Developing Therapeutics for Alzheimer's Disease

Developing Therapeutics for Alzheimer's Disease: Progress and Challenges
provides a thorough overview of the latest advances toward the development of therapeutics for Alzheimer’s disease, along with the major hurdles that still must be overcome and potential solutions to these problems. Despite the lack of progress toward developing therapeutics that can slow or stop the progression of this disease, important discoveries have been made and many promising approaches are advancing in preclinical studies and clinical trials. This book outlines the special challenges related to specific targets and approaches, while presenting a realistic, comprehensive and balanced view of drug discovery and development in this area.

Written by international leaders in the field, the book assesses prospects for the emergence of effective agents and allows readers to better understand the challenges, failures, and future potential for research in Alzheimer’s disease. This book is a valuable resource to academic scientists carrying out translational research in Alzheimer’s disease, industrial scientists engaged in Alzheimer's drug discovery, executives in biopharmaceutical companies making strategic decisions regarding the direction of internal research and potential outside partnerships, and graduate-level students pursuing courses on Alzheimer's therapeutics.

Dedication
List of Contributors
Foreword
Preface
Chapter 1: The Complex Pathways to Mechanism-Based Therapeutics in Alzheimer’s Disease
- Abstract
- Introduction
- The mechanistic study of Alzheimer’s disease melds basic and applied research
- Alzheimer’s disease as a prototype for the molecular elucidation of a chronic brain disorder
- The driving forces that underlie AD research
- Elucidating the AD mechanism: biochemical pathology, then genetics
- The first genetic clues to the etiology of AD
- The discovery of apolipoprotein E4 as the major genetic risk factor for AD
- Presenilin as the site of mutations causing aggressive, early-onset AD
- The discovery of presenilin function supports a mechanistic hypothesis of AD initiation
- Relationship of Aβ accumulation to tau alteration and neurofibrillary degeneration
- An increasingly recognized role for the innate immune system in AD
- Biomarkers in living humans help elucidate the natural history of AD
- A daunting array of apparent downstream effects in the amyloid cascade
- Conclusion: mechanistic research offers many avenues toward disease-modifying treatments
- Acknowledgments
Chapter 2: The Genetic Basis of Alzheimer’s Disease
- Abstract
- Background
- Genetics of early-onset familial AD
- Genetics of late-onset AD
- Common variants associated with late-onset AD beyond APOE
- Functional role of the GWAS susceptibility genes in AD
- Rare variants leading to late-onset AD
- Summary and future
- Acknowledgments
Chapter 3: β-Secretase Inhibition
- Abstract
- The role of β-amyloid in Alzheimer’s disease
- The identification of β-secretase as β-site APP cleaving enzyme (BACE)
- Physiological functions of BACE1
- Small molecule BACE1 inhibitor drugs and clinical trials for AD
- Unanswered questions of relevance to BACE1 inhibitor clinical trials
- Conclusions
- Abbreviations
- Acknowledgments
Chapter 4: γ-Secretase Inhibitors: From Chemical Probes to Drug Development
- Abstract
- The γ-secretase complex
- PS, Nct, Aph1, and Pen2
- γ-Secretase inhibitors
- Active site-directed GSIs
- First-Generation GSIs
- Clinical GSIs for AD
- Concluding remarks
- Acknowledgments
Chapter 5: Therapeutic Targeting of Aβ42
- Abstract
- Introduction
- APP processing pathways
- Targeting Aβ42
- γ-Secretase modulators
- Clinical development of GSMs
- Biological approaches to target Aβ42
- Summary and future directions
Chapter 6: Modulators of Amyloid β-Protein (Aβ) Self-Assembly
- Abstract
- Introduction
- Peptidic or peptidomimetic modulators of Aβ assembly
- Aβ assembly modulators derived from natural sources
- Aβ assembly modulators from nonnatural sources
- Conclusions
- Abbreviations
Chapter 7: Anti-Amyloid-β Immunotherapy for Alzheimer’s Disease
- Abstract
- Introduction to Alzheimer’s disease
- Aβ immunotherapy—an introduction
- Preclinical studies
- Human clinical trials: active Aβ vaccines
- Human clinical trials: passive Aβ immunizations
- Summary and conclusions
Chapter 8: Targeting Aβ Receptors to Modify Alzheimer’s Disease Progression
- Abstract
- Introduction
- General aspects of Aβ receptors
- Potential advantages of targeting an Aβo receptor
- Cellular prion protein (PrP^C) as neuronal cell-surface receptor for Aβo
- Metabotropic glutamate receptor 5 as coreceptor for Aβo bound to PrP^C
- nAchRα7 as receptor for Aβ
- The interaction between Eph receptors and Aβ
- Binding of APP and Aβ to Nogo-receptor 1 (Nf08-01-9780128021736)
- Evidence for other Aβ receptors
- Mechanisms independent of Aβ binding to specific protein receptors
- Concluding remarks
- Acknowledgments
- Disclosure
Chapter 9: Blood–Brain Barrier Transport of Alzheimer’s Amyloid β-Peptide
- Abstract
- Introduction
- Aβ clearance from brain
- Aβ uptake by RAGE
- Peripheral sink and systemic clearance of Aβ
- Aβ degradation
- Regulation and restoration of BBB clearance
- Conclusions
- Acknowledgments
Chapter 10: Alzheimer’s Disease Therapeutics Targeting Apolipoprotein E
- Abstract
- Introduction
- Physiological function of apoE
- ApoE and apoE receptors
- ApoE levels in periphery and CNS
- ApoE and Aβ
- AD therapeutic opportunities targeting apoE
- Conclusions
Chapter 11: Microtubule Stabilization
- Abstract
- Introduction
- Microtubules and tau protein
- Rationale for therapeutic intervention
- The identification of epothilone D as a potential clinical candidate
- Concluding remarks
- Acknowledgments
Chapter 12: Tau Phosphorylation as a Therapeutic Target in Alzheimer’s Disease
- Abstract
- Introduction
- Tau protein structure
- Tau phosphorylation
- Tau localization and tau functions
- Modulation of tau function by phosphorylation
- Phosphotau toxicity and disease
- Tau kinase inhibitors
Chapter 13: Stimulation of Tau Degradation
- Abstract
- Introduction
- The ubiquitin proteasome system
- The autophagy and lysosome pathway
- Cooperation between UPS and ALP in clearing tau
- Acknowledgments
Chapter 14: Passive Immunotherapy for Tau Pathology
- Abstract
- Introduction
- Spread of tau pathology in the human brain
- Spread of tau pathology in the rodent brain
- Tau concentrations and antibody concentrations in the CNS
- Do antibodies act within neurons?
- Blocking neuronal tau uptake
- Microglial uptake
- Tau export from brain
- Are existing mouse models appropriate for testing immunotherapy?
- Problems for active immunization strategies
- Acknowledgments
Chapter 15: Inhibition of Tau Aggregation as a Basis for Treatment and Prevention of Alzheimer’s Disease
- Abstract
- Introduction: challenging common preconceptions underlying the rationale in strategies for prevention and treatment of AD pathology
- Sequence of changes in cerebrospinal fluid amyloid-β and tau biomarkers
- Neuropathological sequence of changes in amyloid-β and tau markers in the neocortex
- Relationship between tau pathology and cognitive impairment and imaging deficits
- Temporal sequencing of tau aggregation, pathology, and cognitive impairment
- The epidemiology of tau aggregation pathology
- Molecular dissection of the neurofibrillary tangle
- Modeling tau aggregation in cells
- Modeling tau aggregation in transgenic animals
- Identification and optimization of tau aggregation inhibitors for treatment and prevention of AD
- Activity of TAIs in tau-transgenic mouse models
- Potential clinical efficacy of TAI therapy in mild or moderate AD
- Conclusions: prion-like processing of tau protein and its implications for drug development
Chapter 16: Neuroprotective Strategies for Alzheimer’s Disease Prevention and Therapy
- Abstract
- Roles for neuroprotective strategies
- Neurotrophin receptors and their signaling pathways
- p75^NTR receptors in AD
- Trk receptors in AD
- Neurotrophin-based AD therapies
- p75^NTR-based AD therapeutic strategies
- TrkA-based AD therapeutic strategies
- TrkB-based AD therapeutic strategies
- Conclusions
Chapter 17: Symptomatic Cognitive Enhancing Agents
- Abstract
- Definition of “symptomatic” treatment
- Advantages of symptomatic drug development
- Targets for symptomatic cognitive enhancing agents
- Outcomes for clinical trials of cognitive enhancing agents
- Clinical trial designs for cognitive enhancing agents
- Biomarkers in cognitive enhancing agent drug development
- Regulatory aspects of cognitive enhancing drug development programs
- Cognitive enhancing drug development programs
- Comment and summary
Chapter 18: Tackling Alzheimer’s Disease by Targeting Oxidative Stress and Mitochondria
- Abstract
- Introduction
- Oxidative biology
- Oxidative stress in Alzheimer’s disease
- Mitochondrial dysfunction in Alzheimer’s disease
- Oxidative stress and mitochondria as feasible therapeutic targets in Alzheimer’s disease
- Conclusions
Chapter 19: Clinical Issues in Alzheimer Drug Development
- Abstract
- Introduction
- Clinical issues in drug development
- Diagnoses for regulatory trials in Alzheimer’s disease
- Biomarkers in Alzheimer trials
- Recent regulatory considerations for drug development in Alzheimer’s disease
- Discussion and future directions
- Acknowledgments
Chapter 20: Molecular Imaging in Alzheimer Clinical Trials
- Abstract
- Introduction
- Why PET?
- PET ligands for amyloid imaging
- Amyloid PET image analysis
- Quantitative amyloid PET for diagnostic classification
- Evaluation of treatment effect
- Tau PET
- FDG PET
- Preclinical imaging
- Future directions
Chapter 21: Fluid Biomarkers and Diagnostics
- Abstract
- Introduction
- Biomarker concept
- CSF in Alzheimer’s disease
- Candidate AD biomarkers and markers of other pathologies
- CSF biomarkers in relation to the latest clinical trials
- Standardization efforts
- Concluding remarks
- Acknowledgments
Chapter 22: Nonpharmacologic Activity Interventions to Prevent Alzheimer’s Disease
- Abstract
- Overview
- Cognitive training
- Physical exercise and activity
- Neurobiological targets of benefit: the prefrontal cortex and hippocampus
- Effects of physical activity on age-related neurobiological targets
- Lifestyle activity, environmental enrichment, and neurocognitive health
- Addressing the challenges of sustaining physical activity in later life
- Yoga and mindfulness activities
- Increasing cognitive and physical activity in later life through social engagement: multimodal interventions
- Measuring activity in daily life and at night
- Conclusions
Chapter 23: Prospects and Challenges for Alzheimer Therapeutics
- Abstract
- Introduction
- Advances in AD pathogenesis and progression
- Therapeutic targets
- Clinical trial results: what have we learned?
- Current pipeline
- Key unanswered questions in AD biology
- Enabling technologies and approaches
- Summary and conclusions
Index

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Developing Therapeutics for Alzheimer's Disease

Progress and Challenges

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Michael S. Wolfe