Alzheimer Disease - New Drugs, Markets and 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  
• 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 
• 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 

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: 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 

Figures 
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
 
Tables 
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 

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

Samples