In healthy aging, nerve cells (neurons) in the brain are not lost in large numbers. In AD, however, many nerve cells stop functioning, lose connections with other nerve cells, and die. At first, AD destroys neurons in parts of the brain that control memory, including the entorhinal cortex and the hippocampus (structures in the brain that help form and store short-term memories) and related structures. As nerve cells in these structures stop working properly, short-term memory fails, and a person’s ability to do easy and familiar tasks can begin to decline. AD later attacks the cerebral cortex (the outer layer of neurons in the brain), particularly the areas responsible for language and reasoning. At this point, AD begins to take away language skills and changes a person’s ability to make judgments. Personality changes also may occur. Emotional outbursts and disturbing behaviors, such as wandering, begin to happen and can become more frequent as the disease progresses. Eventually, many other areas of the brain are damaged and the person with AD becomes bedridden, helpless, and unresponsive to the outside world.
Structure and Function of the Brain
The brain is essential to our survival. With the help of motor and sensory nerves throughout the body, it integrates, regulates, initiates, and helps control the body’s functions. The brain governs thinking, personality, moods, the senses, and physical action. We can speak, move, remember, and feel emotions and physical sensations because of the complex interplay of chemical and electrical processes that takes place in our brains. The brain and the rest of the nervous system also regulate body functions that happen automatically, such as breathing and digesting food.
The healthy human brain is made up of billions of neurons that share information with one another through a diverse array of biological and chemical signals. A typical neuron has a cell body, an axon, and many dendrites, all surrounded by a cell membrane. The nucleus, which is found inside the cell body and contains genes composed of deoxyribonucleic acid (DNA), helps to regulate the cell’s activities in response to signals from outside and inside the cell. The axon, which extends from the cell body, transmits messages to other neurons, sometimes over very long distances. Dendrites, which also branch out from the cell body, receive messages from axons of other nerve cells or from specialized sense organs. Axons and dendrites collectively are called neurites. Neurons are surrounded by glial cells, which support and nourish them.
Neurons generally communicate with each other and with sense organs by producing and releasing special chemicals called neurotransmitters. As a neuron receives messages from the dendrites of surrounding cells, an electrical charge (nerve impulse) builds up within the cell. This charge travels down the axon until it reaches the end. Here, it triggers the release of the neurotransmitters that move from the axon across a gap, called a synapse, between it and the dendrites or cell bodies of other neurons. Scientists estimate that a typical neuron has up to 15,000 synapses. Neurotransmitters bind to specific receptor sites on cell bodies and the receiving end of dendrites of adjacent nerve cells. In this way, signals travel between neurons in a fraction of a second. Millions of signals continuously flash through the brain.
Groups of neurons in the brain have specific jobs. For example, some neurons are involved in thinking, learning, remembering, and planning. Others are responsible for vision or hearing, regulating the body’s biological clock, or managing the many other tasks that keep the human body functioning.
The survival of neurons in the brain depends on the healthy functioning of several processes all working in harmony. These processes are communication, metabolism, and repair. The first process, communication between neurons, depends on the integrity of the neuron and its synapses, as well as the production of neurotransmitters.
The second process is metabolism, or all the chemical reactions that take place in the cell. Some of these reactions break down substances, which releases energy. Other reactions involve building complex substances that the cell needs to function out of simple “building block” molecules. Efficient metabolism requires adequate blood circulation to supply the cells with oxygen and glucose (a sugar), the brain’s major fuel.
The third process is repair. Unlike most other body cells, most neurons are already formed at birth. Neurons are programmed to live a long time—even more than 100 years. In an adult, when neurons die because of disease or injury, they are usually not replaced, although we now know that new neurons can be generated in several areas of the brain. To prevent their own death, living neurons must constantly maintain, repair, and remodel themselves.
Research shows that the damage seen in AD involves changes in all three of these neuronal processes: communication, metabolism, and repair. |
What are the Main Characteristics of the Brain in AD?
The brain in AD has three major characteristics that contribute to the pathology, or damage, of the disease. Though scientists have known about these characteristics for many years, recent research has revealed much about their nature and their possible roles in the development of AD.
Amyloid Plaques
Plaques are found in the spaces between the brain’s nerve cells. They were first discovered by Alois Alzheimer nearly 100 years ago, in 1906. They consist of largely insoluble (cannot be dissolved) deposits of a protein peptide, or fragment, called beta-amyloid, together with other proteins, remnants of neurons, non-nerve cells such as microglia (cells that surround and digest damaged cells or foreign substances), and other glial cells, such as astrocytes.
Beta-amyloid is snipped, or cleaved, from a larger protein called amyloid precursor protein (APP). APP is associated with the cell membrane, but its normal function in the cell is not yet fully known. In AD, plaques develop first in areas of the brain used for memory and other cognitive functions.
Most people develop some plaques in their brain tissue as they age. However, the AD brain has many more plaques in certain brain regions. For many years, scientists thought that these structures might cause all the damage to neurons that is seen in AD. However, that concept has evolved considerably in the past few years. Many scientists now think that beta-amyloid clusters at an earlier stage in the plaque development process—called Aß-derived diffusible ligands, or ADDLs (also known as soluble oligomers)—may be a major culprit. Many also think that plaques are a late-stage attempt by the brain to get harmful beta-amyloid away from neurons.
Neurofibrillary Tangles
The second hallmark of AD pathology, also found by Alois Alzheimer, consists of abnormal collections of twisted protein threads found inside nerve cells. The chief component of these structures, called neurofibrillary tangles, is a protein called tau. Healthy neurons are internally supported in part by structures called microtubules, which help transport nutrients and other cellular components from the body of the cell down to the ends of the axon and back. 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 tau. As a result of this “phosphorylation” process, tau disengages from the micro-tubules and begins to aggregate with other threads of tau. Ultimately, these tau threads become enmeshed with one another, forming tangles. When this happens, the microtubules disintegrate and the neuron’s transport system collapses. This may result first in malfunctions in communication between neurons and later in the death of the cells.
Loss of Connections Between Cells and Cell Death
The third major pathological feature of AD, only described in the past 30 years, is the gradual loss of connections between neurons. This process damages neurons to the point that they cannot function properly. Eventually, they die. As the death of neurons 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.
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What Causes AD?
In a very few families, about half of the children of a parent with AD develop the disease in their 30s, 40s, and 50s. These people have inherited mutations in one of three genes. So, in these “early-onset” cases, we know exactly what causes AD.
However, the vast majority of AD cases—more than 90 percent—develop in people older than 65. This form of AD is called “late-onset” AD. We don’t yet completely understand the causes of late-onset AD, but they probably include a mix of genetic, environmental, and lifestyle factors. The importance of these factors in increasing or decreasing the risk of developing the disease may differ from person to person.
Although many questions about the players and steps involved in the causes and development of AD have been answered, our knowledge still has some surprising gaps. For example, we don’t yet fully understand the normal function of several key players, such as APP. Certainly a better knowledge of normal function would give us clues about the causes of AD.
Perhaps the greatest mystery is why AD largely strikes the elderly. Why does it take 30 to 50 years for people to develop signs of the disease, even those individuals who are born with disease-causing mutations? One possibility is that the environment of the aging brain is subtly different from that of the young brain. We may need to understand more about how the brain changes normally as we age before we can fully understand AD.
Scientists supported by the NIH are working in laboratories and research institutions all across the U.S. and in other countries to assemble the many bits of new knowledge that, combined with our existing understanding, will some day explain this complex biological puzzle.
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A Recent Study Sheds Light on Length of Survival After a Diagnosis of AD
After a diagnosis of AD, one of the first things that the patient and family want to know is how long the person may be expected to live with the disease. However, until a recent study conducted by scientists at the University of Washington and the Group Health Cooperative (GHC) in Seattle, little information was available on this vitally important question (Larson et al., 2004).
During the study period—1987 to 1996—the GHC, a health maintenance organization, had about 23,000 members age 60 and older. At the start of the study, 521 members of this group were newly diagnosed with AD. Not surprisingly, the scientists found that people with AD had a significantly decreased survival compared with the average life expectancy of the U.S. population. For example, men had a median survival of 4.2 years from their initial diagnosis, and women had a median survival of 5.7 years.
Men had poorer survival across all age groups compared to women. The life expectancy of 70-year-old men with AD was 4.4 years compared to 9.3 years for the U.S. population. Survival for 70-year-old women with AD was shortened to 8.0 years compared to 15.7 years for the U.S. population. For men age 85, survival was 3.3 years compared to 4.7 years for the U.S. population. Survival for women at age 85 was 3.9 years compared to 5.9 years for the U.S. population.
Other factors, including severity of cognitive impairment, decreased ability to carry out daily activities, history of falls, and chronic illnesses such as diabetes and heart disease, further shortened the lifespans of people with AD. |
What Do We Know About Diagnosing AD?
AD can be diagnosed conclusively only by examining in an autopsy the brain of a person with dementia to determine whether the plaques and tangles in certain brain regions are characteristic of AD. However, clinicians use a range of tools to diagnose “possible AD” (dementia can also be due to another condition) or “probable AD” (no other cause of dementia can be found) in a living person who is having difficulties with memory or other mental functions. These tools include a medical history; physical exam; tests that measure memory, language skills, and other abilities related to changes in brain function; and sometimes, brain scans.
Much is known about the clinical and behavioral characteristics of the disease, and this also helps in diagnosing AD. The diagnostic process is crucial in identifying AD accurately as well as in ruling out other conditions that might be causing cognitive problems or dementia, such as stroke, tumors, Parkinson’s disease (PD), or side effects of medications. In many older people, AD co-exists with other conditions, such as cerebrovascular disease, that may also cause dementia.
An early, accurate diagnosis of AD is especially important to people with AD and their families because it helps them plan for the future and pursue care options while the person with AD can still take part in making decisions. Researchers are making progress in developing accurate diagnostic tests and techniques. In specialized research facilities, clinicians can now diagnose AD with up to 90 percent accuracy. Scientists are working on methods to improve the ability of clinicians to make accurate diagnoses of AD even earlier in the disease process. These advances are providing important insights into the initial changes that occur in the brain of a person with AD even before a clinical diagnosis is made. For example, the newest neuropsychological diagnostic tests for AD, which measure delayed recall, verbal fluency, and overall cognitive status, are highly accurate in distinguishing between cognitively healthy individuals and people with mild AD. Various neuroimaging techniques, such as positron emission tomography (PET) scanning and magnetic resonance imaging (MRI) also are being used in the laboratory to track early changes that may indicate AD (see p. 16 for more on neuroimaging).
Insights from ongoing studies will help scientists understand the natural history of AD and the ways in which changes in memory and other cognitive functions differ in normal aging, AD, and other dementias. This knowledge will help clinicians diagnose AD earlier and more accurately and also will help researchers pinpoint changes that could be targets for drug therapy.
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How Is AD Treated Today?
For those who already suffer from the effects of AD, the most immediate need is for treatments to control cognitive loss as well as problem behaviors, such as verbal and physical aggression, agitation, wandering, depression, sleep disturbances, and delusions. Treatments are needed that work on many people with AD, remain effective for a long time, ease a broad range of symptoms, improve a person’s cognitive function and ability to carry out activities of daily living, and have no serious side effects. Eventually, scientists hope to develop treatments that attack earlier AD processes, preventing the disease from progressing and damaging cognitive function and quality of life.
The U.S. Food and Drug Administration (FDA) has approved five medications to treat AD symptoms, though only four are used today. The first drug to be approved, tacrine (Cognex), has been replaced by three other drugs—donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne, previously known as Reminyl). These three drugs, which are prescribed to treat mild to moderate AD symptoms, act by stopping or slowing the action of acetylcholinesterase, an enzyme that breaks down acetylcholine. Acetylcholine, a neuro-transmitter that is critically important in the process of forming memories, is used by many neurons in the hippocampus and cerebral cortex—regions devastated by AD. These drugs improve some patients’ abilities to carry out activities of daily living; may improve certain thinking, memory, or speaking skills; and can help with certain behavioral symptoms. However, these medications will not stop or reverse AD and appear to help patients only for months to a few years.
The newest AD medication is memantine (Namenda), which is prescribed to treat moderate to severe AD symptoms (Reisberg et al., 2003; Tariot et al., 2004). This drug appears to work by lowering glutamate levels in the brain. Glutamate is another neurotransmitter involved in memory function, but high levels may damage neurons. Like the cholinesterase inhibitors, memantine will not stop or reverse AD. In addition to these medications, physicians use a number of drug and non-drug approaches to treat the behavioral and psychiatric problems that occur frequently as AD progresses.
Helping people with AD live their daily lives and maintain their cognitive abilities is one of the most important goals of AD treatment research. Many investigators are working to develop new and better treatments to preserve these critical functions for as long as possible. Other investigators are working to improve the quality of life for people with AD and caregivers through research on behavioral management techniques and caregiver skills.
One of the primary characteristics of the NIH AD research effort over the past 25 years has been support for a wide range of studies conducted by a large and multidisciplinary cadre of researchers. All of these studies have contributed to the solid base of knowledge that exists today. The accelerating pace of discovery in AD research continues to expand this base, and it is pointing scientists in new and productive research directions. It is also helping investigators ask better questions about the issues that are still unclear.
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