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Alzheimer Disease - New Drugs, Markets and Companies

  • ID: 4748164
  • Report
  • 555 Pages
  • Jain PharmaBiotech
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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 is memantine. Management of these patients also requires 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. Ongoing as well as discontinued clinical trials of AD are tabulated.

Alzheimer's disease market in the seven major markets is analyzed for the year 2018. 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 2028. 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 116 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 82 collaborations. The bibliography contains over 900 publications that are cited in the report. The report is supplemented with 48 tables and 27 figures.

The report contains information on the following:

  • Clinical features, epidemiology and pathology of Alzheimer disease
  • Diagnostic procedures for Alzheimer's disease
  • Management of Alzheimer's disease
  • Research in Alzheimer's disease
  • Drug discovery and development for Alzheimer's disease
  • Marketing and financial aspects of Alzheimer's disease
  • Companies
Note: Product cover images may vary from those shown
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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
Sleep disorders and AD
Circadian rhythms and sleep in 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
See-through 3D imaging of the AD brain
Sp proteins as biomarkers of neuronal death in AD  
Role of tau in the pathogenesis of AD
RNA-binding proteins and AD
Amyloid precursor protein
APP intracellular domain  
Relation of APP mutations to CNS disorders  
Relation of APP to Aβ deposits and pathogenesis of AD  
Role of neprilysin in Aβ degradation  
Role of secretases in amyloid cascade
Role of exosomal proteins  
Role of nicastrin  
Neurotoxicity of Aβ deposits  
Aβ production and clearance  
Aβ-mediated synaptic and cognitive deficits
Dysfunction of TGF-β signaling accelerates Aβ deposition
Interaction of Aβ with neuron-specific Na+/K+-ATPase α3 subunit  
Relation of Aβ deposits to synaptic activity
Role of TMP21 in presenilin complexes and Aβ formation
Role of Aβ dimers in the pathogenesis of AD
Role of dsDNA breaks in neurodegeneration due to Aß
Structure–neurotoxicity relationships of Aβ oligomers  
Sequence of events in neurotoxicity of Aβ  
AD as an ion channel disorder
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.
AD and age-related macular degeneration  
Blood-brain barrier in AD
Blood vessel damage in AD  
Fibrinogen-induced loss of synapses  
Loss of serotonin 1A receptors in the brain
Myelin hypothesis of AD
Overlapping pathologies of AD and Parkinson disease  
Factors in pathogenesis of AD  
Astrocytes and AD
Axonal transport failure in AD
Cell-cycle hypothesis
Chronic heart failure link with AD  
Creatine and AD
Disturbances in brain metabolism in early AD
Disturbances of interaction of nervous system proteins  
Disturbance of lipid metabolism in the brain
DENN/MADD expression and enhanced pro-apoptotic signaling in AD  
Dopamine and AD
Functioning role of genes in pathomechanism of AD  
Gonadotrophins and AD
Glutamate transport dysfunction in AD  
Herpes simplex virus type 1 and AD  
Innate immune system and AD
Insulin, diabetes and AD  
Mechanisms underlying cognitive deficits in AD
Microglia and 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  
Spread of neurodegeneration  
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
Epigenetic link between aging and AD
Exposure to magnetic fields  
Family history of AD  
Homocysteine and AD
Hypertension 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
Molecular genetics of familial AD
Presenilins and calcium channel pathogenesis of familial AD
Presenilin-1 mutations and familial AD
Late onset AD  
Genomics of AD
Introduction to genomics  
Genes associated with Alzheimer disease  
AlzGene database
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 A
Arctic mutation
BCHE gene
BRCA1 and AD  
CALHM1 polymorphism and AD
CLU, CRI and PICALM  
Genetic variants associated with early-onset AD  
Genetic variants associated with late-onset AD  
ApoE polymorphisms associated with LOAD  
BMI1 mutations  
Copy number variation (CNV) in LOAD
CYP46 and risk for AD
DAPK1 gene variants and AD  
LRRTM3 as a candidate gene for AD  
MTHFD1L gene variant associated with AD
Mutation in APP gene with protective effect against AD  
OGG1 mutations associated with AD  
SORL1 gene in AD
TOMM40 gene and risk of AD  
TREM2 variants in AD  
International Genomics of Alzheimer's Project
Sequencing in Alzheimer disease
Whole genomic sequencing in AD  
Single-cell RNA sequencing in AD  
Molecular neuropathology
Gene recombination in AD
Role of microRNAs in AD
DNA methylation 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

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  
Activities of Daily Living
Alzheimer Disease Cooperative Study  
Artificial intelligence-based test for diagnosis of AD
CDR-SOB score
Clinician's Interview-Based Impression of Change
DETECT System  
Measurement of aggregation in anterior segment of the eye
Resource Utilization in Dementia Battery  
SymptomGuide™  
Electrophysiology
Quantitative EEG for investigation of early AD  
EEG-based bispectral index  
Event-related potentials
Correlation of electrical activity of the brain with cognition
Concluding remarks on the role of EEG in diagnosis of AD  
Ocular findings for the diagnosis of AD
Early detection of cataract associated with AD  
Retinal imaging to detect Aβ deposits  
Laboratory methods for diagnosis of AD  
Examination of cerebrospinal fluid  
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  
Monoclonal antibody-based in vitro diagnosis of AD from brain tissues  
Multi-tissue RNA signature of aging as diagnostic for AD  
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
Tau proteins in CSF
Tests for the detection of Aβ in CSF
Tests combining CSF tau and Aβ
Concluding remarks about CSF biomarkers of AD  
Urine tests for AD  
Blood tests for AD  
A serum protein-based algorithm for the detection of AD
α2-macroglobulin as a biomarker of preclinical and early AD  
Blood Aβ level as biomarker of AD
Blood test for AD based on heme oxygenase-1
Blood test for AD based on RNA hybridization
GSK-3 elevation in white blood cells  
Lipid biomarkers for preclinical detection of AD
Lymphocyte Proliferation Test
Metabolomic biomarker profiling
MGAT3 as biomarker for prognosis of AD
MicroRNA-based test for AD
Protein kinase C in red blood cells
Sphingolipids  
Tests based on protein biomarkers in blood  
Skin test for early detection of AD  
Saliva-based tests for AD  
Saliva Aβ42 level as a biomarker of AD  
Smell identification test  
Nanotechnology to measure Aβ-derived diffusible ligands
Simultaneous measurement of several biomarkers for AD
Nutritional biomarkers in plasma of AD patients
Plasma biomarkers of drug response in AD  
Biomarkers of disease modifying therapies 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 Aβ deposits by PET  
Pittsburgh compound B and PET
Florbetapir-PET
Florbetaben-PET
Flutemetamol-PET
Future prospects of the PET imaging in AD
In vivo detection of Aβ plaques by MRI
Imaging agents for Aβ and neurofibrillary tangles  
Hyperspectral Raman imaging of neuritic plaques in AD  
Targeting of a chemokine receptor as biomarker for brain imaging
Radioiodinated clioquinol as a biomarker for Aβ
In vivo imaging of tau by PET  
Imaging neuroinflammation in AD by PET
Preclinical diagnosis of AD
Correlation of imaging with CSF biomarkers for early detection of AD  
Meta-analysis of literature on imaging in AD  
Alzheimer Disease Neuroimaging Initiative  
Computer aided diagnosis systems for AD based on imaging data  
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  
MRI for detection of MCI  
PET for detection of MCI  
Role of APOE genotype in early MCI  
Presymptomatic detection of AD  
Biomarkers for AD screening  
Biomarker changes in autosomal dominantly inherited AD  
Blood test for preclinical diagnosis of AD  
Gait analysis during cognitive tasks
Genetic screening for AD  
PredictAD project
Prediction of AD in patients with MCI  
Biochemical biomarkers in CSF for prediction of AD
Clinical and biochemical biomarkers for profiling prodromal AD
Combination of MMSE and a memory test for prediction of AD  
Plasma protein biomarkers of conversion of MCI to AD  
MRI for prediction of AD
Magnetoencephalography for detection of MCI and AD
MRI-based index to measure the severity of AD in MCI  
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  
Monitoring of treatment of AD
Monitoring treatment of mixed AD and vascular dementia  
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
Combination of cholinesterase inhibitors and a cholinergic precursor  
An assessment and future prospects of anticholinergic therapies  
Neuroprotection in Alzheimer's disease
Memantine  
Pharmacology of memantine  
Clinical trials of 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
Cerebrospinal fluid shunting  
Deep brain stimulation
Exposure of the brain to electromagnetic fields for treatment of AD
Application of electrical fields for improvement of cerebral function
High-frequency electromagnetic field treatment of AD
Transcranial magnetic stimulation
Mental training for management of memory loss in AD
Microchip-based hippocampal prosthesis for AD
Omental transposition  
Photo-induced inhibition of Aβ accumulation in AD
Scanning ultrasound for removal of Aβ
Vagal nerve stimulation  
Nutritional therapies for AD
Axona
Cocktail of dietary supplements for AD
Docosahexaenoic acid.
Ketogenic diet
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  
Nutritional factors in prevention of AD and MCI
Black and green teas
Caffeine
Caloric restriction  
Cinnamon  
Cocoa flavonol consumption
Grapes and red wine
Vitamin D and docosahexaenoic acid
Drugs to prevent Alzheimer disease
Preimplantation genetic diagnosis of inherited Alzheimer disease
Presymptomatic detection of AD  
Management of mild cognitive impairment  
Slowing the progression of MCI to AD
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 A
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  
Improved mouse models of AD expressing human genes
Cholesterol-fed rabbits as models for AD.
Canine dementia as model for AD  
Zebrafish model for AD
Transgenic invertebrate models of Alzheimer disease
Drosophila model of AD
Caenorhabditis elegans Alzheimer disease model  
Correlation of studies in animal models and human clinical trials  
Cell systems for AD research
In vitro neuronal cell Lines  
Single-gene expression system for use in cell culture
Stem cells for testing efficacy of AD drugs  
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 eIF2α 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
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  
N20C
AMPA modulators  
Glutamate release inhibitors  
INI-0602
Drugs affecting multiple neurotransmitters
Ensaculin  
RS-1259
Lecozotan
Vaccines for AD  
Active immunization with Aβ
AN-1792 vaccine
DNA vaccine for AD
Strategies to avoid undesirable effect of Aβ vaccination  
Passive immunization in AD
Passive immunization with MAbs
Clinical trials of MAbs in AD  
Delivery of the passive antibody directly to the brain
Systemic injection of MAbs to treat AD  
Combination of Aβ immunotherapy and CD40-CD40L blockade  
Shaping the immune responses elicited against Aβ
Delivery of AD vaccines  
Gene vaccination  
Modified Aβ nasal vaccine  
Transdermal Aβ vaccination
Other vaccines for AD
Nasal vaccination with Proteosome adjuvant  
T cell vaccination with glatiramer acetate adjuvant
Early start of immunotherapy for clearing Aβ plaques
Reversal of cholinergic dysfunction by anti-Aβ antibody  
Immune modulation via Toll-like receptors to reduce Aβ
Mechanisms by which Aβ antibodies 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 α-secretase cleaved APP  
Inhibitors of β-secretase  
Inhibitors of γ-secretase  
Amyloid-derived diffusible ligands  
GABA receptor modulation by etazolate and APP processing  
Depletion of serum amyloid P  
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  
Masitinib
NSAIDs
Flurbiprofen analogs with Aβ42-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 Aβ
Retro-inverso peptide inhibitor  
Scyllo-cyclohexanehexol
Selective serotonin reuptake inhibitor
Small molecule drug discovery for inhibiting Aβ aggregation
Trojan-horse approach to prevent build-up of Aβ aggregates
Ubiquitin C-terminal hydrolase L1  
Drugs to prevent the formation of NFTs
Tau suppression
Anthraquinones
Anti-tau antibodies
Tau aggregation inhibitor rember™  
LMTX®
Microtubule stabilizers  
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
ANAVEX 2-73  
Beta-sheet breakers
Bexarotene
Blocking ApoE/Aβ interaction to reduce Aβ plaques  
CD33 inhibitors  
Clearance of Aβ across the blood-brain barrier
Enhanced PKCє activity promotes clearance of Aβ  
Galantamine-induced Aβ clearance
Hemopheresis
Inhibitors of Aβ dehydrogenase
Intravenous immune globulin  
Monoclonal antibodies for removal of Aβ
Crenezumab
Gantenerumab
Solanezumab
Nanotechnology for removal of Aβ deposits
Role of matrix metalloproteinases in clearance of Aβ  
Serum amyloid P component depletion
Small molecule DAPH for clearance of amyloid
Tramiprosate prodrug ALZ-801  
Companies developing Aβ-directed therapeutics for AD  
Nootropics
Acetyl-L-carnitine
Cerebrolysin  
Ergot derivatives  
Lisuride
Dihydroergocryptine  
Neuroprotective effect drugs not primarily developed for AD  
Antiepileptic drugs
Lamotrigine  
Levetiracetam  
Antiinflammatory and antimicrobial drugs
Dapsone  
Antimicrobial drugs against C. pneumoniae  
PPAR-gamma agonists
Antidiabetic drugs  
Insulin
Metformin  
Rosiglitazone  
Pioglitazone  
Antihypertensive drugs
Angiotensin-converting enzyme inhibitors  
Angiotensin receptor blockers
Nilvadipine
Antiretroviral drugs  
Bexarotene
Dimebon
Drugs acting on estrogen receptors  
Estrogen  
Raloxifene  
Granulocyte-macrophage colony-stimulating factor
Gingipain inhibitors  
Inhibitors of neuroinflammation
Ceramide
CSP-1103  
Cyclophosphamide  
Etanercept
Fingolimod
Interferon beta-1a  
MW01-5-188WH
Neurosteroids  
Pregnenolone sulfate
Dehydroepiandrosterone  
Lithium
MAO-B inhibitors  
Ladostigil tartrate
Memoquin
Methylene blue  
Nilotinib  
Nimodipine  
Rapamycin  
Saracatinib  
Statins
Testosterone
Valproic acid
Future prospects of neuroprotection in AD.
Targeting Cdk5 pathway  
Antioxidants  
Colostrinin  
Curcumin  
Dehydroascorbic acid
Reservatrol
Synthetic catalytic scavengers
Vitamins  
Vitamin E as antioxidant
Vitamin B for lowering 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
Nostocarboline derived from cyanobacteria
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  
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  
Donecopride
Restoration of factors deficient in the aging brain
Reversal of cognitive impairment in aging by activation of creb protein
Reversal of cognitive impairment in aging by GDF11 protein
Restoration of repressor element 1-silencing transcription factor
Cell therapy for AD.
Choroid plexus epithelial cells for AD  
Stem cell transplantation for AD  
Autologous adipose tissue derived mesenchymal stem cells
Neural stem cells transplantation  
Neuronal differentiation of implanted NSCs enhanced by drugs
NSCs improve cognition in AD via BDNF
Potential benefits of grafting NSCs in AD  
Use of autologous stem cells for dementia
Gene therapy for AD  
ApoE gene therapy
APPsα gene transfer for rescuing synaptic failure in AD  
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  
Antisense PNA in AD
Antisense tau in AD  
RNAi approaches to AD  
Development of miRNAs for AD therapy  
Combined therapeutic approaches to AD
Drug delivery for Alzheimer disease  
Delivery of biologicals across the BBB
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
Ongoing clinical trials of AD
Concluding remarks on clinical trials of AD  
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
New chemical entities for AD by combining galantamine and memantine  
Novel rivastigmine-hydroxycinnamic acid hybrids for AD
Novels targets/receptors for AD drug discovery
Activation of cerebral Rho GTPases
Activators of insulin-degrading enzyme  
Blockade of TGF--Smad2/3 signaling in peripheral macrophages
Calcium channel blockers
Calpain inhibitors  
Casein kinase 1  
Cyclin-dependent kinase-5
Drugs against arginine deprivation and immune suppression in AD
Heat shock protein 90 inhibitors  
Histone deacetylase inhibitors  
Inhibition of PDK1 to slow progression of both AD and prion disease
Melatonin
Neurotrophic compound J147
NF-B 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
Single drugs for multiple targets in AD  
Src homology-containing protein-1 inhibitors  
Targeting GABAergic system  
TSPO ligands  
Proteomics and drug discovery for AD  
Small molecule compounds binding to neurotrophin receptor p75NTR
Targeting Vav in tyrosine kinase signaling pathway
LM11A-31 as p75NTR ligand
Pharmacogenomics of Alzheimer disease  
Biomarkers and companion diagnostics for AD
Genotyping and AD therapeutics  
Incorporation of genetic diversity into mouse models of AD
Personalized therapy of AD
Regulatory aspects of drug development for AD  
EMEA guidelines for drug development for AD
FDA guidelines for drug development for AD
Concluding remarks and future of AD research  
Future for AD therapeutics  

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
Pharmacoenonomics studies using memantine.
Epidemiology of AD  
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  
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  
Statins
Future growth of AD market  
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: 2011 Revised criteria for diagnosis of dementia due to Alzheimer Disease
Table 1-7: Relation of mutations in amyloid precursor protein to CNS disorders
Table 1-8: Risk factors for Alzheimer's disease  
Table 1-9: Genes linked to AD
Table 1-10: 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: 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: Potential applications of fluid biomarkers of Alzheimer disease
Table 2-8: Companies involved in the diagnosis/monitoring 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 4-2: Correlation of studies in animal models with human clinical trials
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: Preclinical studies of secretase modulators  
Table 5-8: Secretase modulators in clinical trials
Table 5-9: Companies developing Aβ-directed therapeutics for AD
Table 5-10: Innovative neuroprotective approaches for Alzheimer disease  
Table 5-11: Herbal therapies for AD
Table 5-12: Novel drug delivery methods for Alzheimer disease therapies
Table 5-13: Clinical trials in Alzheimer disease  
Table 5-14: Discontinued, failed or inconclusive clinical trials of Alzheimer disease  
Table 6-1: Prevalence of AD in major markets 2018-2028  
Table 6-2: Direct and indirect costs associated with Alzheimer disease
Table 6-3: AD market values from 2018-2028 in major world markets
Table 6-4: Markets for currently approved AD drugs 2018-2028  
Table 6-5: Potential markets for drugs in development 2018-2028  
Table 6-6: Limitations of AD drug 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: Structure of tau in a brain with AD  
Figure 1-5: Aβ deposits in the brain
Figure 1-6: Major pathological features of AD  
Figure 1-7: Mechanisms of Aβ clearance
Figure 1-8: Pathways for Aβ-induced nerve cell death  
Figure 1-9: Insulin signaling in Alzheimer disease and diabetes
Figure 1-10: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease
Figure 1-11: Oxidative stress and Alzheimer disease  
Figure 1-12: Role of proteosome inhibition in Aβ generation and neurodegeneration  
Figure 1-13: Cholesterol-related pathways to AD
Figure 1-14: Pathomechanism of AD  
Figure 2-1: Pathophysiology of biomarkers of AD in relation to the neuron  
Figure 3-1: Metabolism of acetylcholine  
Figure 3-2: Neuroprotective effective of tamine in AD
Figure 3-3: Strategies for the management of Alzheimer disease
Figure 5-1: Therapeutic strategies based on amyloid hypothesis of AD
Figure 5-2: Activation of α7 nicotinic acetylcholine receptors
Figure 5-3: NMDA receptor ion channel complex.
Figure 5-4: Neurotoxicity due to misfolding of A1-42  
Figure 5-5: Interactions of players in clinical trials of Alzheimer disease in the USA  
Figure 5-6: Role of proteomics in drug discovery/development for Alzheimer disease
Figure 5-7: FDA industry interaction during drug development for AD  
Figure 5-8: FDA’s accelerated approval pathway in early Alzheimer disease  
Figure 6-1: Unmet needs in the management of Alzheimer disease 

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