Contents:

0. Executive Summary 1. Clinical Features, Epidemiology and Pathology Introduction Historical aspects Clinical features of Alzheimer disease Seven stages of Alzheimer disease Detection of AD in the preclinical phase Differentiation of AD from other dementias Differentiation of AD from non-dementing disorders Cerebral insufficiency and AD Memory deficits and preclinical AD Mild cognitive impairment Diagnostic criteria of AD Epidemiology Epidemiology of aging Epidemiology of dementia Epidemiology of AD Prevalence of AD according to age Mortality in AD Pathophysiology of AD Cerebral atrophy and neuronal loss Neuritic plaques and neurofibrillary tangles Sp proteins as markers of neuronal death in AD Role of tau in the pathogenesis of AD Amyloid precursor protein Relation of APP mutations to CNS disorders Relation of APP to Aß deposits and pathogenesis of AD Role of secretases in amyloid cascade Role of exosomal proteins Role of nicastrin Neurotixicity of A? deposits Relation of Aß deposits to synaptic activity Dysfunction of TGF-ß signaling accelerates Aß deposition Role of TMP21 in presenilin complexes and A? formation Role of A? dimers in the pathogenesis of AD A? deposit and clearance Impairment of mitochondrial energy metabolism A?-binding alcohol dehydrogenase links AD to mitochondrial toxicity Neural thread protein Loss of synaptic proteins AD and Down syndrome Overlapping pathologies of AD and Parkinson disease AD and age-related macular degeneration Myelin hypothesis of AD Blood-brain barrier in AD Blood vessel damage in AD Loss of serotonin 1A receptors in the brain Factors in pathogenesis of AD Astrocytes and AD Axonal transport failure in AD Cell-cycle hypothesis Creatine and AD Disturbances of interaction of nervous system proteins DENN/MADD expression and enhanced pro-apoptotic signaling in AD Gonadotrophins and AD Glutamate transport dysfunction in AD Innate immune system and AD Insulin, diabetes and AD Mechanisms underlying cognitive deficits in AD Monoamine oxidase and AD Neuroinflammation and AD Neurotransmitter deficits Neurotrophic factors NF-?B signaling and the pathogenesis of neurodegeneration Nitric oxide and AD Nogo receptor pathway Oxidative stress and AD Prostaglandins and AD Quinolinic acid and AD Retromer deficiency Serotonin and AD Spherotoxin Synaptic failure in AD Transmission of AD Ubiquitin-proteasome system in pathogenesis of AD Risk factors in the etiology of AD Aging and developmental abnormalities of the cholinergic system Cholesterol, dietary lipids, and A? Exposure to magnetic fields Family history of AD Homocysteine and AD Level of education/type of job and risk of AD Metals and AD Obesity Proneness to psychological distress and risk of AD Traumatic brain injury and AD Vascular risk factors for AD Vitamin B12 and folate AD versus non-dementing changes in the aging brain AD and impairment in cognitive aging Concluding remarks on pathophysiology of AD Genetics of AD Familial AD Presenilins and calcium channel leak in pathogenesis of familial AD Late onset AD Genomics of AD Introduction to genomics Genes associated with Alzheimer disease ApoE gene ApoE genotype and nitric oxide APOE genotype and age-related myelin breakdown CALHM1 polymorphism and AD Interaction between ApoE receptor and NMDA receptor ApoE and ApoER2 LR11 receptor for ApoE as regulator of A? DAPK1 gene variants and AD CYP46 and risk for AD Genetic variants associated with late-onset AD OGG1 mutations associated with AD Role of SORL1 gene in AD The Arctic mutation LRRTM3 as a candidate gene for AD AlzGene database Molecular neuropathology Proteomics of AD Introduction Application of proteomic technologies to study AD Protein misfolding in AD Common denominators of AD and prion diseases Amyloid fibrils as a common feature of AD and prion diseases 2. Diagnostic Procedures for Alzheimer Disease Importance of the diagnosis of Alzheimer disease Methods of diagnosis of AD Self-administered olfactory test Neuropsychological testing Assessment and evaluation The seven minute screen Measurement of aggregation in anterior segment of the eye Activities of Daily Living Alzheimer Disease Cooperative Study CDR-SOB score Clinician's Interview-Based Impression of Change Resource Utilization in Dementia Battery DETECT? System Electrophysiology Early detection of cataract associated with AD Laboratory methods for diagnosis of AD Monitoring of synthesis and clearance rates of A? in the CSF Molecular diagnostics for AD Genetic tests for AD ApoE genotyping Gene expression patterns in AD Molecular fingerprinting of the immune system in AD Microarray-based tests for AD Monoclonal antibody-based in vitro diagnosis of AD from brain tissues Biomarkers of AD The ideal biomarker for AD CSF biomarkers of AD CSF sulfatide as a biomarker for AD Glycerophosphocholine as CSF biomarker in AD Protein biomarkers of AD in CSF Amyloid precursor protein Tau proteins in CSF Tests for the detection of A? in CSF Tests combining CSF tau and A? Urine tests for AD Blood tests for AD Blood A? levels Blood test for AD based on RNA hybridization GSK-3 elevation in white blood cells Lymphocyte Proliferation Test Protein kinase C in red blood cells A skin test for early detection of AD Nanotechnology to measure amyloid-derived diffusible ligands Simultaneous measurement of several biomarkers for AD Concluding remarks about biomarkers for AD Imaging in AD Computed tomography Magnetic resonance imaging Arterial spin labeling with MRI Magnetic resonance microscopy Magnetic resonance spectroscopy Single photon emission computed tomography and modifications Positron emission tomography In vivo imaging of A? deposits by PET In vivo detection of A? plaques by MRI Imaging agents for A? and neurofibrillary tangles Targeting of chemokine receptor as biomarker for brain imaging Radioiodinated clioquinol as a biomarker for Aß Preclinical diagnosis of AD Diagnosis of AD in the living patient Meta-analysis of literature on imaging in AD Alzheimer Disease Neuroimaging Initiative Diagnosis of MCI and prediction of AD Diagnosis of MCI Computer-Administered Neurophychological screen for MCI Infrared eye-tracking technology to detect MCI PET for detection of MCI MRI for detection of MCI Presymptomatic detection of AD PredictAD project Use of biomarkers to predict AD in patients with MCI Magnetoencephalography for detection of MCI and AD Concluding remarks about prediction of AD in MCI Ethical aspects of diagnostics for AD Genetic testing for AD Ethical issues of brain imaging in AD Companies involved in diagnosis of AD 3. Management of Alzheimer Disease Introduction Cholinergic approaches Mechanism of action of cholinesterase inhibitors Choline and lecithin Donepezil Rivastigmine Galantamine Duration of treatment with ChE inhibitors Comparative studies of ChE inhibitors Donepezil versus rivastigmine Donepezil versus galantamine An assessment and future prospects of anticholinergic therapies Neuroprotection in Alzheimer's disease Memantine Combination of memantine with ChE inhibitors Monoamine oxidase inhibitors Selegiline Synaptoprotection in AD Drugs for noncognitive symptoms in AD Antidepressants Antipsychotics ChE inhibitors for behavioral and psychological disorders in AD Concluding remarks and other drugs for agitation in AD Sensory stimulation Non-pharmacological treatments of AD Management of memory loss in AD Application of electrical fields for improvement of cerebral function in AD Vagal nerve stimulation Cerebrospinal fluid shunting Omental transposition Microchip-based hippocampal prosthesis for AD Nutritional therapies for AD Omega-3 fatty acids Docosahexaenoic acid Cocktail of dietary supplements for AD Preventing decline of mental function with aging and dementia Prevention of Alzheimer disease Mental training Physical exercise Higher level of conscientiousness and decreased risk of AD Caloric restriction Nutritional factors in prevention of AD Red wine antioxidants Black and green teas Caffeine Drugs to prevent Alzheimer disease Preimplantation genetic diagnosis of inherited Alzheimer disease Presymptomatic detection of AD Management of mild cognitive impairment Management of Down syndrome Guidelines for use of anti-dementia drugs in clinical practice General care of the Alzheimer disease patients Strategies for the management of Alzheimer disease 4. Research in Alzheimer Disease Introduction Animal models of Alzheimer disease Lesional models Cerebroventricular injection of A? in rats Lentiviral vector-based models of amyloid pathology AAV-mediated gene transfer to increase hippocampal A? Transgenic mouse models Quantitative assessment of amyloid load in transgenic models Neuropathological studies on transgenic models of AD In vivo magnetic resonance microimaging in transgenic models of AD Transgenic model of AD with suppression of Aß production Transgenic AD11 anti-NGF mice Genetically altered mice with deficiency of vesicular ACh transporter Limitations of mouse models of Alzheimer disease Cholesterol-fed rabbits as models for AD Zebrafish model for AD Transgenic invertebrate models of Alzheimer disease Drosophila model of AD Caenorhabditis elegans Alzheimer disease model Cell systems for AD research In vitro neuronal cell Lines Single-gene expression system for use in cell culture Transgenic cells In silico models Estimation of progression rates of Alzheimer disease Clinical trial methods in Alzheimer disease Molecular imaging as a guide to drug development Use of MRI and PET in clinical trials Cognitive-function assessment in clinical trials Clinical trials in mild cognitive impairment Research in AD as a basis for future therapies Use of microarrays for studying pathogenesis of AD Computational brain mapping in AD Study of neurogenesis in AD Study of 3D structure of A? Solid-state NMR to study precursors of A? Research in Alzheimer disease at academic centers Role of NIH in AD research NIH Clinical Trials Database for AD Alzheimer Research Consortium The National Institute on Aging and AD research 5. Drug Discovery & Development for Alzheimer Disease Introduction Categories of drugs in development for AD Memory-enhancing drugs Enhancing memory by drugs that block eIF2a phosphorylation Drugs based on cholinergic approaches AP2238 Ganstigmina T-82 Butyrylcholinesterase inhibitors Muscarinic receptor modulators Muscarinic M1 agonists Muscarinic M2 antagonists Nicotinic receptor modulators Nicotine Nicotinic receptor modulators Drugs modulating gamma-aminobutyric acid receptors AVE-3933 SGS742 Neuropeptide/neurotransmitters Somatostatin release enhancers Glutamate receptor modulators Physiology and pharmacology of glutamate receptors NMDA receptor ion channel complex Metabotropic glutamate receptors Glutamate receptor modulators as potential therapeutics for AD Non-competitive NMDA modulators AMPA modulators Drugs affecting multiple neurotransmitters Ensaculin NS2330 RS-1259 Lecozotan Vaccines for AD Active immunization with A? AN-1792 vaccine Complications in clinical trials with AN-1792 Effects of A? vaccine on the brain Strategies to avoid undesirable effect of A? vaccination Passive immunization in AD with monoclonal antibodies Delivery of the passive antibody directly to the brain Systemic injection of MAbs to treat AD Combination of A? immunotherapy and CD40-CD40L blockade Shaping the immune responses elicited against A? Gene vaccination Modified A? nasal vaccine Transdermal A? vaccination Other vaccines for AD Nasal vaccination with Proteosome? adjuvant T-cell vaccination with glatiramer acetate adjuvant Early start of immunotherapy to clear A? plaques Reversal of cholinergic dysfunction by anti-A? antibody Mechanisms by which A? antibodies reduce amyloid accumulation in the brain Perspectives on vaccines for AD Companies involved in AD vaccines Inhibition of amyloid precursor protein aggregation Secretase inhibitors Neuroprotection by ?-secretase cleaved APP ?-secretase inhibitors ?-secretase inhibitors Substrate-targeting big ?-secretase modulators Amyloid-derived diffusible ligands GABA receptor modulation by etazolate and APP processing Depletion of serum amyloid P Trojan-horse approach to prevent build-up of A? aggregates Drugs that inhibit the formation of A? 22R-hydroxycholesterol Acylaminopyrazole Alzhemed Antihypertensive drugs Valsartan Clioquinol and PBT2 Copper chelation by FKBP52 Zinc chelation from amyloid plaques Tetrahydrocannabinol NSAIDs Flurbiprofen analogs with A?42-lowering action Nitric oxide-donating NSAIDs In vivo demonstration of the effects of NSAIDs on brain in AD Imatinib mesylate Laminin Paclitaxel Phenserine Tolserine Platinum-based inhibitors of A? Heparin and its derivatives A reassessment of the role of heparin in AD Enoxaparin HF0420 Heparan sulfate Scyllo-cyclohexanehexol Ubiquitin C-terminal hydrolase L1 Drugs to prevent the formation of NFTs Tau suppression ApoE4 as a therapeutic target in AD Strategies to enhance clearance of A? Removal of A? deposits by nanotechnology Enhanced PKC? activity promotes clearance of A? Role of matrix metalloproteinases in clearance of A? Small molecule DAPH for clearance of amyloid Therapeutics to reverse cerebral A? deposits ABCA1 overexpression to lower amyloid deposits ?-sheet breakers Intravenous immune globulin Meptides 4,5-dianilinophthalimide for disruption of A?1-42 fibrils Blocking ApoE/A? interaction to reduce A? plaques Inhibitors of A? dehydrogenase Companies developing A?-directed therapeutics for AD Antiinflammatory and antimicrobial drugs Dapsone Antimicrobial drugs against C. pneumoniae PPAR-gamma agonists Inhibitors of neuroinflammation Etanercept MW01-5-188WH VP015 Antidiabetic drugs Rosiglitazone Pioglitazone Nootropics Acetyl-L-carnitine Cerebrolysin Ergot derivatives Lisuride Dihydroergocryptine Neuroprotective effect drugs not primarily developed for AD Angiotensin-converting enzyme inhibitors Dimebon Drugs acting on estrogen receptors Estrogen Raloxifene Neurosteroids Pregnenolone sulfate Dehydroepiandrosterone Lithium MAO-B inhibitors Ladostigil tartrate Memoquin Methylene blue Nimodipine Valproic acid Future prospects of neuroprotection in AD Targeting Cdk5 pathway Antioxidants Colostrinin Curcumin Melatonin Synthetic catalytic scavengers Dehydroascorbic acid Omega-3 fatty acids Vitamins Vitamin E as antioxidant Vitamins to lower homocysteine Folic acid Aminopyridazines Nanobody-based drugs for AD Nitric oxide based therapeutics for AD Nitric oxide mimetics iNOS inhibitors for AD Novel drugs for AD from natural resources Berberine chloride Centella asiatica Ginko biloba Gilatide (from saliva of the Gila monster) Huperzine-A Hyperforin Melissa officinalis Nostocarboline derived from cyanobacteria PTI-00703 Salvia Securinega suffruticosa Withania somnifera ZT-1 Cholesterol and AD Role of statins in reducing the risk of Alzheimer disease ACAT inhibitors Role of gene for cholesterol ester transfer protein Cholesterol 24S-hydroxylase as a drug target for AD Selectively increase of ApoA-I production Neurotrophic factors Brain derived neurotrophic factor Nerve growth factor Neotrofin (AIT-082) Activity-dependent neuroprotective protein Limitations of the use of NTFs for AD Role of serotonin modulators in AD Xaliproden 5-HT1A receptor antagonists 5-HT6 antagonists 5-HT4 receptor agonists PRX-03140 Cell therapy for AD Stem cell transplantation Implantation of encapsulated cells for delivering NGF Gene therapy for AD ApoE gene therapy Humanin gene therapy Neprilysin gene therapy NGF gene therapy Targeting plasminogen activator inhibitor type-1 gene Antisense approaches to AD RNAi approaches to AD Combined therapeutic approaches to AD Drug delivery for Alzheimer disease Delivery of thyrotropin-releasing hormone analogs by molecular packaging Nanoparticle-based drug delivery for Alzheimer’s disease Transdermal drug delivery in Alzheimer's disease Intranasal delivery of nerve growth factor to the brain Circadian rhythms and timing of cholinesterase inhibitor therapy Clinical trials for AD Drugs for AD that were discontinued in clinical trials Evaluation of clinical trials of AD Monitoring of cognitive function during clinical trials Drug discovery for AD Genomics-based drug discovery Proteomics and drug discovery for AD High through screening for AD drug candidates Drugs acting on signaling pathways Activation of GTPase signaling by Cytotoxic Necrotizing Factor 1 Drugs to reverse inhibition of the PKA/CREB pathway in AD Inhibition of the CD40 signaling pathway JNK pathway as a target Mitogen-activated protein kinase pathway as target Protein kinase C activators Small molecule compounds binding to neurotrophin receptor p75NTR Targeting Vav in tyrosine kinase signaling pathway Novels targets/receptors for AD drug discovery Activation of cerebral Rho GTPases Blockade of TGF-?-Smad2/3 signaling in peripheral macrophages Casein kinase 1 Cyclin-dependent kinase-5 Heat shock protein 90 inhibitors Inactivation of aph-1 and pen-2 reduces APP cleavage NF-?B inhibitors Kinases and phosphatases as targets for AD therapeutics Phosphodiesterase inhibitors Pin 1 as a target in AD Receptor for advanced glycation end products Src homology-containing protein-1 inhibitors Targeting GABAergic system Pharmacogenomics of Alzheimer disease Personalized therapy of AD Genotyping and AD therapeutics Concluding remarks and future prospects of drugs for AD 6. Markets & Finances of AD Care Introduction Pharmacoecnonomics of treatment of AD Costs associated with Alzheimer disease Pharmacoeconomics of donepezil Pharmacoeconomics studies using rivastigmine Pharmacoenonomics studies using galantamine A comparison of pharmacoenonomics outcomes with different ChE inhibitors Pharmacoenonomics studies using memantine Patterns of AD care in major markets Care of AD patients in the US Cost of care Medicare and AD Patterns of practice in AD care Opinions of physicians’ organizations on drugs for dementia Care of AD patients in the UK Cost of care Patterns of practice in AD care Retraction of NICE recommendations to NHS Care of AD patients in Germany Care of AD patients in France Care of AD patients in Italy Care of AD patients in Spain Care of AD patients in Japan Markets for AD diagnostics Markets for AD therapeutics Geographical markets for AD Markets for currently approved drugs for AD Markets for generic AD drugs Future growth of AD market Statins Limitations of AD drug development by the biotechnology industry Unmet needs in the management of AD Drivers of AD markets Increase of the aged populations Increase in the number of approved drugs for AD Limitations of the current therapies Improvements in diagnosis Increasing awareness of the disease 7. Companies Introduction Profiles of companies Collaborations 8. References Tables Table 1 1: Historical landmarks relevant to Alzheimer disease Table 1 2: Clinical features of Alzheimer disease Table 1 3: Non-Alzheimer dementias Table 1 4: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease Table 1 5: Relation of mutations in amyloid precursor protein to CNS disorders Table 1 6: Risk factors for Alzheimer's disease Table 1 7: Genes linked to AD Table 1 8: Abnormalities of expression of brain proteins in Down's syndrome and AD Table 2 1: Classification of methods of diagnosis of Alzheimer disease Table 2 2: Neuropsychological test batteries and scales for Alzheimer's disease Table 2 3: Available molecular diagnostic tests for Alzheimer disease Table 2 4: Classification of biochemical markers of AD in blood and CSF Table 2 5: Characteristics of an ideal biomarker for Alzheimer disease Table 2 6: Companies involved in the diagnosis of Alzheimer disease Table 3 1: Classification of treatments for Alzheimer disease Table 3 2: Cholinergic approaches used in the treatment of Alzheimer disease Table 3 3: Categories of neuroprotective agents for Alzheimer disease Table 3 4: Strategies for prevention of Alzheimer disease Table 3 5: Guidelines for the treatment of dementia Table 4 1: Transgenic mouse models of Alzheimer disease Table 5 1: Classification of therapies in development for Alzheimer disease Table 5 2: Drugs for AD targeting nACh receptors Table 5 3: Ionotropic glutamate receptors Table 5 4: Classification of mGluRs Table 5 5: Glutamate receptor modulators as potential therapeutic agents in AD Table 5 6: Companies involved in developing vaccines for AD Table 5 7: Companies developing A?-directed therapeutics for AD Table 5 8: Innovative neuroprotective approaches for Alzheimer disease Table 5 9: Herbal therapies for AD Table 5 10: Novel drug delivery methods for Alzheimer disease therapies Table 5 11: Clinical trials in Alzheimer disease Table 5 12: Discontinued, failed or inconclusive clinical trials of Alzheimer disease Table 6 1: Direct and indirect costs associated with Alzheimer disease Table 6 2: Prevalence of AD in major markets 2007-2017 Table 6 3: AD market values from 2007-2017 in the seven major world markets Table 6 4: Markets for currently approved AD drugs 2007-2017 Table 6 5: Potential markets for drugs in development 2007-2017 Table 6 6: Limitations of AD drug discovery and development by the biotechnology industry Table 6 7: Factors that drive AD markets Table 7 1: Major players in Alzheimer's disease therapeutics Table 7 2: Collaborations relevant to Alzheimer disease 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. Figure 1 2: Prevalence of different types of dementia Figure 1 3: Mechanisms of Aß clearance Figure 1 4: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease Figure 1 5: Oxidative stress and Alzheimer disease Figure 1 6: Role of proteosome inhibition in Aß generation and neurodegeneration Figure 1 7: Pathomechanism of AD Figure 3 1: Metabolism of acetylcholine Figure 3 2: Neuroprotective effective of galantamine in AD Figure 3 3: Strategies for the management of Alzheimer disease Figure 5 1: NMDA receptor ion channel complex. Figure 5 2: Neurotoxicity due to misfolding of A?1-42 Figure 5 3: Role of proteomics in drug discovery and development for Alzheimer disease Figure 6 1: Unmet needs in the management of Alzheimer disease