging..............28
Epidemiology of dementia ........29
Epidemiology of AD 29
Prevalence of AD according to age.........30
Mortality in AD30
Pathophysiology of AD ............. 30
Cerebral atrophy and neuronal loss ............30
Neuritic plaques and neurofibrillary tangles .30
Sp proteins as markers of neuronal death in AD..............31
Role of tau in the pathogenesis of AD .........31
Amyloid precursor protein ........32
Relation of APP mutations to CNS disorders...............32
Relation of APP to Aß deposits and pathogenesis of AD ................33
Role of secretases in amyloid cascade....34
Role of exosomal proteins ...36
Role of nicastrin 36
Neurotixicity of Ab deposits .37
Relation of Aß deposits to synaptic activity ................37
Dysfunction of TGF-ß signaling accelerates Aß deposition .............37
Role of TMP21 in presenilin complexes and Ab formation..............38
Ab deposit and clearance..........38
Impairment of mitochondrial energy metabolism.............39
Ab-binding alcohol dehydrogenase links AD to mitochondrial toxicity
................39
Neural thread protein ..............40
Loss of synaptic proteins ..........40
AD and Down syndrome......40
Overlapping pathologies of AD and Parkinson disease .41
AD and age-related macular degeneration41
Myelin hypothesis of AD ......42
Blood-brain barrier in AD.....42
Blood vessel damage in AD..43
Loss of serotonin 1A receptors in the brain ................43
Factors in pathogenesis of AD...43
Astrocytes and AD..............44
Axonal transport failure in AD ...............44
Cell-cycle hypothesis ..........44
Creatine and AD45
Disturbances of interaction of nervous system proteins ................45
DENN/MADD expression and enhanced pro-apoptotic signaling in
AD................45
Gonadotrophins and AD ......45
Glutamate transport dysfunction in AD...46
Innate immune system and AD .............47
Insulin, diabetes and AD .....47
Mechanisms underlying cognitive deficits in AD ..........48
Monoamine oxidase and AD.49
Neuroinflammation and AD..49
Neurotransmitter deficits.....51
Neurotrophic factors ...........51
NF-kB signaling and the pathogenesis of neurodegeneration.........51
Nitric oxide and AD.............52
Nogo receptor pathway .......54
Oxidative stress and AD ......54
Prostaglandins and AD ........56
Quinolinic acid and AD ........56
Serotonin and AD ...............56
Spherotoxin....57
Synaptic failure in AD .........57
Transmission of AD.............58
Ubiquitin-proteasome system in pathogenesis of AD ...58
Risk factors in the etiology of AD................59
Aging and developmental abnormalities of the cholinergic system .60
Cholesterol, dietary lipids, and Ab .........60
Exposure to magnetic fields.61
Family history of AD ...........61
Homocysteine and AD.........61
Level of education/type of job and risk of AD .............61
Metals and AD 62
Obesity ..........64
Proneness to psychological distress and risk of AD .....64
Traumatic brain injury and AD ..............64
Vascular risk factors for AD .65
Vitamin B12 and folate........67
AD versus non-dementing changes in the aging brain......67
Concluding remarks on pathophysiology of AD ................67
Genetics of AD ...... 69
Familial AD..........69
Presenilins and calcium channel leak in pathogenesis of familial AD .70
Late onset AD ......71
Genomics of AD..... 71
Introduction to genomics .........71
Genes associated with Alzheimer disease ....71
ApoE gene......73
ApoE genotype and nitric oxide .............74
APOE genotype and age-related myelin breakdown ....75
Interaction between ApoE receptor and NMDA receptor................75
ApoE and ApoER2...............75
LR11 receptor for ApoE as regulator of Ab 76
DAPK1 gene variants and AD ................76
CYP46 and risk for AD.........76
Genetic variants associated with late-onset AD ..........77
OGG1 mutations associated with AD......77
Role of SORL1 gene in AD ...77
The Arctic mutation ............78
LRRTM3 as a candidate gene for AD ......78
AlzGene database...............78
Molecular neuropathology ........78
Proteomics of AD .. 79
Introduction ........79
Application of proteomic technologies to study AD...........79
Protein misfolding in AD...........81
Common denominators of AD and prion diseases ............82
Amyloid fibrils as a common feature of AD and prion diseases ......82
2. Diagnostic Procedures for Alzheimer Disease... 83
Importance of the diagnosis of Alzheimer disease....... 83
Methods of diagnosis of AD...... 83
Neuropsychological testing .......84
Assessment and evaluation ......85
The seven minute screen ....85
Measurement of aggregation in anterior segment of the eye.........85
Activities of Daily Living ......85
Alzheimer Disease Cooperative Study ....86
Clinician's Interview-Based Impression of Change ......86
Resource Utilization in Dementia Battery86
DETECTä System...............86
Electrophysiology .86
Early detection of cataract associated with AD ................87
Laboratory methods for diagnosis of AD ......87
Monitoring of synthesis and clearance rates of Ab in the CSF .............87
Molecular diagnostics for AD.....88
Genetic tests for AD ...........89
ApoE genotyping ................89
Gene expression patterns in AD ............89
Molecular fingerprinting of the immune system in AD..89
Microarray-based tests for AD...............90
Monoclonal antibody-based in vitro diagnosis of AD from brain
tissues..............90
Biomarkers of AD .90
The ideal biomarker for AD.......91
CSF biomarkers of AD..............92
CSF sulfatide as a biomarker for AD.......92
Glycerophosphocholine as CSF biomarker in AD .........92
Protein biomarkers of AD in CSF............93
Amyloid precursor protein ...94
Tau proteins in CSF ............95
Tests for the detection of Ab in CSF .......95
Tests combining CSF tau and Ab ...........96
Urine tests for AD.96
Blood tests for AD 96
Protein kinase C in red blood cells .........97
Lymphocyte Proliferation Test ...............97
Blood test for detection of amyloid plaques in brain ....97
GSK-3 elevation in white blood cells ......98
Blood test for AD based on RNA hybridization ............98
A skin test for early detection of AD............98
Nanotechnology to measure amyloid-derived diffusible ligands ..........99
Simultaneous measurement of several biomarkers for AD 99
Concluding remarks about biomarkers for AD 99
Imaging in AD..... 100
Computed tomography .......... 100
Magnetic resonance imaging... 100
Arterial spin labeling with MRI............. 101
Magnetic resonance microscopy .......... 101
Magnetic resonance spectroscopy........ 101
Single photon emission computed tomography and modifications..... 102
Positron emission tomography 103
In vivo imaging of Ab deposits by PET....... 104
In vivo detection of Ab plaques by MRI ..... 105
Imaging agents for Ab and neurofibrillary tangles.......... 106
Targeting of chemokine receptor as biomarker for brain imaging...... 107
Radioiodinated clioquinol as a biomarker for Aß ............ 107
Preclinical diagnosis of AD ...... 107
Diagnosis of AD in the living patient ......... 108
Meta-analysis of literature on imaging in AD 109
Alzheimer Disease Neuroimaging Initiative 109
Diagnosis of MCI and prediction of AD .... 110
Diagnosis of MCI 110
Computer-Administered Neurophychological screen for MCI........ 110
Infrared eye-tracking technology to detect MCI........ 110
PET for detection of MCI.... 110
MRI for detection of MCI ... 111
Presymptomatic detection of AD .............. 111
Use of biomarkers to predict AD in patients with MCI..... 112
Magnetoencephalography for detection of MCI and AD... 112
Concluding remarks about prediction of AD in MCI ........ 113
Ethical aspects of diagnostics for AD....... 113
Genetic testing for AD............ 113
Ethical issues of brain imaging in AD ........ 114
Companies involved in diagnosis of AD ... 115
3. Management of Alzheimer Disease 117
Introduction....... 117
Cholinergic approaches.......... 117
Mechanism of action of cholinesterase inhibitors ........... 118
Choline and lecithin ............... 119
Donepezil.......... 120
Rivastigmine...... 121
Galantamine...... 122
Duration of treatment with ChE inhibitors.. 123
Comparative studies of ChE inhibitors..... 123
Donepezil versus rivastigmine. 123
Donepezil versus galantamine. 124
An assessment and future prospects of anticholinergic therapies...... 124
Neuroprotection in Alzheimer's disease .. 125
Memantine ........ 126
Combination of memantine with ChE inhibitors ........ 128
Monoamine oxidase inhibitors . 129
Selegiline ..... 129
Synaptoprotection in AD ........ 129
Drugs for noncognitive symptoms in AD . 130
Antidepressants . 130
Antipsychotics.... 130
ChE inhibitors for behavioral and psychological disorders in AD........ 131
Concluding remarks and other drugs for agitation in AD. 131
Sensory stimulation............... 132
Non-pharmacological treatments of AD .. 132
Management of memory loss in AD .......... 132
Application of electrical fields for improvement of cerebral function in
AD............. 133
Vagal nerve stimulation ......... 133
Cerebrospinal fluid shunting ... 134
Omental transposition............ 134
Microchip-based hippocampal prosthesis for AD ............ 135
Nutritional therapies for AD ... 135
Omega-3 fatty acids ......... 135
Docosahexaenoic acid....... 136
Cocktail of dietary supplements for AD. 137
Preventing decline of mental function with aging and dementia. 137
Prevention of Alzheimer disease ............. 138
Mental training 139
Physical exercise .............. 139
Higher level of conscientiousness and decreased risk of AD ........ 140
Caloric restriction ............. 140
Nutritional factors in prevention of AD . 140
Red wine antioxidants....... 140
Black and green teas ........ 141
Caffeine ....... 142
Drugs to prevent Alzheimer disease.......... 142
Preimplantation genetic diagnosis of inherited Alzheimer disease ..... 142
Presymptomatic detection of AD .............. 142
Management of mild cognitive impairment ................ 143
Management of Down syndrome............. 144
Guidelines for use of anti-dementia drugs in clinical practice ..... 144
General care of the Alzheimer disease patients ......... 145
Strategies for the management of Alzheimer disease 145
4. Research in Alzheimer Disease ...... 147
Introduction....... 147
Animal models of Alzheimer disease ....... 147
Lesional models . 147
Cerebroventricular injection of Ab in rats 147
Lentiviral vector-based models of amyloid pathology 148
AAV-mediated gene transfer to increase hippocampal Ab............ 148
Transgenic mouse models ...... 148
Quantitative assessment of amyloid load in transgenic models.... 150
Neuropathological studies on transgenic models of AD ............... 150
In vivo magnetic resonance microimaging in transgenic models of AD ............
150
Transgenic model of AD with suppression of Aß production......... 150
Transgenic AD11 anti-NGF mice.......... 151
Genetically altered mice with deficiency of vesicular ACh transporter
.............. 151
Limitations of mouse models of Alzheimer disease.... 151
Cholesterol-fed rabbits as models for AD... 152
Zebrafish model for AD .......... 152
Transgenic invertebrate models of Alzheimer disease..... 153
Drosophila model of AD..... 153
Caenorhabditis elegans Alzheimer disease model ..... 154
Cell systems for AD research . 154
In vitro neuronal cell Lines ..... 154
Single-gene expression system for use in cell culture..... 155
Transgenic cells . 155
In silico models.. 155
Estimation of progression rates of Alzheimer disease 156
Clinical trial methods in Alzheimer disease ................ 157
Molecular imaging as a guide to drug development........ 157
Use of MRI and PET in clinical trials ..... 158
Cognitive-function assessment in clinical trials.............. 158
Clinical trials in mild cognitive impairment. 158
Research in AD as a basis for future therapies........... 159
Use of microarrays for studying pathogenesis of AD ...... 159
Computational brain mapping in AD.......... 159
Study of neurogenesis in AD... 159
Study of 3D structure of Ab .... 160
Solid-state NMR to study precursors of Ab . 160
Research in Alzheimer disease at academic centers... 160
Role of NIH in AD research ..... 160
NIH Clinical Trials Database for AD........... 160
Alzheimer Research Consortium ............... 161
The National Institute on Aging and AD research........... 161
5. Drug Discovery & Development for Alzheimer Disease ...... 163
Introduction....... 163
Categories of drugs in development for AD................ 163
Memory-enhancing drugs....... 165
Enhancing memory by drugs that block eIF2a phosphorylation ........ 165
Drugs based on cholinergic approaches .. 165
AP2238............. 166
Ganstigmina...... 166
T-82 166
Butyrylcholinesterase inhibitors................ 166
Muscarinic receptor modulators................ 167
Muscarinic M1 agonists ..... 167
Muscarinic M2 antagonists. 168
Nicotinic receptor modulators . 168
Nicotine ....... 168
Nicotinic receptor modulators ............. 169
Drugs modulating gamma-aminobutyric acid receptors .. 171
AVE-3933..... 171
SGS742 ....... 171
Neuropeptide/neurotransmitters............ 171
Somatostatin release enhancers............... 172
Glutamate receptor modulators .............. 172
Physiology and pharmacology of glutamate receptors .... 172
NMDA receptor ion channel complex......... 173
Metabotropic glutamate receptors ............ 174
Glutamate receptor modulators as potential therapeutics for AD ...... 175
Non-competitive NMDA modulators ..... 175
AMPA modulators ............. 176
Drugs affecting multiple neurotransmitters ............... 176
Ensaculin .......... 176
NS2330 ............ 176
RS-1259 ........... 177
Lecozotan ......... 177
Vaccines for AD... 177
Active immunization with Ab... 178
AN-1792 vaccine .............. 178
Complications in clinical trials with AN-1792 ............ 178
Effects of Ab vaccine on the brain........ 179
Strategies to avoid undesirable effect of Ab vaccination.............. 180
Passive immunization with monoclonal antibodies ......... 180
Delivery of the passive antibody directly to the brain 181
Other vaccines for AD ............ 182
T-cell vaccination with glatiramer acetate adjuvant .. 182
Nasal vaccination with ProteosomeÔ adjuvant ......... 183
Modified Ab nasal vaccine.. 183
Gene vaccination.............. 183
Early start of immunotherapy to clear Ab plaques.......... 184
Reversal of cholinergic dysfunction by anti-Ab antibody.. 184
Mechanisms by which Ab antibodies reduce amyloid accumulation in the brain......
184
Perspectives on vaccines for AD ............... 185
Companies involved in AD vaccines .......... 186
Inhibition of amyloid precursor protein aggregation.. 187
Secretase inhibitors............... 187
Neuroprotection by a-secretase cleaved APP............ 187
b-secretase inhibitors........ 188
g-secretase inhibitors ........ 189
Amyloid-derived diffusible ligands ............ 189
Depletion of serum amyloid P . 189
Trojan-horse approach to prevent build-up of Ab aggregates ........... 189
Drugs that inhibit the formation of Ab..... 190
- 8 -
22R-hydroxycholesterol ......... 190
Acylaminopyrazole ................ 191
Alzhemed.......... 191
Antihypertensive drugs .......... 191
Valsartan ..... 191
Clioquinol and PBT2............... 192
Zinc chelation from amyloid plaques......... 193
Tetrahydrocannabinol ............ 193
NSAIDS ............ 194
Flurbiprofen analogs with Ab42-lowering action........ 195
Nitric oxide-donating NSAIDs.............. 196
In vivo demonstration of the effects of NSAIDs on brain in AD .... 196
Imatinib mesylate 196
Laminin............ 197
Paclitaxel .......... 197
Phenserine ........ 197
Tolserine...... 198
Heparin and its derivatives ..... 198
A reassessment of the role of heparin in AD ............ 198
Enoxaparin ... 199
HF0420........ 199
Heparan sulfate ............... 199
Scyllo-cyclohexanehexol ........ 200
Ubiquitin C-terminal hydrolase L1............. 200
Drugs to prevent the formation of NFTs.. 200
Tau suppression.. 201
ApoE4 as a therapeutic target in AD........ 201
Therapeutics that reverse cerebral amyloid deposits. 201
ABCA1 overexpression to lower amyloid deposits .......... 201
b-sheet breakers 202
Intravenous immune globulin . 202
Meptides ........... 203
4,5-dianilinophthalimide for disruption of Ab1-42 fibrils.. 203
Removal of Ab deposits by nanotechnology . 204
Enhanced PKC? activity promotes clearance of Ab ......... 204
Role of matrix metalloproteinases in clearance of Ab...... 205
Blocking ApoE/Ab interaction to reduce Ab plaques........ 205
Inhibitors of Ab dehydrogenase................ 205
Companies developing Ab-directed therapeutics for AD .............. 206
Antiinflammatory and antimicrobial drugs 207
Dapsone ........... 207
Antimicrobial drugs against C. pneumoniae . 208
PPAR-gamma agonists........... 208
Inhibitors of neuroinflammation ............... 209
VP015.......... 209
MW01-5-188WH .............. 209
Antidiabetic drugs. 209
Rosiglitazone ..... 210
Pioglitazone....... 210
Nootropics .......... 211
Acetyl-L-carnitine. 211
Cerebrolysin ...... 211
Ergot derivatives 212
Lisuride........ 212
Dihydroergocryptine ......... 212
Neuroprotective effect drugs not primarily developed for AD
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