Alzheimer Disease

=>March 17, 2009 -- Scientists have made a significant step forward in developing a test to help diagnose the early stages of Alzheimer’s disease sooner and more accurately by measuring two biomarkers—tau and beta-amyloid proteins—in cerebrospinal fluid.In a new report, researchers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) not only confirmed that certain changes in biomarker levels in cerebrospinal fluid may signal the onset of mild Alzheimer’s, but also established a method and standard of testing for these biomarkers.

What is Alzheimer's disease (AD)?

Alzheimer’s disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks of daily living. In most people with AD, symptoms first appear after age 60.

AD is the most common cause of dementia among older people, but it is not a normal part of aging. Dementia refers to a decline in cognitive function that interferes with daily life and activities. AD starts in a region of the brain that affects recent memory, then gradually spreads to other parts of the brain. Although treatment can slow the progression of AD and help manage its symptoms in some people, currently there is no cure for this devastating disease.

AD is named after Dr. Alois Alzheimer, a German doctor. In 1906, Dr. Alzheimer described changes in the brain tissue of a woman who had died of an unusual mental illness. He found abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary tangles).

Today, these plaques and tangles in the brain are considered hallmarks of AD. The third main feature of AD is the gradual loss of connections between nerve cells (neurons) in the brain. This loss leads to diminished cell function and cell death.

We don’t know what starts the AD process, but we do know that damage to the brain begins as many as 10 to 20 years before any obvious signs of forgetfulness appear.

As nerve cells die throughout the brain, affected regions begin to shrink. By the final stage of AD, damage is widespread, and brain tissue has shrunk significantly.

What causes AD?

Scientists don’t yet fully understand what causes AD, but it is clear that it develops because of a complex series of events that take place in the brain over a long period of time. It is likely that the causes include genetic, environmental, and lifestyle factors. Because people differ in their genetic make-up and lifestyle, the importance of these factors for preventing or delaying AD differs from person to person.

Genetics play a role in some people with AD. A rare type of AD, called early-onset AD, affects people ages 30 to 60. Some cases of early-onset AD, called familial AD, are inherited. Familial AD is caused by mutations (permanent changes) in three genes. Offspring in the same generation have a 50-50 chance of developing familial AD if one of their parents had it.

Most cases of AD are late-onset AD, which develops after age 60. Although a specific gene has not been identified as the cause of late-onset AD, genetic factors do appear to increase a person’s risk of developing the disease. This increased risk is related to the apoliprotein E (APOE) gene. The APOE gene has several forms. One of them, APOE ε4, occurs in about 40 percent of all people who develop late-onset AD. However, at least one-third of people with AD do not have this form of the gene.

Four to seven other AD risk-factor genes may exist as well. One of them, SORL1, was discovered in 2007. Large-scale genetic research studies are looking for other risk-factor genes. For more information, see the Alzheimer’s Disease Genetics Fact Sheet.

Research suggests that certain lifestyle factors, such as a nutritious diet, exercise, social engagement, and mentally stimulating pursuits, might help to reduce the risk of cognitive decline and AD. Scientists are investigating associations between cognitive decline and heart disease, high blood pressure, diabetes, and obesity. Understanding these relationships and testing them in clinical trials will help us understand whether reducing risk factors for these diseases may help with AD as well.

Can AD be prevented?

We can’t control some risk factors for AD such as age and genetic profile. But scientists are studying a number of other factors that could make a difference. Only further research will reveal whether these health, lifestyle, and environmental factors can help prevent AD. Some of these factors are: physical activity, dietary factors such as antioxidants and DHA, and damage to the vascular system.

What are the symptoms of AD?

The course of AD is not the same in every person with the disease, but symptoms seem to develop over the same general stages.

Very early signs and symptoms

Memory problems are one of the first signs of AD. Some people with mild AD have a condition called amnestic mild cognitive impairment (MCI). People with MCI have more memory problems than normal for people their age, but their symptoms are not as severe as those of people with AD. More people with MCI go on to develop AD than people without MCI.

Mild AD

As AD progresses, memory loss continues and changes in other cognitive abilities appear. Symptoms in this stage can include:

• getting lost
• trouble handling money and paying bills
• repeating questions
• taking longer than before to complete normal daily tasks
• poor judgment
• losing things or misplacing them in odd places
• mood and personality changes

In most people with AD, symptoms first appear after age 60. AD is often diagnosed at this stage.

Also see: The Seven Warning Signs of AD

Moderate AD

In moderate AD, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought. Symptoms may include:

• increased memory loss and confusion
• problems recognizing family and friends
• inability to learn new things
• difficulty carrying out tasks that involve multiple steps (such as getting dressed)
• problems coping with new situations
• delusions and paranoia
• impulsive behavior

Severe AD

People with severe AD cannot communicate and are completely dependent on others for their care. Near the end, the person with AD may be in bed most or all of the time. Their symptoms often include:

• inability to recognize oneself or family
• inability to communicate
• weight loss
• seizures
• skin infections
• difficulty swallowing
• groaning, moaning, or grunting
• increased sleeping
• lack of control of bowel and bladder

The most frequent cause of death for people with AD is aspiration pneumonia. This type of pneumonia develops when a person cannot swallow properly and takes food or liquids into the lungs instead of air.

How is AD diagnosed?

The only definite way to diagnose AD is with an autopsy, which is an examination of the body done after a person dies. However, doctors can determine fairly accurately whether a person who is having memory problems has “possible AD” (the symptoms may be due to another cause) or “probable AD” (no other cause for the symptoms can be found). To diagnose AD, doctors:

• ask questions about a person’s overall health, past medical problems, ability to carry out daily activities, and changes in behavior and personality
• conduct tests of memory, problem solving, attention, counting, and language skills
• carry out medical tests, such as tests of blood, urine, or spinal fluid
• perform brain scans, such as a computed tomography (CT) scan or magnetic resonance imaging (MRI) test

These tests may be repeated to give doctors information about how the person’s memory is changing over time. Sometimes these tests help doctors find other possible causes of the person's symptoms. For example, thyroid problems, drug reactions, depression, brain tumors, and blood-vessel disease in the brain can cause AD-like symptoms. Some of these other conditions can be treated successfully.

Why is early diagnosis important?

Early diagnosis is beneficial for several reasons. Having an early diagnosis and starting treatment in the early stages of AD can help preserve function for months to years, even though the underlying AD process cannot be changed.

Having an early diagnosis also helps patients and their families:

• plan for the future
• make living arrangements
• take care of financial and legal matters
• develop support networks

Finally, an early diagnosis can provide greater opportunity for people with AD to get involved in clinical trials. Clinical trials are research studies in which scientists test the safety, side effects, or effectiveness of a medication or other intervention.

To find out more about AD clinical trials, talk with your health care provider, contact NIA’s ADEAR Center at 1-800-438-4380, or visit the Alzheimer’s Disease Clinical Trials database. You can also sign up for email alerts that let you know when new clinical trials are added to the database. More information is available at www.ClinicalTrials.gov.

What new methods for diagnosing AD are being studied?

Scientists are exploring ways to help physicians diagnose AD earlier and more accurately. The ultimate goal is a reliable, valid, inexpensive, and early diagnostic test that can be used in any doctor’s office.

Some studies focus on changes in personality and mental functioning, measured through memory and recall tests, that might point to early AD or predict which individuals are at higher risk of developing AD in the future. Other studies are examining the relationship between early damage to brain tissue and outward clinical signs. Still others are looking at changes in blood and cerebrospinal fluid that may indicate the progression of AD.

One of the most exciting areas of ongoing diagnostic research is neuroimaging. Scientists have developed sophisticated imaging systems that may help measure the earliest changes in brain function or structure to identify people in the very first stages of AD—well before they develop apparent signs or symptoms.

The National Institute on Aging’s AD Neuroimaging Initiative is a large study that uses MRI and positron emission tomography (PET) scans to learn when and where in the brain changes occur as memory problems develop. These types of neuroimaging scans are still primarily research tools, but one day they may be used more commonly to help physicians diagnose AD at very early stages.

How is AD treated?

AD is a complex disease, and no single “magic bullet” is likely to prevent or cure it. That’s why current treatments focus on several different issues, including helping people maintain mental function; managing behavioral symptoms; and slowing, delaying, or preventing AD.

AD research has developed to a point where scientists can look beyond treating symptoms to think about addressing the underlying disease process. Scientists are looking at many possible interventions, such as cardiovascular treatments, antioxidants, immunization therapy, cognitive training, and physical activity.

What drugs are currently available to treat AD?

No treatment has been proven to stop AD. The U.S. Food and Drug Administration has approved four drugs to treat AD. For people with mild or moderate AD, donepezil (Aricept®), rivastigmine (Exelon®), or galantamine (Razadyne®) may help maintain cognitive abilities and help control certain behavioral symptoms for a few months to a few years. Donepezil can be used for severe AD, too. Another drug, memantine (Namenda®), is used to treat moderate to severe AD. However, these drugs don’t change the underlying disease process.

These drugs work by regulating neurotransmitters, the chemicals that transmit messages between neurons. They also may help maintain thinking, memory, and speaking skills and may help with certain behavioral problems.

Other medicines may ease the behavioral symptoms of AD—sleeplessness, agitation, wandering, anxiety, anger, and depression. Treating these symptoms often makes patients more comfortable and makes their care easier for caregivers.

No published study directly compares the four approved AD drugs. Because they work in a similar way, it is not expected that switching from one of these drugs to another will produce significantly different results. However, an AD patient may respond better to one drug than another.

Also see: AD Medications Fact Sheet

What potential new treatments are being researched?

NIA, part of the National Institutes of Health, is the lead Federal agency for AD research. NIA-supported scientists are testing a number of drugs and other interventions to see if they prevent AD, slow the disease, or help reduce symptoms.

Beta-amyloid

Scientists are very interested in the toxic effects of beta-amyloid—a part of amyloid precursor protein found in deposits (plaques) in the brains of people with AD. Studies have moved forward to the point that researchers are carrying out preliminary tests in humans of potential therapies aimed at removing beta-amyloid, halting its formation, or breaking down early forms before they can become harmful. Specific areas of research include immunization with beta-amyloid and beta-amyloid’s disruption of cellular communication.

The aging process

Some age-related changes may make AD damage in the brain worse. Researchers think that inflammation may play a role in AD. Studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) might help slow the progression of AD, but clinical trials so far have not shown a benefit from these drugs. Researchers are continuing to look at how NSAIDs might affect the development or progression of AD.

Scientists are also looking at free radicals, which are oxygen or nitrogen molecules that combine easily with other molecules. The production of free radicals can damage nerve cells. The discovery that beta-amyloid generates free radicals in some AD plaques is a potentially significant finding in the quest to understand AD better.

Lifestyle factors

A number of studies suggest that factors such as exercise, a healthy diet, and social engagement may be related to the risk of cognitive decline and AD. For example, studies in older people have shown that higher levels of physical activity or exercise are associated with a reduced risk of dementia.

Scientists have also studied whether certain foods can impact cognitive decline. One study found that mice that ate a diet high in a type of omega-3 fatty acid had reduced beta-amyloid and plaques in brain tissue. The AD Cooperative Study is now testing this fatty acid, DHA, to see if it can slow cognitive and functional decline in people with mild to moderate AD. Also, large-scale clinical trials are studying whether vitamin E and selenium supplements can help prevent memory loss and dementia.

Many studies are looking into other possible treatments. For example, scientists are studying the effects of ginkgo biloba, an extract from a tree, in delaying cognitive decline and treating AD symptoms. Other studies have suggested that estrogen used by women to treat the symptoms of menopause also protects the brain and could reduce the risk of AD or slow the disease.

What are clinical trials?

People who want to help scientists test possible treatments may be able to take part in clinical trials, which are research studies that test the safety, side effects, or effectiveness of a medication or other intervention. Study volunteers help scientists learn abut the brain in healthy aging as well as what happens in AD. Results of AD clinical trials are used to improve prevention and treatment approaches.

NIA sponsors many AD clinical trials, including those conducted by Alzheimer's Disease Centers located throughout the United States. To find out more about clinical trials, talk with your health care provider or contact NIA’s ADEAR Center at 1-800-438-4380. Or, visit the ADEAR Center clinical trials database at AD Clinical Trials Database. Additional clinical trials information is available at www.ClinicalTrials.gov.