Alzheimer's Disease: Recent Findings in Pathophysiology, Diagnostic and Therapeutic Modalities

Cover
Preface
Contents
Chapter 1 Alzheimer’s is a Multifactorial Disease
	1.1 Introduction
	1.2 Pathological Events
		1.2.1 Amyloid Burden
		1.2.2 Tau Toxicity
		1.2.3 Metal Ion Toxicity
		1.2.4 Oxidative Stress
		1.2.5 Biomolecule Damage
		1.2.6 Membrane Toxicity
		1.2.7 Calcium Dyshomeostasis
		1.2.8 Role of Cholesterol
		1.2.9 Mitochondrial Dysfunction
		1.2.10 Endoplasmic Reticulum Stress
		1.2.11 Impairment in Telomerase Activity
		1.2.12 Cholinergic Toxicity
		1.2.13 Synaptic Dysfunction
		1.2.14 Immune Outrage
		1.2.15 Neurovascular Toxicity
		1.2.16 Lymphatic Dysfunction
		1.2.17 α-Synuclein Mediated Toxicity
		1.2.18 Apoptosis Dysfunction
		1.2.19 Aberrant Post-translational Modification
		1.2.20 Microbiome Imbalance: Gut Bacterial Dysfunction
		1.2.21 Glucose Hypometabolism
		1.2.22 Insulin Resistance and Diabetes
		1.2.23 Autophagy Dysfunction
		1.2.24 Genetic Risk
	1.3 Biomarkers and Diagnosis
	1.4 Therapy
	1.5 Conclusion
	References
Chapter 2 The Genetic and Biochemical Basis of Alzheimer’s Disease
	2.1 Alzheimer’s Disease: A Malady Rooted in Genetics and Pathophysiology
		2.1.1 Hallmarks for AD
		2.1.2 Genetics Controlling AD
	2.2 Molecular Basis of AD: Seeing AD at the Level of Molecular Interactions
		2.2.1 Formation of β-Amyloid Plaques
		2.2.2 Decline in Neurotransmission
		2.2.3 Tau Protein and Its Phosphorylation
		2.2.4 Involvement of Oxidative Stress and Metabolism
		2.2.5 Role of Calcium
		2.2.6 Clinical Manifestation: Biochemical and Physiology Contribution
	2.3 Amyloid Plaques: A Sticky Substance That Affects Brain Function
		2.3.1 Neurofibrillary Tangles: Tau Turning Around Wrongly
		2.3.2 When Amyloid Plaque Dysfunctions Together With Tau Pathology That Results in Havoc
		2.3.3 Other Cellular Mishaps That Converge in the Anomaly of Homeostasis
	2.4 Genetics as a Promising Tool for Alzheimer’s Disease
	References
Chapter 3 Alzheimer’s Disease Pathology: A Tau Perspective
	3.1 Tau and Alzheimer’s Disease
		3.1.1 Alzheimer’s Disease
			3.1.1.1 Tau Protein
			3.1.1.2 Tau in AD Pathology
			3.1.1.3 Tau Aggregation and Implications in AD
			3.1.1.4 Tau in AD Diagnosis
			3.1.1.5 Recent Advances in Tau-based Therapeutics
	3.2 Conclusions
	3.3 Future Perspectives for Small Molecules As Tau Therapeutics
	References
Chapter 4 Structural Insights Into the Amyloidogenic Ab and Tau Species in Alzheimer’s disease Pathophysiology: Defining Functional Motifs
	4.1 Introduction
		4.1.1 Factors Influencing Amyloid Aggregation
	4.2 Mechanistic Insight Into Amyloidogenesis: Defining the Intermediate Steps
	4.3 Structural Correlation of Ab Pathological Aggregates in AD Etiology
		4.3.1 Structural Elucidation of the Molecular Intermediates: Benefits of Using NMR
		4.3.2 Probing the Ab Surface Interactions
		4.3.3 Water Dynamics in Peptide Aggregation
		4.3.4 NMR Derived Structural Models of Ab Fibrils
		4.3.5 Role of the GxxxG Motif in Regulating the Aggregation and Neurotoxicity of Aβ
		4.3.6 Role of Aβ-membrane Interactions in Prompting AD Pathophysiology
	4.4 Tau Aggregation and Its Relevance in AD: Insights From NMR Spectroscopy
		4.4.1 Molecular Events Underlying Tau Aggregation
		4.4.2 Recent Structural Developments on Tau From NMR and Cryo-EM
		4.4.3 Role of Liquid–Liquid Phase Separation in Amyloid Aggregation of Tau
	4.5 Conclusion and Future Outlook
	Acknowledgements
	References
Chapter 5 Structural Insights on Aggregation Species of Aβ and Tau, and Their Implications in Alzheimer’s Disease
	5.1 Amyloid Aggregation of Aβ and Tau in Alzheimer’s Disease
		5.1.1 Different Amyloid Aggregation Species in Alzheimer’s Disease
		5.1.2 Aggregation Species of Aβ and Their Pathological Relevance to AD
			5.1.2.1 Aβ Oligomers
			5.1.2.2 Aβ Fibrils
		5.1.3 Aggregation Species of Tau and Their Pathological Relevance to AD
			5.1.3.1 Tau Oligomers
			5.1.3.2 Tau Fibrils
	5.2 Atomic Structures of Tau and Aβ Fibrils
		5.2.1 Atomic Structures of Tau Fibrils
			5.2.1.1 Atomic Structures of Tau-derived Amyloid-forming Peptides by X-ray Crystallography
			5.2.1.2 Atomic Structures of Tau Fibrils by Cryo-EM
			5.2.1.3 Chemical Modifications Mediate the Structural Diversity of Tau Fibril Polymorphs
		5.2.2 Atomic Structures of Aβ Fibrils
			5.2.2.1 Aβ Fibril Structures Determined by ssNMR
			5.2.2.2 Aβ Fibril Structures Determined by Cryo-EM
	5.3 Fibril Polymorphism and Its Implication in AD
	Abbreviations
	Acknowledgements
	References
Chapter 6 Aggregation Species of Amyloid-β and Tau Oligomers in Alzheimer’s Disease: Role in Therapeutics and Diagnostics
	6.1 Introduction
	6.2 Protein Aggregation Cascades and Various Species of Aggregates
	6.3 Protein Aggregation Initiation and Underlying Mechanism
	6.4 Propagation and Seeding Effect of Oligomeric Species
	6.5 Isolation, Preparation and Characterization of Oligomeric Species
		6.5.1 Amyloid-β (Aβ)
		6.5.2 Tau
		6.5.3 Co-oligomers
	6.6 Pathological Aspects of Soluble Oligomers in AD
		6.6.1 Neuron
		6.6.2 Glia
	6.7 Oligomers as Therapeutic Targets and Biomarkers
		6.7.1 Therapeutic Targets
			6.7.1.1 Small Molecules
			6.7.1.2 Immunotherapy
		6.7.2 Biomarkers
	6.8 Conclusion
	Abbreviations
	Acknowledgements
	References
Chapter 7 Role of Metal Ions in Alzheimer’s Disease: Mechanistic Aspects Contributing to Neurotoxicity
	7.1 Introduction
		7.1.1 The Amyloid Cascade Hypothesis
		7.1.2 The Metal Hypothesis
		7.1.3 Link Between the Two Hypotheses
		7.1.4 Concluding Notes
	7.2 Metal Ions, Aβ Peptides and Their Interactions
		7.2.1 Cu(II)
		7.2.2 Cu(I)
		7.2.3 Zn(II)
		7.2.4 Concluding Notes
	7.3 Copper-mediated ROS Production
		7.3.1 Redox Properties of Cu(Aβ) Species
		7.3.2 Oxidative Damage
			7.3.2.1 General Targets
			7.3.2.2 Aβ Oxidative Damage
		7.3.3 Influence on Aβ Self-assembly
		7.4 Modulation of Aβ Self-assembly by Cu and Zn
	7.4 Modulation of Ab Self-assembly by Cu and Zn
		7.4.1 General Features
		7.4.2 Mechanisms of Toxicity
		7.4.3 Influence of the Aggregation State on the Cu(Aβ)induced ROS Production
		7.4.4 Other Important Points to Consider
		7.4.5 Future Lines of Research
	7.5 Metal Targeting Compounds
	7.6 Concluding Remarks
	Abbreviations
	Acknowledgements
	References
Chapter 8 Microglial Blockade of the Amyloid Cascade: A New Therapeutic Frontier
	8.1 Overview – Old and New Positions for Microglia in the Amyloid Cascade
	8.2 Human Genetic Bases for AD Pathogenesis and Microglial Protection
		8.2.1 Autosomal Dominant AD and Typical AD – Same Villain (Aβ), Different Origin Stories
		8.2.2 Non-inflammatory Microglial Activation Lowers the Risk of AD
			8.2.2.1 Microglial Activation Proteins – TREM2 and PLCγ2
			8.2.2.2 Microglial Inhibition Proteins – PILRA, CD33, and INPP5D
		8.2.3 Microglial Activation Defects Are a Typical AD Feature
	8.3 Microglial TREM2 Activity Opposes the Amyloid Cascade
		8.3.1 Microglial TREM2 and the Endo/Lysosomal System Oppose the Seeding of Amyloid Plaques
		8.3.2 Microglial TREM2, ApoE, and TAM Receptors Attenuate amyloid Neurotoxicity Through Plaque Compaction
			8.3.2.1 How Plaque Pathology Alters Microglia – The DAM Response
			8.3.2.2 How Microglia Alter Plaque Pathology – A DAM Protective Barrier
		8.3.3 AD-related Synapse Loss Is Independent of Trem2 and DAM Activation
		8.3.4 TREM2 Restricts β-amyloid-facilitated Tau Pathogenesis
	8.4 Therapeutic Strategies to Enhance Microglial Protection in AD
		8.4.1 Augmenting the Activity of TREM2 and Its Downstream Effectors
		8.4.2 Promoting Microglial Activity by Blocking ITIM/Checkpoint Proteins
		8.4.3 Aducanumab Treatment May Confound Microglial Drug Responses
	8.5 Concluding Remarks
	Author Contributions
	Acknowledgements
	References
Chapter 9 Post-translational Modifications and Alzheimer’s Disease
	9.1 Introduction
	9.2 PTMs in AD
	9.3 Protein Misfolding and Their Aggregation in AD Pathology
	9.4 Phosphorylation
		9.4.1 Phosphorylation of APP
		9.4.2 Phosphorylation of BACE1
		9.4.3 Phosphorylation of Tau
	9.5 Glycosylation
		9.5.1
		Glycosylation of APP
		9.5.2
		Glycosylation of AD Related Proteins
		9.5.3
		and
		Glycosylation of Tau
	9.6 Ubiquitination
		9.6.1 Ubiquitination of APP
		9.6.2 Ubiquitination of BACE1
		9.6.3 Ubiquitination of Tau
	9.7 Sumoylation
		9.7.1 Sumoylation of APP
		9.7.2 Sumoylation of BACE1
		9.7.3 Sumoylation of Tau
		9.7.4 Sumoylation of HDAC1
	9.8 Acetylation
		9.8.1 Acetylation of BACE1
		9.8.2 Acetylation of Tau
		9.8.3 Acetylation of Histone
	9.9 Acylation
		9.9.1 Palmitoylation and N-myristoylation
		9.9.2 Prenylation
	9.10 S-Nitrosylation
	9.11 Methylation
	9.12 Solutions and Recommendations to Current Challenges
	9.13 Conclusion and Future Trends
	Abbreviations
	References
Chapter 10 Autophagy: Role in Alzheimer’s Disease Pathophysiology and Therapeutic Avenues
	10.1 Introduction
	10.2 Alzheimer’s Disease: Etiological Hypothesis
	10.3 Autophagy Dysfunction in Neurons During AD – Mechanisms Involved
		10.3.1 Autophagy Initiation is Altered in AD – Defects in Autophagosome Formation, Elongation and Maturation
		10.3.2 Impairment in Retrograde Transportation of Autophagosomes
		10.3.3 Defects in Lysosomal Biogenesis
		10.3.4 Defective Autophagosome–Lysosome Fusion and Lysosomal Proteolysis in AD
	10.4 Autophagy in Glial Cells
	10.5 Aβ Degradation and Autophagy
	10.6 Cross-talk Between Apoptosis and Autophagy
	10.7 Neuroinflammation and Autophagy
	10.8 Targeting Autophagy for Therapeutic Strategies
		10.8.1 Genetic Manipulation of Autophagy Regulators
		10.8.2 Small Molecule Autophagy Inducers
			10.8.2.1 mTOR Inhibitors
			10.8.2.2 Enhancers of Autophagosome Synthesis
			10.8.2.3 Enhancers of TFEB Activity – Targeting Lysosome Biogenesis
			10.8.2.4 Promoters of Autophagosome Transport and Their Fusion with Lysosomes
			10.8.2.5 Facilitators of Lysosomal Acidification and Digestion
	10.9 Conclusion and Future Perspectives
	List of Abbreviations
	Conflict of Interest
	Acknowledgements
	References
Chapter 11 Transmission of Pathogenic Proteins and the Role of Microbial Infection in Alzheimer’s Disease Pathology
	11.1 Introduction
	11.2 AD Transmission
		11.2.1 Cell-to-cell Transmission of Aβ and Tau
		11.2.2 Transmission of Aβ and Tau Within the Brain
		11.2.3 Human-to-human Transmission of AD Pathology
	11.3 Role of Microbial Infection in Alzheimer’s Disease
		11.3.1 Herpes Simplex Virus 1 (HSV 1) in AD
		11.3.2 Human Herpes Virus (HHV) and Other Viruses
		11.3.3 Role of Bacterial and Fungal Infection in AD
		11.3.4 Microbial Role in the Gut–Brain Axis and AD
	11.4 Conclusion and Future Outlook
	References
Chapter 12 The Role of Gut Microbiome in Alzheimer’s Disease and Therapeutic Strategies
	12.1 Introduction
	12.2 Benefits of Gut Bacteria
	12.3 Gut Microbiota and Brain Function
	12.4 Gut Dysbiosis
		12.4.1 Bacterial Amyloids, Inflammation, and Oxidative Stress
	12.5 Therapy
		12.5.1 Probiotic and Oligosaccharides Treatment
		12.5.2 FMT Treatment
		12.5.3 Small Molecule and Natural Product Treatment
	12.6 Conclusion and Future Outlook
	References
Chapter 13 Molecular Probes for the Diagnosis of Alzheimer’s Disease with Implications for Multiplexed and Multimodal Strategies
	13.1 Introduction
	13.2 Ab Biomarkers
		13.2.1 Fluorescent Probes
			13.2.1.1 Aβ Monomer
			13.2.1.2 Aβ Oligomers (AβOs)
			13.2.1.3 Aβ Plaques
		13.2.2 Positron Emission Tomography (PET)
			13.2.2.1 Antibody-based PET Probes for Ab
		13.2.3 MRI Probes
		13.2.4 Theranostic Probes: Drugs of the Future
	13.3 Tau as a Biomarker
		13.3.1 Fluorescent Probes
		13.3.2 PET Probes for Tau
	13.4 Neurodegeneration
	13.5 Indirect Biomarkers
	13.6 Challenges in AD Diagnosis
		13.6.1 Meticulous Design and Targeting of Different Alloforms
		13.6.2 Blood–Brain Barrier (BBB)
		13.6.3 Circulating Biomarkers in Biofluids
	13.7 Conclusion and Future Outlook
	References
Chapter 14 Circulating Biomarkers for the Diagnosis of Alzheimer’s Disease
	14.1 Introduction
		14.1.1 Alzheimer’s Disease
		14.1.2 Current Diagnosis and Limitations
		14.1.3 Need for Circulating Biomarkers: Blood Biomarkers and Beyond
		14.1.4 Classification of Circulating Biomarkers
	14.2 Core AD Pathology Biomarkers in CSF and Blood
		14.2.1 Ab Pathology Biomarkers
		14.2.2 Tau Pathology Biomarkers
		14.2.3 Inflammation Biomarkers
		14.2.4 Synaptic Degeneration Biomarkers
		14.2.5 Neuronal Injury Biomarkers
		14.2.6 Vascular Injury Biomarkers
		14.2.7
		synuclein Pathology Biomarkers
		14.2.8 TDP-43 Pathology Biomarkers
	14.3 Associated Blood Biomarkers in AD Diagnosis
		14.3.1 Associated Protein Biomarkers
		14.3.2 Associated Metabolite Biomarkers
		14.3.3 Circulating RNAs
	14.4 Non-invasive Sources for Circulating Biomarkers – Saliva, Urine and Tears
		14.4.1 Salivary Biomarkers
			14.4.1.1 Ab Biomarkers
			14.4.1.2 Tau Biomarkers
			14.4.1.3 Lactoferrin
			14.4.1.4 Acetylcholinesterase (AChE)
		14.4.2 Urine Biomarkers
		14.4.3 Tear Biomarkers
	14.5 Challenges and Prospects for Circulating Biomarkers
	14.6 Conclusion
	References
Chapter 15 Lactoferrin: A Potential Theranostic Candidate for Alzheimer’s Disease
	15.1 Introduction
	15.2 Lactoferrin in AD
	15.3 Lf: A Promising Circulatory Biomarker
	15.4 Lf: A Multifunctional Therapeutic Candidate
	15.5 Conclusion and Outlook
	References
Chapter 16 Multifunctional Inhibitors of Multifaceted Ab Toxicity of Alzheimer’s Disease
	16.1 Introduction
	16.2 Targeting Individual Routes of Amyloid Pathology
		16.2.1 Targeting Enzymatic Functions
		16.2.2 Targeting Amyloid Aggregation
		16.2.3 Targeting Membrane Toxicity
		16.2.4 Targeting Metal Toxicity
		16.2.5 Targeting Oxidative Stress
		16.2.6 Targeting Mitochondrial Dysfunction
		16.2.7 Targeting Neuroinflammation
	16.3 Targeting Multiple Toxicities of AD Pathology
		16.3.1 Small Molecule-based Multifunctional Inhibitors
		16.3.2 Peptide-based Multifunctional Inhibitors
		16.3.3 Polymeric Multifunctional Inhibitors
		16.3.4 Natural Product-derived Multifunctional Inhibitors
	16.4 Theranostic Probes
	16.5 Conclusion and Future Directions
	References
Chapter 17 Tau-targeting Therapeutic Strategies for Alzheimer’s Disease
	17.1 Introduction
	17.2 Strategies to Target Tau Pathology
	17.3 Modulators of PTMs
		17.3.1 Phosphatase Modulators
		17.3.2 Kinase Inhibitors
			17.3.2.1 GSK-3 and CDK5
			17.3.2.2 CDK-5
			17.3.2.3 c-Jun N-terminal kinases (JNK) and Other Kinases
		17.3.3 Acetylation Modulators
	17.4 Tau Aggregation Inhibitors
		17.4.1 Small Molecule Inhibitors
		17.4.2 Peptide Inhibitors
	17.5 Microtubule Stabilizers
	17.6 Immunotherapy
		17.6.1 Active Immunotherapy
		17.6.2 Passive Immunotherapy
	17.7 Gene Therapy
	17.8 Conclusions and Future Directions
	Acknowledgements
	References
Chapter 18 Computational Development of Alzheimer’s Therapeutics and Diagnostics
	18.1 Introduction
	18.2 AD Associated Drug Targets and Biomarkers
	18.3 Molecular Mechanism of Amyloid Plaque Formation
	18.4 Molecular Mechanism of the Formation of Paired Helical Filaments of Tau Protein
	18.5 Computational Approaches for Developing Therapeutics and Diagnostics for AD
		18.5.1 Molecular Docking, De Novo Design and Virtual Screening
		18.5.2 Molecular Dynamics and Steered Molecular Dynamics
		18.5.3 Binding Free Energy Calculations
		18.5.4 Electronic Structure Theory Based Calculations
		18.5.5 Machine Learning Approaches for Binding Affinity Prediction
	18.6 Computational Design of Novel Therapeutics Against Drug Targets in AD
		18.6.1 Design of Amyloid and Tau Busting Molecules
		18.6.2 Design of Inhibitors for BACE1
		18.6.3 Design of γ-Secretase Inhibitors
		18.6.4 Design of Inhibitors for Acetylcholinesterase and Butyrylcholinesterase
		18.6.5 Design of Inhibitors for Muscarinic and Nicotinic ACh Receptors (mAchR, nAchRs)
		18.6.6 Design of Inhibitors for Monoamine Oxidases A and B
	18.7 Computational Investigation of Off-target Binding of Diagnostic Agents
	18.8 Design of Dual Targeting and Multifunctional Ligands
	18.9 Design of PET Tracers for AD
	18.10 Design of Optical Probes for Amyloid Imaging
	18.11 Outlook and Conclusions
	Acknowledgements
	References
Chapter 19 Targeted Protein Degradation as a Therapeutic Avenue for Alzheimer’s Disease
	19.1 Introduction
	19.2 Targeted Protein Degradation (TPD)
		19.2.1 Proteolysis Targeting Chimeras (PROTACs)
		19.2.2 Photoswitchable PROTACs (PHOTACs)
		19.2.3 Lysosome Targeting Chimeras (LYTACs)
	19.3 Alzheimer’s Disease (AD)
		19.3.1 Specific Knockdown of Endogenous Tau Protein
		19.3.2 Amyloid Precursor Protein (APP) Processing
		19.3.3 α-Secretase Cleavage Sites
		19.3.4 Aβ Degrading Enzymes
		19.3.5 Transcriptional Upregulation of ADAM10
		19.3.6 Proteolytic Enzymes and Importance of Artificial Proteases
		19.3.7 Metalloenzyme Mimic
	19.4 Mimic of α-Secretase
	19.5 Miniature Artificial Protease (mAP)
	19.6 Conclusions and Future Directions
	References
Chapter 20 Cell-based Therapy for Alzheimer’s Disease
	20.1 Cell-based Therapy
		20.1.1 Different Cell Sources for Cell Therapy and Their Categorization
	20.2 Stem Cell Treatments for AD
	References
Chapter 21 Experimental Models to Study Alzheimer’s Disease
	21.1 In Vivo Models
		21.1.1 Lipopolysaccharide (LPS) Induced Model
		21.1.2 Streptozotocin Induced Model
		21.1.3 Okadaic Acid Induced Model
		21.1.4 Scopolamine Induced Memory Impairment
		21.1.5 Amyloid Beta-peptide Induced Model
		21.1.6 Transgenic Models
	21.2 In Vitro AD Models
		21.2.1 Induced Pluripotent Stem Cells (iPSCs) and a 3D Brain Organoid System
		21.2.2 SH-SY5Y Cell Line
		21.2.3 N2a Cells
		21.2.4 Pheochromocytoma Cell Line (PC-12)
	21.3 Conclusion
	Acknowledgements
	References
Chapter 22 Ethnic and Racial Differences in The Pathophysiology of Alzheimer’s Disease
	22.1 Introduction
	22.2 Cross-comparison of Racial and Ethnic Disparities Worldwide
		22.2.1 North America
		22.2.2 South America
		22.2.3 Africa
		22.2.4 Asia
		22.2.5 Europe
		22.2.6 Israel
	22.3 Reasons for Ethnic and Racial Disparities
		22.3.1 Genetic Factors
		22.3.2 Cardiovascular and Cerebrovascular Disease and Other Comorbidities
		22.3.3 Socioeconomic Factors
		22.3.4 Cultural Differences
		22.3.5 Immunity
	22.4 Impact of Ethno-racial Aspects on Diagnostic Techniques
		22.4.1 Impact of Cognitive Based Testing in AD
		22.4.2 Impact of Neuro-imaging and Bio Fluids in AD
		22.4.3 Impact of Electroencephalogram (Eeg) in Ethno-racial AD
	22.5 Genetic Risk for Alzheimer’s Disease: Epidemiological Comparison
		22.5.1 Apolipoprotein (APOE)
		22.5.2 Sortilin-related Receptor 1 (SORL1)
		22.5.3 Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
		22.5.4 Myeloid Cell Surface Antigen CD33 (CD33)
		22.5.5 Myc Box-dependent-interacting Protein 1 (BIN1)
		22.5.6 Phosphatidylinositol-binding Clathrin Assembly Protein (PICALM)
		22.5.7 Clusterin (CLU)
		22.5.8 A Few Other Genes
	22.6 Non-genetic Risk for Alzheimer’s Disease: Epidemiological Comparison
		22.6.1 Age
		22.6.2 Gender
		22.6.3 Family History
		22.6.4 Cardiovascular Disease
		22.6.5 Stroke
		22.6.6 Hypertension
		22.6.7 Diabetes
		22.6.8 Lifestyle
	22.7 Participation of Cohort Groups in Clinical Trials, Respective Outcomes and Medication
	22.8 Neuropsychiatric Symptoms of AD in Ethno-racial Groups
	22.9 Impact of Ethno-racial Factors in the Pathogenesis of Alzheimer’s Disease
	22.10 Interferences to Lessen the Racial and Ethnic Disparities
		22.10.1 Cultural Competence
		22.10.2 Agencies and Grants
		22.10.3 Outreach to Minorities
		22.10.4 Screening Tool
	22.11 Conclusion and Future Perspective
	Acknowledgements
	References
Subject Index