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Alzheimer disease - new drugs, markets and companies

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Abstract

Summary

Alzheimer's disease remains a challenge in management. With nearly 8 million sufferers from this condition in the seven major markets of the world and anticipated increases in the future. Considerable research is in progress to understand the pathomechanism of the disease and find a cure. The only drugs approved currently are acetylcholinesterase inhibitors but they do not correct the basic pathology of the disease, beta amyloid deposits and neurofibrillary tangles. Several new approaches emphasize neuroprotection as well.

Early diagnosis of Alzheimer's disease is an important first step in management. Several biomarkers in cerebrospinal fluid, blood and urine can detect the disease. They provide a valuable aid to the clinical examination and neuropsychological testing which are the main diagnostic methods supplemented by brain imaging. Genotyping, particularly of ApoE gene alleles is also useful in the evaluation of cases and planning management.

The current management of Alzheimer's disease is reviewed and it involves a multidisciplinary approach. Acetylcholinesterase inhibitors are mostly a symptomatic treatment but some claims are made about a neuroprotective effect. Currently the only approved neuroprotective therapy in is memantine. Management of these patients also require neuroleptics for aggressive behavior and antidepressants. There is an emphasis on early detection at the stage of mild cognitive impairment and early institution of neuroprotective measures. The value of mental exercise in delaying the onset of Alzheimer's disease is being recognized.

Research in Alzheimer's disease still aims at elucidating the basic pathomechanisms. Animal models are important for research, particularly in testing some of the potential therapeutic approaches. There is considerable research in progress at the various centers, some of which is funded by the National Institute of Aging of the National Institutes of Health.

Over 300 different compounds are at various stages of development for the treatment of Alzheimer's disease. These are classified and described. There are non-pharmacological approaches such as vagal nerve stimulation and cerebrospinal fluid shunting, which are in clinical trials. Over 176 clinical trials are listed, of which 126 are still in progress and 50 were discontinued for various reasons.

Alzheimer's disease market in the seven major markets is analyzed for the year 2010. Several new therapies are expected to be in the market and the shares of various types of approaches are estimated for the future up to the year 2020. As a background to the markets, pharmacoeconomic aspects of care of Alzheimer disease patients and patterns of practice are reviewed in the seven major markets.

Profiles of 142 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 107 collaborations. The bibliography contains over 600 publications that are cited in the report.The report is supplemented with 44 tables and 14 figures.

Table of Contents

0. Executive Summary

1. Clinical Features, Epidemiology and Pathology

  • Introduction
  • Historical aspects
  • Clinical features of Alzheimer disease
  • Seven stages of Alzheimer disease
  • AD as a terminal illness
  • 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
  • Evolution of diagnostic criteria of AD
  • Revised criteria for the clinical diagnosis 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 AΒ deposits and pathogenesis of AD
  • APP intracellular domain
  • Role of secretases in amyloid cascade
  • Role of exosomal proteins
  • Role of nicastrin
  • Neurotixicity of AΒ deposits
  • Relation of AΒ deposits to synaptic activity
  • Dysfunction of TGF-Β signaling accelerates AΒ deposition
  • Role of TMP21 in presenilin complexes and AΒ formation
  • Role of AΒ dimers in the pathogenesis of AD
  • Structure neurotoxicity relationships of AΒ oligomers
  • AΒ deposit and clearance
  • Impairment of mitochondrial energy metabolism
  • AΒ-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
  • Aerobic glycolysis and AD
  • Astrocytes and AD
  • Axonal transport failure in AD
  • Cell-cycle hypothesis
  • Chronic heart failure link with AD
  • 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-kΒ 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 AΒ
  • 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
  • Reduced muscle strength
  • Sleep deprivation
  • 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 cognitive impairment with aging
  • Pathomechanism of memory impairment and AD
  • 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
  • AlzGene database
  • ApoE gene
  • ApoE genotype and nitric oxide
  • ApoE genotype modulates AD phenotype
  • APOE genotype and age-related myelin breakdown
  • ApoE receptor interaction with NMDA receptor
  • ApoE and ApoER2
  • ApoE receptor LR11 as regulator of Aβ
  • Arctic mutation
  • CALHM1 polymorphism and AD
  • CLU, CRI and PICALM
  • CYP46 and risk for AD
  • DAPK1 gene variants and AD
  • Genetic variants associated with late-onset AD
  • Copy number variation (CNV) in LOAD
  • LRRTM3 as a candidate gene for AD
  • MTHFD1L gene variant associated with AD
  • OGG1 mutations associated with AD
  • SORL1 gene in AD
  • TOMM40 gene and risk of AD
  • International Genomics of Alzheimer's Project
  • Molecular neuropathology
  • Role of microRNAs in AD
  • AD as a polygenic disorder
  • 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
  • FE65 proteins and AD

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
  • 7-minute screen
  • 15-point risk index
  • 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
  • DETECTäð System
  • Electrophysiology
  • EEG-based bispectral index
  • Event-related potentials
  • Correlation of electrical activity of the brain with cognition
  • Early detection of cataract associated with AD
  • Retinal imaging to detect AΒ deposits
  • Laboratory methods for diagnosis of AD
  • Monitoring of synthesis and clearance rates of AΒ 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 Aβin CSF
  • Tests combining CSF tau and Aβ115
  • Urine tests for AD
  • Blood tests for AD
  • Blood AΒ levels
  • Blood test for AD based on heme oxygenase-1
  • 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
  • Sphingolipids
  • Tests based on protein biomarkers in blood
  • A skin test for early detection of AD
  • Saliva-based tests for AD
  • Saliva AΒ42 level as a biomarker of AD
  • Nanotechnology to measure AΒ-derived diffusible ligands
  • Simultaneous measurement of several biomarkers for AD
  • Plasma biomarkers of drug response in AD
  • A serum protein-based algorithm for the detection of 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 Aβdeposits by PET
  • Pittsburgh compound B and PET
  • Florbetapir-PET
  • Florbetaben-PET
  • In vivo detection of AΒ plaques by MRI
  • Imaging agents for AΒ and neurofibrillary tangles
  • Targeting of a chemokine receptor as biomarker for brain imaging
  • Radioiodinated clioquinol as a biomarker for AΒ
  • Imaging neuroinflammation in AD
  • Preclinical diagnosis of AD
  • Meta-analysis of literature on imaging in AD
  • Alzheimer Disease Neuroimaging Initiative
  • Concluding remarks on imaging for diagnosis of AD
  • 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
  • Prediction of AD in patients with MCI
  • Combination of MMSE and a memory test for prediction of AD
  • Biochemical biomarkers in CSF for prediction of AD
  • Structural MRI biomarkers for prediction of AD
  • Magnetoencephalography for detection of MCI and AD
  • Concluding remarks about prediction of AD in MCI
  • Criteria for diagnosis of AD
  • Role of biomarkers in diagnosis of AD dementia
  • 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
  • Exposure to electromagnetic fields for treatment of AD
  • Application of electrical fields for improvement of cerebral function
  • High-frequency electromagnetic field treatment of AD
  • Vagal nerve stimulation
  • Cerebrospinal fluid shunting
  • Omental transposition
  • Microchip-based hippocampal prosthesis for AD
  • Nutritional therapies for AD
  • Axona
  • Cocktail of dietary supplements for AD
  • Docosahexaenoic acid
  • Magnesium
  • Nicotinamide for the treatment of AD
  • Omega-3 fatty acids
  • 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
  • Grapes and red wine
  • 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
  • Donepezil and/or memantine
  • 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 AΒ in rats
  • Lentiviral vector-based models of amyloid pathology
  • AAV-mediated gene transfer to increase hippocampal Aβ176
  • Transgenic mouse models
  • Quantitative assessment of amyloid load in transgenic models
  • In vivo magnetic resonance microimaging in transgenic models of AD
  • Transgenic model of AD with suppression of AΒ 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 AΒ
  • Solid-state NMR to study precursors of AΒ
  • 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 eIF2ƒ¿ phosphorylation
  • Drugs based on cholinergic approaches
  • AP2238
  • Butyrylcholinesterase inhibitors
  • Donepezil-tacrine hybrids
  • Drugs modulating gamma-aminobutyric acid receptors
  • Ganstigmina
  • Methanesulfonyl fluoride
  • Muscarinic receptor modulators
  • Muscarinic M1 agonists
  • Muscarinic M2 antagonists
  • Nicotine and nicotinic receptor modulators
  • Nicotine
  • Nicotinic receptor modulators
  • GTS21
  • Ispronicline
  • JWB1-84-1
  • 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 Aβ208
  • AN-1792 vaccine
  • Complications in clinical trials with AN-1792
  • Effects of AΒ vaccine on the brain
  • Strategies to avoid undesirable effect of AΒ vaccination
  • Passive immunization in AD
  • Passive immunization with MAbs
  • Delivery of the passive antibody directly to the brain
  • Systemic injection of MAbs to treat AD
  • Combination of Aβimmunotherapy and CD40-CD40L blockade
  • Shaping the immune responses elicited against Aβ213
  • Delivery of AD vaccines
  • Gene vaccination
  • Modified AΒ nasal vaccine
  • Transdermal AΒ vaccination
  • Other vaccines for AD
  • Nasal vaccination with ProteosomeÔ-adjuvant
  • T-cell vaccination with glatiramer acetate adjuvant
  • Early start of immunotherapy to clear Aβplaques
  • Reversal of cholinergic dysfunction by anti-Aβantibody
  • Immune modulation via TRL9 to reduce AΒ
  • Mechanisms by which Aβantibodies reduce amyloid accumulation in the brain
  • Perspectives on vaccines for AD
  • Companies involved in AD vaccines
  • Inhibition of amyloid precursor protein aggregation
  • Secretase modulators
  • Neuroprotection by ƒ¿-secretase cleaved APP
  • Inhibitors of Β-secretase
  • Inhibitors of ƒÁ-secretase
  • 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 AΒ aggregates
  • Drugs that inhibit the formation of AΒ
  • 22R-hydroxycholesterol
  • Acylaminopyrazole
  • Cadmium telluride nanoparticles prevent AΒ fibril formation
  • Cannabinoids
  • Chelation therapy for AD
  • Clioquinol and PBT2
  • Copper chelation by FKBP52
  • Zinc chelation from amyloid plaques
  • Next generation multifunctional chelating agents for AD
  • Heparin and its derivatives
  • A reassessment of the role of heparin in AD
  • Enoxaparin
  • Heparan sulfate
  • Imatinib mesylate
  • Laminin
  • NSAIDs
  • Flurbiprofen analogs with Aβ2-lowering action
  • Nitric oxide-donating NSAIDs
  • In vivo demonstration of the effects of NSAIDs on brain in AD
  • Paclitaxel
  • Phenserine
  • Tolserine
  • Platinum-based inhibitors of Aβ235
  • 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 prevent deposits and enhance clearance of AΒ
  • 4,5-dianilinophthalimide for disruption of AΒ1-42 fibrils
  • ABCA1 overexpression to lower amyloid deposits
  • Beta-sheet breakers
  • Blocking ApoE/Aβinteraction to reduce AΒ plaques
  • Clearance of AΒ across the blood-brain barrier
  • Enhanced PKCT activity promotes clearance of AΒ
  • Galantamine-induced AΒ clearance
  • Inhibitors of AΒ dehydrogenase
  • Intravenous immune globulin
  • Meptides
  • Monoclonal antibodies for removal of AΒ
  • Nanotechnology for removal of AΒ deposits
  • Role of matrix metalloproteinases in clearance of AΒ
  • SAN-61 for cleavage of fibril and soluble amyloid
  • Serum amyloid P component depletion
  • Small molecule DAPH for clearance of amyloid
  • Companies developing AΒ-directed therapeutics for AD
  • Antiinflammatory and antimicrobial drugs
  • Dapsone
  • Antimicrobial drugs against C. pneumoniae
  • PPAR-gamma agonists
  • Inhibitors of neuroinflammation
  • Cyclophosphamide
  • Etanercept
  • MW01-5-188WH
  • Antidiabetic drugs
  • Rosiglitazone
  • Pioglitazone
  • Nootropics
  • Acetyl-L-carnitine
  • Cerebrolysin
  • Ergot derivatives
  • Lisuride
  • Dihydroergocryptine
  • Neuroprotective effect drugs not primarily developed for AD
  • Antihypertensive drugs
  • Angiotensin-converting enzyme inhibitors
  • Angiotensin receptor blockers
  • Dimebolin
  • Drugs acting on estrogen receptors
  • Estrogen
  • Raloxifene
  • Neurosteroids
  • Pregnenolone sulfate
  • Dehydroepiandrosterone
  • Lithium
  • MAO-B inhibitors
  • Ladostigil tartrate
  • Memoquin
  • Methylene blue
  • Nimodipine
  • Rapamycin
  • Statins
  • Testosterone
  • 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
  • Huperzine-A
  • Hyperforin
  • Melissa officinalis
  • Nostocarboline derived from cyanobacteria
  • PTI-00703
  • Salvia
  • Securinega suffruticosa
  • Withania somnifera
  • ZT-1
  • Cholesterol and AD
  • 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
  • Activity-dependent neuroprotective protein
  • Brain derived neurotrophic factor
  • Insulin-like growth factor-1
  • Nerve growth factor
  • Neotrofin (AIT-082)
  • 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 for AD
  • Potential benefits of grafting NSCs in AD
  • NSCs improve cognition in AD via BDNF
  • Drugs for enhancing neuronal differentiation of implanted NSCs
  • Implantation of encapsulated cells for delivering NGF
  • Gene therapy for AD
  • ApoE gene therapy
  • FGF2 gene transfer in AD
  • 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
  • Transdermal rivastigmine
  • Intranasal delivery of therapeutics for AD
  • Intranasal delivery of tacrine
  • 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
  • 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
  • Electrophysiological detection of drug target for neuroprotection in early AD
  • Genomics-based drug discovery
  • High through screening for AD drug candidates
  • Proteomics and drug discovery for AD
  • 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
  • Activators of insulin-degrading enzyme
  • Blockade of TGF-βSmad2/3 signaling in peripheral macrophages
  • Calcium channel blockers
  • Casein kinase 1
  • Cyclin-dependent kinase-5
  • Heat shock protein 90 inhibitors
  • Histone deacetylase 1
  • Inactivation of aph-1 and pen-2 reduces APP cleavage
  • NF-kΒ inhibitors
  • Kinases and phosphatases as targets for AD therapeutics
  • Neutral sphingomyelinase inhibitors
  • Phosphodiesterase inhibitors
  • Pin 1 as a target in AD
  • Protein phosphatase 5 as a neuroprotective in AD
  • Src homology-containing protein-1 inhibitors
  • Targeting GABAergic system
  • Pharmacogenomics of Alzheimer disease
  • Personalized therapy of AD
  • Genotyping and AD therapeutics
  • Biomarkers and companion diagnostics for AD
  • Regulatory aspects of drug development for AD
  • EMEA guidelines for drug development for AD
  • Concluding remarks and future prospects of drugs for AD

6. Markets & Finances of AD Care

  • Introduction
  • Pharmacoeconomics of treatment of AD
  • Quality of Life in relation to economics 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: A guide to evaluation for MCI due to AD
  • Table 1 5: NINCDS-ADRDA Criteria for diagnosis of Alzheimer disease
  • Table 1 6: Relation of mutations in amyloid precursor protein to CNS disorders
  • Table 1 7: Risk factors for Alzheimer's disease
  • Table 1 8: Genes linked to AD
  • Table 1 9: 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 biomarkers of AD in blood and CSF
  • Table 2 5: Characteristics of an ideal biomarker for Alzheimer disease
  • Table 2 6: Role of biomarkers in diagnosis of AD dementia
  • Table 2 7: 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: Secretase modulators in clinical trials
  • Table 5 8: Companies developing AΒ-directed therapeutics for AD
  • Table 5 9: Innovative neuroprotective approaches for Alzheimer disease
  • Table 5 10: Herbal therapies for AD
  • Table 5 11: Novel drug delivery methods for Alzheimer disease therapies
  • Table 5 12: Clinical trials in Alzheimer disease
  • Table 5 13: 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 2011-2021
  • Table 6 3: AD market values from 2011-2021 in major world markets
  • Table 6 4: Markets for currently approved AD drugs 2011-2021
  • Table 6 5: Potential markets for drugs in development 2011-2021
  • 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: Correlation between aging and AD in the US from 2000 to 2020
  • Figure 1 3: Prevalence of different types of dementia
  • Figure 1 4: Mechanisms of AΒ clearance
  • Figure 1 5: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease
  • Figure 1 6: Oxidative stress and Alzheimer disease
  • Figure 1 7: Role of proteosome inhibition in AΒ generation and neurodegeneration
  • Figure 1 8: 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 Aβ-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
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