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Alzheimer Disease - New Drugs, Markets and Companies

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  • 575 Pages
  • November 2021
  • Region: Global
  • Jain PharmaBiotech
  • ID: 4748164

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 asymptomatic 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 the 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 are 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 2020. 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 2030. As a background to the markets, pharmacoeconomic aspects of care of Alzheimer's disease patients and patterns of practice are reviewed in the seven major markets.

Profiles of 117 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with 89 collaborations. The bibliography contains over 900 publications that are cited in the report. The report is supplemented with 48 tables and 28 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

Table of Contents

Alzheimer Disease
Part I: Pathogenesis and Therapeutics 

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  
  • Insufficient sleep and 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 
  • 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 
  • 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 
  • CD2AF and AD  
  • 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 
  • Disturbances of interaction of nervous system proteins 
  • Protein misfolding in AD
  • Common denominators of AD and prion diseases 
  • Metabolomics of AD 
  • Glucose hypometabolism in 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  
  • 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 
  • The pupillary light reflex test for 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 
  • Lumipulse G CSF assays for routine diagnosis of AD
  • Neurogranin as a cognitive biomarker in AD 
  • 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 concentrations of tau and neurofilament light chain
  • 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 multiple 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 AD1
  • 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  
  • Assessment of future of anticholinergic therapies 
  • Neuroprotection in Alzheimer's disease 
  • Memantine  
  • Pharmacology of memantine
  • Clinical trials of memantine  
  • Combination of memantine with ChE inhibitors 
  • Aducanumab 
  • Pharmacology 
  • Clinical trials of aducanumab
  • Adverse effects of aducanumab
  • 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 
  • 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 
  • Cholesterol-fed rabbits as models for AD. 
  • Canine dementia as model for AD  
  • Herpes-induced AD brain model 
  • 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 transgenic mouse models of Alzheimer disease 
  • Improved mouse models of AD expressing human genes 
  • Transgenic invertebrate models of Alzheimer disease 
  • Drosophila model of AD 
  • Caenorhabditis elegans Alzheimer disease model
  • Zebrafish model for AD 
  • 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 
  • 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 
  • Clusterin for clearance of Aβ  
  • 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 
  • Donanemab 
  • 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
  • Antiepiletic drugs 
  • Lamotrigine
  • Levetiracetam
  • Antiinflammatory and antimicrobial drugs 
  • Dapsone
  • Antimicrobial drugs against C. pneumoniae
  • PPAR-gamma agonists 
  • Antidiabetic drugs
  • Insulin 
  • Metformin  
  • DPP-4 and Alzheimer disease in type 2 diabetes mellitus 
  • 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 
  • 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 
  • ATH-1017  
  • Activation of cerebral Rho GTPases 
  • Activators of insulin-degrading enzyme  
  • Blockade of TGF--Smad2/3 signaling in peripheral macrophages 
  • Calcium channel blockers 
  • Calcineurin inhibitors 
  • Calpain inhibitors
  • Casein kinase 1  
  • Chemokines 
  • 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  
  • Sodium oligomannate  
  • Src homology-containing protein-1 inhibitors  
  • Targeting GABAergic system
  • TSPO ligands  
  • Type 5 cyclic nucleotide phosphodiesterase inhibitors  
  • 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 

6. Innovative approaches to Alzheimer disease

  • Introduction  
  • 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  
  • Gene therapy for restoring brain cholesterol metabolism 
  • 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  
  • 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
  • Non-pharmacological treatments of AD 
  • Non-invasive neuromodulation  
  • Application of electrical fields for improvement of cerebral function 
  • Exposure of the brain to electromagnetic fields for treatment of AD. 
  • High-frequency electromagnetic field treatment of AD 
  • Photo-induced inhibition of Aβ accumulation in AD  
  • Transcranial magnetic stimulation 
  • Ultrasound-based treatments for AD  
  • Ultrasound for removal of Aβ
  • Ultrasound-based brain stimulation 
  • Ultrasound for opening the BBB
  • Mental training for management of memory loss in AD 
  • Neurosurgical procedures for AD
  • Cerebrospinal fluid shunting 
  • Deep brain stimulation 
  • Microchip-based hippocampal prosthesis for AD  
  • Omental transposition 
  • Vagal nerve stimulation 

7. Future and Regulatory Aspects of Alzheimer disease 

  • Introduction  
  • Personalized therapy of AD
  • Pharmacogenomics of Alzheimer disease
  • Biomarkers and companion diagnostics for AD 
  • Genotyping and AD therapeutics
  • Incorporation of genetic diversity into mouse models of AD 
  • Future for AD therapeutics
  • Regulatory aspects of drug development for AD
  • EMEA guidelines for drug development for AD 
  • FDA guidelines for drug development for AD 
  • FDA’s accelerated approval pathway in early Alzheimer disease 

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: Preclinical studies of secretase modulators
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: Companies involved in developing vaccines for AD 

Figure 1-1: Percentages of the 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 galantamine 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: Effect of DPP-4 inhibitor on AD 
Figure 5-6: Interactions of players in clinical trials of Alzheimer disease in the USA
Figure 5-7: Role of proteomics in drug discovery/development for Alzheimer disease 
Figure 7-1: FDA industry interaction during drug development for AD  
Figure 7-2: FDA’s accelerated approval pathway in early Alzheimer disease  

Alzheimer Disease 
Part II: Markets & Companies 

8. Markets & Finances of AD Care 

  • Introduction  
  • Pharmacoeconomics of treatment of AD
  • Quality of Life in relation to the 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
  • Support for AD research 

9. Companies  

  • Introduction
  • Profiles of companies. 
  • Collaborations

10. References
Table 8-1: Prevalence of AD in major markets 2020-2030  
Table 8-2: Direct and indirect costs associated with Alzheimer disease 
Table 8-3: AD market values from 2020-2030 in major world markets 
Table 8-4: Markets for currently approved AD drugs 2020-2030
Table 8-5: Potential markets for drugs in development 2020-2030
Table 8-6: Limitations of AD drug development by the biotechnology industry 
Table 8-7: Factors that drive AD markets 
Table 9-1: Major players in Alzheimer's disease therapeutics. 
Table 9-2: Collaborations relevant to Alzheimer disease 

Figure 8-1: Unmet needs in the management of Alzheimer disease