The Alzheimer's Epidemic

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Danton O'Day. The Alzheimer's Epidemic

Dedication

Acknowledgements

Preface

Chapter 1. Introduction and Overview

The Alzheimer’s Epidemic

Three Types of Alzheimer’s Disease

Fighting the Odds

Lifestyles and Alzheimer’s Disease

We All Forget Things but Alzheimer’s Is Different

Cells of the Alzheimer’s Brain

A Very Short History of Alzheimer’s Disease

The Personal Side of Alzheimer’s Disease

The Reality of Alzheimer’s Disease

You, Your Family and Alzheimer’s Disease

Healthcare Workers and Alzheimer’s Disease

Quality of Life: An Important Issue

Plaques and Tangles

The Search for Biomarkers

The Pharmaceutical Landscape

The Stage is Set

Chapter 2. The Alzheimer’s Epidemic by the Numbers

The Aging Crisis

Why Focus on Alzheimer’s Disease?

The Epidemic by the Numbers

Demographics Play a Big Part

Different Countries, Different Problems

Developing an Action Plan

Chapter 3. The Stages of Alzheimer’s Disease

The Onset and Progression of Alzheimer’s Disease

How Does Alzheimer’s Start?

Personality Changes Can Be a Signal

MCI: Mild Cognitive Impairment

Attributes of Dementia: Delusions

Types of Dementia

The Three Stages of Dementia

Chapter 4. The Alzheimer’s Brain

The Wiring of the Brain

Why Alzheimer’s Brain Cells Fail to Communicate

The Alzheimer’s Brain: Outside In

The Normal Brain and Its Functions

The Cerebral Cortex and Alzheimer’s Disease

Alzheimer’s Disease Sequentially Affects Brain Functions

Chapter 5. Brain Cells, Plaques and Tangles

Microglia

Astrocytes

Ependymal Cells

Oligodendrocytes

Nerve Cells

Brain Neurons Communicate via Neurotransmitters

Plaques and Tangles

Brain Cell Death during Alzheimer’s Disease

Chapter 6. What Are Amyloid Plaques?

The Detection of Amyloid Plaques

The Structure of Amyloid Plaques

Glia and Amyloid Plaques

Some Proteins Found in Amyloid Plaques

Herpes Virus Proteins Are Found in Plaques

The Amyloid Hypothesis: An In-Depth Look

The End-Product Troublemaker

A Controversial Current View

Do Nucleating Agents Initiate Plaque Formation?

Chapter 7. The Tangled Web. A Scientific Battle

Tau and Neurodegeneration

Tangles in the Brain

Tau Binds to Microtubules

Good Tau Can Be Turned Bad

Tau in Neurons

Tau Phosphorylation Gets Hyper!

Tau Phosphorylation: Identifying the Culprits

Tangling Tau: A Complex Web of Kinases

Tau and the Mind of a Mouse

Tau Can Move from Neuron to Neuron

Chapter 8. Plaques and Tangles as Pharmaceutical Targets. The Major Hypotheses for Alzheimer’s Disease

The Yin-Yang of Plaque Formation as a Target

Amyloid Hypothesis-Based Drugs

Beta-Secretase as a Pharmaceutical Target

The Continuing Search for Secretase Inhibitors

Will New Beta-Secretase Inhibitors Ride to the Rescue?

Treatments Targeting Tau

Many Kinases Turn Good Tau Bad

Drugs that Prevent or Reduce Tangles

Why Do Some Promising Drugs Fail?

Chapter 9. Targeting the Cholinergic Hypothesis

The Cholinergic Hypothesis

Therapies Based on Acetylcholine

Acetylcholinesterase Inhibitors

FDA-Approved Cholinergic Drugs

Clinical Variations Can Hide Information

Chapter 10. NMDA Receptors as Pharmaceutical Targets

Glutamate and NMDA Receptors

NMDA Receptors as Pharmacological Targets

Memantine as an Alzheimer’s Drug

NMDA Receptors and Neuron Death

Chapter 11. Biomarkers: Detecting Alzheimer’s Disease. Biomarkers and Their Uses

The Search for Causes and Predictors

Required Attributes of Biomarkers

Biochemical Biomarkers: Assessing Preclinical Stages

Tracking the Movements of Amyloid Beta

Other Biochemical Markers of Alzheimer’s

Brain Imaging as a Biomarker

Magnetic Resonance Imaging (MRI)

Episodic versus Semantic Memory

Functional versus Structural MRI

PET Scans

Sugar for Your PET

EEG: Electrical Imaging of the Alzheimer’s Brain

Cognitive Self-Testing for Alzheimer’s Disease

Formal Cognitive Screening

The Biomarker Future

Alzheimer’s May Start Decades before Any Symptoms

Chapter 12. Searching for Alzheimer’s Genes

Genetic Links to Alzheimer’s Disease

Down Syndrome and Alzheimer’s Disease

The Link to Tangle Formation

Three Bad Genes Linked to Early-Onset Alzheimer’s

Some Good News: Gene Mutation Defends Against Alzheimer’s

Late-Onset Susceptibility Genes

Good Genes Can Do Bad Things

APOE: A Cholesterol-Associated Protein Linked to Alzheimer’s

Chapter 13. More Susceptibility Genes

Putting Amyloid Beta in the Garbage Instead of in Plaques

Nine Offenders with Unfriendly Names

PICALM Stands Out in One Study

GWAS: Genome-Wide Association Studies

Chapter 14. Developing a Drug Takes Time

Dealing with Symptoms versus Causes

Why is it Taking So Long?

Stages of Drug Development

Scientist versus Clinician versus Patient: Different Points of View

The Problems Facing Alzheimer’s Drug Research

Analyzing Drug Success Is an Issue

A New Drug for Detecting Plaques

Chapter 15. The Pharmaceutical Landscape. A Timeline of Major Clinical Therapies

Chelation Therapy

The Little Powerhouses that Shouldn’t

Pharmaceutical Antioxidant Therapies

Anti-Inflammatory Drugs

The Trend Away from Using Anti-Psychotics

Chapter 16. A Final View

A Basic Model for Alzheimer’s Disease

The Calcium Hypothesis

Early and Accurate Diagnosis Is Key

The Future of Alzheimer’s Research

How Low Can You Go?

Is Systems Biology the Answer?

Why Does Alzheimer’s Exist?

Evolutionary Research, Medicine and Alzheimer’s Disease

The First Alzheimer’s Patient Re-Examined

The Future Holds Hope

Selected References

The Alzheimer’s Epidemic Website

About the author

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To Susan, my patient and loving wife, who as an RN has served on the front-lines of eldercare and Alzheimer’s disease counseling. Her advice, insightful guidance and encouragement were central to the completion of this book.

Danton H. O’Day, PhD

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But Alzheimer’s disease presents itself as more than a short-term loss of memory or forgetfulness, it begins with a major loss in one’s ability to recall and reason. More importantly, it can progress to the state were the sufferer is often confused about where they are or what they are doing. It can cause them to forget who their loved ones are. Having said this, the disease is not something that is a natural extension of growing old. Also, the progression from loss of memory to full-fledged dementia is not a given. Understanding exactly what separates simple loss of memory from aging versus true Alzheimer’s disease is important and will become much clearer as the reader progresses through this volume.

It’s tough to worry about the world around you and what the future will bring when you or someone close to you has developed Alzheimer’s disease. While the implications of losing one’s touch with reality are overwhelming, the disease has other wide-ranging effects. It decreases the quality of life not only for the sufferer but also for family members, for whom the impact is equally devastating. One’s own family is the predominant cornerstone for the care of the Alzheimer’s sufferer. For example, it has been estimated that in Canada the psychological impact of having the responsibility of being the primary caregiver is immense. Between 40 and 70% of caregivers have been shown to experience psychological problems because of the pressures they face in having to assist someone with the disease. With 15–30% of caregivers, these responsibilities led to full clinical depression. There is little doubt that these numbers can be extrapolated to family caregivers worldwide. The number of hours family caregivers lovingly sacrifice is great and increases as the disease continues to progress in the family member they care for. In Canada, the total time dedicated to caring for family members with the disease will approach 800 million hours per year. When this is coupled with annual healthcare costs reaching up to 150 billion dollars within the next 25–30 years, it becomes clear why we are facing a true Alzheimer’s epidemic.

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