2007 Progress Report on Alzheimer's Disease: Discovery ...

2007 Progress Report on Alzheimer's Disease: Discovery and Hope -- 1 Introduction

INTRODUCTION

Alzheimer's disease is an age-related, irreversible brain disorder that develops over many years. In the very early stage, people experience memory loss, which can be mistaken for memory changes that happen in normal aging. As the disease progresses, these symptoms gradually lead to dementia, a condition characterized by marked memory loss and behavior and personality changes. Eventually, the disease also leads to a decline in other cognitive abilities (such as decision making and language skills), an inability to recognize family and friends, and a severe loss of mental function. These losses are related to the breakdown of the connections between neurons (nerve cells) in the brain and the eventual death of many of these cells.

The course of AD varies from person to person, as does the rate of decline. In most people, symptoms first appear after age 60. AD and other dementing disorders are caused by diseases that affect the brain, although age-related brain and body changes also can affect the development of dementia.

Dr. Alois Alzheimer, a German psychiatrist and neuropathologist, first described what we now know as AD when he reported the case of 51-year-old Auguste D. in 1906. He described the unusual features of her brain tissue—the numerous globs of sticky proteins in the spaces between neurons (what we now call beta-amyloid plaques) and tangled bundles of fibrils within neurons (what we now call neurofibrillary tangles). However, it was not until the 1960s and 1970s that scientists began to recognize AD as a pathology associated with aging (Katzman, 1976).

The public AD research enterprise began in earnest in the 1970s. Initially, investigators focused on understanding the manifestations and natural progression of the disease. Findings from these studies, combined with advances in many scientific areas—diagnostic imaging, genetic analysis, molecular and cellular biology, and the development of animal models, to name just a few—have led to an explosion of knowledge about AD.

Today, some 30 years later, the maturing field of AD research encourages the creativity and insights of individual investigators and targets special areas for emphasis. Enormous progress has been made, and many promising avenues lie ahead. However, if one theme predominates today, it is the growing appreciation of the pathological and clinical complexity of AD. It is clear that AD has no single cause but develops from multiple factors that interact over many years. A variety of scientific disciplines must collaborate if we are to understand the genetic and environmental influences, including lifestyle and health factors, that may increase or decrease an individual’s risk of developing cognitive decline, amnestic mild cognitive impairment, or AD. (Amnestic mild cognitive impairment, or aMCI, is a condition of greater-than-normal memory problems but no impairment in multiple cognitive domains.)

The National Institutes of Health’s (NIH’s) broad program of AD research taps into those varied disciplines, with a growing emphasis on bringing what scientists learn in the laboratory to the clinical arena as rapidly as possible.


An Urgent National Health Priority

The urgency of the AD research task cannot be underestimated. AD is the most common form of dementia. Its impact on the Nation is illustrated by studies estimating its prevalence (the number of people with the disease at any one time). For example, recent estimates from a nationally representative sample in the Aging, Demographics, and Memory Study (part of the ongoing NIA-supported Health and Retirement Study) suggest that among Americans age 72 and older, one in seven has dementia and about 2.4 million have AD (Plassman et al., 2007). Other investigators, using projections from community-based studies, estimate that the number of Americans aged 65 or older with AD will be 5.1 million in 2010 (Evans et al., 1990; Hebert et al., 2003).

Despite the differing methodologies and results of their studies, experts agree that the number of people with AD will increase significantly if current U.S. population trends continue and no prevention methods emerge (Hebert et al., 2003).

Our aging society makes AD an especially critical issue because the number of people with the disease doubles for every 5-year age interval beyond age 65. The U.S. Census Bureau estimates that the population age 65 and older is expected to double to about 72 million people in the next 25 years. Moreover, the 85-and-older age group is now the fastest growing segment of the U.S. population.


About This Report

The 2007 Progress Report on Alzheimer’s Disease describes NIH’s important AD research effort. It begins with a brief primer on AD that reviews the main features of the disease, discusses the causes, and describes how AD is diagnosed and treated. The next section, “Progress in AD Research Continues,” highlights recent advances in nine major areas. The Progress Report concludes with an outline of the diverse ways in which NIH is building on the momentum of 3 decades of groundbreaking AD research.


How Many People Have AD?

Published estimates of the prevalence of AD vary. That’s because investigators use different methods for counting, and each method has its own strengths and weaknesses.

NIA continues its research interest in studies to estimate AD prevalence because having an as-accurate-as-possible number indicates the scope of AD as a public health problem. This helps scientists, policy makers, health care providers, and health care insurers determine the costs of AD to the Nation and develop appropriate services and resources to address the problem.

Equally important, the ability to reliably track trends in AD prevalence and incidence (the number of new cases in a specified time period) helps investigators correlate these trends with changes in environmental and biological factors. Results from these correlations may provide insights into potential risk and protective factors and help inform the design of prevention and treatment interventions.

Some scientists have obtained a prevalence count by using a random sample of older adults that reflects characteristics of the overall U.S. population. Sample findings are then extrapolated to the entire population. Other scientists calculate a national estimate by projecting results from one or more studies of particular communities within the United States. No matter which method scientists use, getting a complete and accurate count of people with AD is a daunting challenge.

Measuring AD in a population requires a different approach than diagnosing the disease in an individual at, for example, a major AD clinical center. In populations, researchers try to identify all the people in a selected group with AD, ruling out those who do not have the condition. There is no simple test to do this, and the count can be further compromised if individuals or their caregivers decline to participate in a study.

To make population assessments easier and more cost-efficient to conduct, investigators often use screening tests and abbreviated cognitive test batteries. These study instruments may help, but they risk overlooking milder cases of AD or diagnosing AD in individuals who have another type of dementia. Further, prevalence studies generally test people at only one point in time, and the tests may not be able to pick up the disease in its early stages. Better diagnostic tools are needed to capture cognitive impairment and AD at their earliest stages, both in population studies and studies conducted in major AD clinical centers, so that we can get a better measure of the scope of the problem.

One of the toughest issues is who to include in the count, a decision that can be driven by budget and staff limitations as well as by study design considerations. For example, including only people older than 65 will miss younger people who may have the disease. If scientists exclude people in nursing homes and assisted living facilities, then they also are likely to end up with an underestimate. Also, many people choose not to participate in these kinds of studies because they don’t want to find out if they have AD or because participation is inconvenient.


A BRIEF PRIMER ON ALZHEIMER'S DISEASE

The healthy human brain is made up of billions of different kinds of neurons that are connected through chemical and electrical signals. A typical neuron has a nucleus in a cell body, an axon, and many dendrites. Neuronal function is supported by other kinds of cells called glial cells.

As with all cells, the nucleus of a neuron contains the cell’s genetic blueprint and helps regulate the cell’s activities in response to signals from outside and inside the cell. The axon transmits messages to other neurons. Dendrites receive messages from axons of other nerve cells or from specialized sense organs. The survival of neurons depends on the healthy functioning of several interdependent processes:

* Communication. When a neuron receives enough messages from surrounding cells, an electrical charge is generated that travels to the end of the axon. Here, it triggers the release of chemicals called neurotransmitters that move across a gap, or synapse, to the dendrites of neighboring neurons. Scientists estimate that the typical neuron has up to 15,000 synapses. The neurotransmitters bind to specific receptor sites on the dendrites of neighboring neurons, triggering chemical changes and building up new electrical charges.
* Metabolism. This process encompasses all the chemical reactions that take place in the cell. Efficient metabolism requires adequate blood circulation to supply the cells with oxygen and glucose, the brain’s major fuel.
* Repair. Neurons are programmed to live a long time—even more than 100 years—so they must constantly maintain, repair, and remodel themselves.


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Visit the NIA Alzheimer’s Disease Education and Referral (ADEAR) Center website at www.nia.nih.gov/Alzheimers/ADvideo to view a short video about AD and the brain.
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How Does AD Affect the Brain?

In healthy aging, most types of brain neurons are not lost in large numbers. In AD, however, many neurons stop functioning, lose connections with other neurons, and die because communication, metabolism, and repair are disrupted.

At first, AD typically destroys neurons in parts of the brain that control memory, including the entorhinal cortex, the hippocampus, and related structures. AD later attacks areas responsible for language and reasoning. Eventually, many other areas of the brain are damaged, and the person becomes helpless and unresponsive to the outside world.


What are the Main Characteristics of the Brain in AD?

Many changes take place in the brain of a person with AD. The three major characteristics that reflect the pathology, or damage, caused by the disease are:

* Amyloid plaques. Found in the spaces between neurons, plaques consist of largely insoluble deposits of aggregated protein fragments called beta-amyloid peptides, other proteins, remnants of neurons, degenerating dendrites and axons, glia, and other cellular material. Scientists used to think that plaques caused the damage to neurons seen in AD. Now, however, many think that earlier, more soluble forms of beta-amyloid may be the major culprits.
* Neurofibrillary tangles. Found inside neurons, neurofibrillary tangles are abnormal aggregates of a protein called tau. Healthy neurons are internally supported in part by structures called microtubules, which help guide nutrients and molecules from the cell body to the ends of the axon. Tau, which normally has a certain number of phosphate molecules attached to it, binds to microtubules and stabilizes them. In AD, an abnormally high number of additional phosphate molecules attach to the tau. As a result, tau disengages from the microtubules and begins to clump together with other threads of tau, eventually forming neurofibrillary tangles. When this happens, the microtubules disintegrate and the neuron’s transport system collapses. As with beta-amyloid, some scientists think that early soluble forms of abnormal tau may cause the damage to neurons.
* Loss of connections between cells and cell death. This feature of AD likely results from the accumulation of beta-amyloid and abnormal tau. When neurons lose their connections, they cannot function properly and eventually die. As neuronal death spreads through the brain, affected regions begin to shrink in a process called brain atrophy. By the final stage of AD, damage is widespread, and brain tissue has shrunk significantly.


What Causes AD?

Very rarely, people develop AD in their 30s, 40s, and 50s. In many of these cases, the disease runs in families and is caused by a mutation in one of three genes that a person has inherited from a parent. This form of the disease is called “early-onset” AD. Other early-onset cases are not caused by such mutations.

More than 90 percent of AD cases develop in people older than 60. The development and pathology of this form of AD, called “late-onset” AD, are very similar to those of early-onset AD. We don’t yet completely understand the causes of late-onset AD, but they probably include genetic, environmental, and lifestyle factors. The importance of these factors in increasing or decreasing the risk of developing AD differs from person to person. Scientists hope that what they learn about early-onset AD also can be applied to the late-onset form of the disease.

Perhaps the greatest mystery is why AD largely strikes elderly people. Why does it take 30 to 50 years for people to develop signs of the disease? Research on how the brain changes normally as people age will help provide answers to this important question.


How Is AD Diagnosed?

Clinicians use a range of tools to diagnose “possible AD” (dementia that could be due to another condition) or “probable AD” (no other cause of dementia can be found). These tools include a medical history; physical exam; tests that measure memory, language skills, and other abilities related to brain functioning; and brain scans. Knowledge about the clinical and behavioral characteristics of the disease also helps in diagnosing AD. At this time, AD can be diagnosed conclusively only by an autopsy of the brain after death. However, in specialized research facilities, clinicians can diagnose AD in a living person with up to 90 percent accuracy.

Early, accurate diagnosis is crucial because it tells people whether they have AD or whether their symptoms are being caused by something else. Stroke, tumor, Parkinson’s disease, sleep disturbances, or side effects of medications are all known to affect cognitive function and memory. Early diagnosis also helps families plan for the future while the person with AD can still participate in making decisions. Researchers are making progress in developing accurate diagnostic tests and techniques that may one day be used in general medical practice to detect the disease early—ideally before symptoms emerge.


How Is AD Treated?

A variety of treatments address behavioral and psychiatric problems that occur as AD progresses. Only a few medications have been approved by the U.S. Food and Drug Administration (FDA) to help control the cognitive loss that characterizes AD. Donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®, formerly known as Reminyl®) are prescribed to treat mild to moderate AD symptoms. Donepezil also is approved to treat severe AD. These drugs act by stopping or slowing the action of acetylcholinesterase, an enzyme that breaks down acetylcholine (a neurotransmitter that helps in memory formation). The drugs maintain some patients’ abilities to carry out activities of daily living and may maintain some thinking, memory, or speaking skills. They also may help with certain behavioral symptoms. However, they do not stop or reverse AD and appear to help patients only for months to a few years.

Another type of AD medication, memantine (Namenda®), is prescribed to treat moderate to severe AD symptoms. This drug appears to work by regulating levels of glutamate, another neurotransmitter involved in memory function. Like the cholinesterase inhibitors, memantine does not stop or reverse AD.

In addition to these medications, physicians use other drugs and nondrug approaches to treat behavioral and psychiatric problems associated with AD. These problems include agitation, verbal and physical aggression, wandering, depression, sleep disturbances, and delusions.