Research over the last two decades has revealed many pieces of the Alzheimer's disease puzzle. Using recent advances in genetics and molecular biology, scientists have begun to put these pieces into place. In doing so, they've vastly increased our understanding of AD and opene many avenues that could lead to effective treatments.
It has become clear that there probably isn't a "magic bullet" that will, by itself, prevent or cure AD. However, scientists may be able to identify a number of interventions that can be used to reduce risk and treat the disease. Today, it is estimated that the National Institute on Aging, other NIH Institutes, and private industry are conducting clinical trials (studies involving humans that rigorously test how well an intervention works) on around 30 compounds that may be active against AD. These studies focus on three main areas:
- Helping people with AD maintain their mental functioning
- Slowing the progress of AD, delaying its onset, or preventing it
- Managing symptoms
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Helping People with AD Maintain their Mental Functioning
In the mid-1970s, scientists discovered that levels of a neurotransmitter called acetylcholine fell sharply in people with Alzheimer's disease (see the section A Walking Tour Through the Brain for more on neurotransmitters). This discovery was one of the first that linked AD with biochemical changes in the brain.
Scientists have found that acetylcholine is a critical player in the process of forming memories. It is used by neurons in the hippocampus and cerebral cortex, which are areas of the brain important to memory function.
By late 2003, the Food and Drug Administration (FDA) had approved five medications to treat AD symptoms. Of these, four are known as cholinesterase inhibitors and are prescribed to treat mild to moderate AD symptoms. The first, tacrine (Cognex), has been replaced by three newer drugs - donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne® (formerly known as Reminyl®)). They act by stopping or slowing the action of acetylcholinesterase, an enzyme that normally breaks down acetylcholine. 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 fifth medication is memantine (Namenda), which can be prescribed to treat moderate to severe AD symptoms. This drug appears to work by regulating excess glutamate in the brain. Glutamate is another chemical involved in memory function. Like the cholinesterase inhibitors, memantine will not stop or reverse AD. Studies have shown that memantine may delay loss of daily functions in patients with moderate to severe AD.
Helping people with AD carry out their daily lives and maintain their mental abilities is one of the most important goals of AD treatment research. Many investigators are working to develop new and better drugs that can preserve this critical function for as long as possible.
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Slowing, Delaying, or Preventing Alzheimer's Disease
Understanding how AD develops-from beginning to end-is vital for finding drugs or other factors that may slow, delay, or even prevent the disease.
Investigators are looking at a number of possibilities for drug treatments. For example, inflammation of tissue in the brain and overproduction of free radicals are two processes that are thought to be a feature of AD. Clinical trials in both of these areas are looking at whether specific anti-inflammatory agents and agents that protect against oxidative damage can slow or prevent the development of AD.
Scientists are also conducting clinical trials to see if substances already used to reduce cardiovascular risk factors also help lower AD risk or delay progression of the disease. These trials are testing whether supplementation with folic acid and vitamins B6 and B12 can slow the rate of cognitive decline in cognitively normal men and women, women at increased risk of developing dementia, and people diagnosed with AD. A study of statins, the most common type of cholesterol-lowering drug, is also underway to see whether these drugs can slow the rate of disease progression in AD patients.
Estrogen is a hormone produced by a woman's ovaries during her childbearing years. Over the past 25 years, laboratory and animal studies, as well as observational studies in women, have suggested that estrogen has some positive effects on brain activity. These findings have created scientific interest in the relationship among estrogen, memory, and cognitive function.
Studies of estrogen in postmenopausal women with mild to moderate AD did not find estrogen beneficial. But, even if estrogen does not slow the progression of the disease in women already affected with AD, scientists thought perhaps menopausal hormone therapy might in some way affect age-related cognitive decline or protect a woman from developing AD. Two types of such therapies have been investigated-the use of estrogen alone in women who have had a hysterectomy and the use of estrogen plus progestin, which reduces the risk of thickening of the lining of the uterus and endometrial cancer, in other women.
In 2002 a large clinical trial showed that combined estrogen/progestin therapy taken daily for just over 5 years increased the risk of heart disease and breast cancer in some women. More recently, a substudy of that trial showed that this same therapy taken daily by women over age 65 actually increased their chance of developing dementia.
Scientists are continuing to evaluate estrogen alone to prevent dementia. This includes an NIA clinical trial of estrogen alone to prevent or delay development of AD in cognitively normal older women with a family history of dementia.
Questions remain. Scientists do not know whether estrogen or progestin causes the increased risk of disease. Would giving a different estrogen or progestational agent change the result? Would starting therapy around the age of 50, rather than 65, be more beneficial or more harmful? More research is needed on this complex matter.
Another area of work involves nerve growth factor (NGF). NGF is one of several growth factors in the body that maintain the health of neurons. NGF also promotes the growth of axons and dendrites, the neuron branches that connect with other neurons and that are essential in nerve cells' ability to communicate (see the section A Walking Tour Through the Brain for more on the structure and function of neurons).
Studies have turned up a number of clues that link NGF to the neurons that use acetylcholine as a neurotransmitter, so researchers have been eager to see what happens when NGF is added to aging brain tissue. In animal studies, researchers have been able to reverse most of the age-related neuronal shrinkage and loss of ability to make acetylcholine. This success has led to a small-scale, privately-funded gene therapy trial that is testing whether this procedure can be done safely in humans and whether it might lessen symptoms of AD.
Finally, a number of clinical trials are focusing on the earliest stages of the disease process. For example, scientists are developing drugs that prevent enzymes from clipping beta-amyloid out from APP. Others are working on ways to stop beta-amyloid from clumping together into plaques. Teams of investigators are also studying certain enzymes that seem to be able to break beta-amyloid into pieces after it is released from cells but before it has a chance to form into plaques.
Still other scientists are exploring the role of neurotransmitter systems other than acetylcholine, such as glutamate. One especially active area of research involves the possibility that a vaccine might be able to stimulate the immune system into getting rid of plaques once they have formed, stopping beta-amyloid and plaque buildup, or even getting rid of plaques once they have formed.
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Science on the Cutting Edge
Immunizing Against AD: Just a Neat Idea or a Real Possibility?
Getting vaccinated against measles, tetanus, polio, and other diseases is common practice these days. A person is injected with a weakened form of a disease-causing bacterium or virus. His or her immune system mobilizes to fight against it, and this protects the person against getting the disease. One scientist wondered whether this approach could work for Alzheimer's disease as well.
Researchers have developed special kinds of mice (called transgenic mice) that gradually develop AD beta-amyloid plaques in the brain. These mice are invaluable tools to test how plaques can be stopped from forming. Over the course of several studies, scientists tested the effects of injections of a vaccine composed of beta-amyloid and a substance known to stimulate the immune system.
They found that long-term immunization resulted in much less beta-amyloid being deposited in the brains of the mice. Similar transgenic mice that had been immunized also performed far better on memory tests than did a group of these mice that had not been immunized.
These exciting developments led to preliminary studies in humans to test the safety and effectiveness of the vaccine. Based on positive results, a further study was designed to measure the immune response in participants with AD who received immunizations with the beta-amyloid vaccine. In this study, which began in the fall of 2001, inflammation unexpectedly developed in the brains of some of the participants. As a result of this complication, the pharmaceutical companies that were conducting the research stopped the trial and are continuing to closely monitor the health of the participants.
Despite their disappointment with this development, the scientists and funders involved in this research emphasize that a tremendous amount of valuable information has been gained from this work so far. It is not unusual for such a revolutionary concept to have setbacks, and they are moving forward with other possible strategies.
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Managing Symptoms
"My father is often agitated. He paces up and down, wringing his hands and crying. I know he's sad or anxious about something but he can't tell me what's bothering him. Asking him about it just makes him more upset."
"Last week, I visited Gran in the nursing home. We had a great time. Then yesterday, I went to see her again. When I walked in her room, she started screaming and calling for help. I didn't know what to do."
"Mom has been getting up in the night and wandering around the house. Last night, I found her all dressed and trying to get out the front door. None of us is getting any sleep anymore."
"My husband used to be such an easy-going, calm person. Now, he suddenly lashes out at me and uses awful language. Last week, he got angry when our daughter and her family came over and we sat down to eat. I never know when it's going to happen. He's changed so much - it scares me sometimes."
As Alzheimer's disease makes inroads into memory and mental abilities, it also begins to change a person's emotions and behaviors. Between 70 to 90 percent of people with Alzheimer's disease eventually develop one or more behavioral symptoms. These include sleeplessness, wandering and pacing, aggression, agitation, anger, depression, and hallucinations and delusions. Some of these symptoms may become worse in the evening, a phenomenon called "sundowning," or during daily routines, especially bathing.
Unlike a stroke, in which damage to part of the brain occurs all at once, the damage of Alzheimer's disease spreads slowly over time and affects many different parts of the brain. Even small tasks require the brain to engage in a complex process that can involve more than one region of the brain. If this process is disrupted, the person may not be able to do the task or may act in a strange or inappropriate way.
In light of our growing understanding about the effects of AD on the brain, behavior that may seem bizarre suddenly makes sense:
For a man who can no longer distinguish between past and present, the anguish caused by the death of his parent may be as real today as it was many years before.
An unknown young man suddenly appearing in her room may be threatening and terrifying to a woman who does not recognize her grandson.
Feelings of responsibility toward a long-ago night job resurface and compel a woman to get up in the night to go to work.
Sitting down to a family meal may produce intense anxiety when a person has no idea what to do with the knife and fork in front of him and all the conversation and activity feel overwhelming.
Behavioral symptoms are one of the hardest aspects of the disease for families and other caregivers to deal with. They are emotional and upsetting. They are also a visible sign of the terrible change that has taken place in the person with AD. Researchers are slowly learning more about why they occur, and they are studying new treatments - both drug and non-drug - to deal with them.
A number of ongoing and planned clinical trials are looking at ways to treat agitation. These trials include participants who are living in nursing homes or at home. They involve the study of a variety of drugs, including a beta-blocker, an anti-seizure medication, a cholinesterase inhibitor, and an antipsychotic.
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The Human Side of AD Research
Participating in a Clinical Trial
Rapid advances in our knowledge about AD have led to the development of many new drugs and treatment strategies. However, before these new strategies can be adopted, they must be shown to work in patients. This means that clinical trials - studies in people to rigorously test how well a treatment works - have become an increasingly important part of AD research. Advances in treatment are only possible through the participation of patients and family members in clinical trials.
Clinical trials are the primary way that researchers find out if a promising treatment is safe and effective for patients. Clinical trials also tell researchers which treatments are more effective than others. Trials take place at private research facilities, teaching hospitals, specialized AD research centers, and doctors' offices.
Participating in a clinical trial is a big step for people with AD and their caregivers. That's why physicians and clinical trials staff spend lots of time talking with participants about what it's like to be in a trial and the pros and cons of participating. Here are some things that potential participants might want to know about clinical trials.
What kind of trials are there?
- Treatment trials with existing drugs assess whether an already approved drug or compound is useful for other purposes. For example, one current trial is testing whether anti-inflammatory drugs already used to treat arthritis might help to prevent AD.
- Treatment trials with experimental drugs or strategies find out whether a brand new drug or treatment strategy can help improve cognitive function or lessen symptoms in people with AD, slow the progression to AD, or prevent it. Potential drugs tested in these trials are developed from knowledge about the mechanisms involved in the AD disease process. These compounds are rigorously tested in tissue culture and in animals for their action. Safety and effectiveness studies are also conducted in animals before the compounds are tested in humans.
What are the phases of clinical trials
- During Phase I trials, a study team gives the treatment to a small number of volunteers and examines its action in the body, its safety, and its effects at various doses. Phase I trials generally last only a few months.
- If results show that the treatment appears safe, it will be tested in Phase II and Phase III clinical trials. These trials involve larger numbers of people over longer periods of time. In these trials, the study team wants to know whether the treatment is safe and effective and what side effects it might have.
After these phases are complete and investigators are satisfied that the treatment is safe and effective, the study team may submit its data to the Food and Drug Administration (FDA) for approval. The FDA reviews the data and decides whether to approve the drug or treatment for use in patients.
What happens when a person signs up for a clinical trial?
First it is important to learn about the study. Study staff explain the trial in detail to potential research participants and describe possible risks and benefits. Staff also talk about the participants' rights as research volunteers, including their right to leave the study at any time. Participants and their family members are entitled to have this information repeated and explained until they feel they understand the nature of the study and any potential risks.
Once all questions have been answered and if there is still interest in being a part of the study, a patient participant is asked to sign an informed consent form. Laws and regulations regarding informed consent differ across States and research institutions, but all are intended to ensure that patient participants are protected and well cared for.
In some cases, a patient participant may no longer be able to provide informed consent because of problems with memory and confusion. In such cases, it is still possible for an authorized representative (usually a family member) to give permission for the patient to participate. For example, the patient participant may have previously included research participation as part of his or her durable power of attorney. The person (proxy) exercising the durable power of attorney can decide to let the patient participate in a trial if they are convinced that the patient would have wanted to consent if able to do so. Even so, it is still important that patients assent to be in the study, even if they can no longer formally consent to it. Different States have different laws about who is a legal representative. These laws are in a state of flux as researchers and the public grapple with the ethical issues of proxy consent.
Next, patients go through a screening process to see if they qualify to participate in the study. If they qualify and can safely participate, they can proceed with the other parts of the study.
What happens during a trial?
If participants agree to join the study and the screening process shows they're a good match, they have a "baseline" visit with the study staff. This visit generally involves a full physical exam and extensive cognitive and physical tests. This give the study team information against which to measure future mental and physical changes. Participants also receive the test drug or treatment. As the study progresses, participating patients and family members usually must follow strict medication or treatment instructions and keep detailed records of symptoms. Every so often, participants visit the clinic or research center to have physical and cognitive exams, give blood and urine samples, and talk with study staff. These visits allow the investigators to assess the effects of the test drug or treatment, see how the disease is progressing, and see how the participant and the caregiver are doing.
In most clinical trials, participants are randomly assigned to a study group. One group, the test group, receives the experimental drug. Other groups may receive a different drug or a placebo (an inactive substance that looks like the study drug). Having the different groups is important because only by comparing them can researchers be confident that changes in the test group are the result of the experimental treatment and not some other factor. In many trials, no one - not even the study team - knows who is getting the experimental drug and who is getting the placebo or other drug. This is called "masking" meaning that the patient/family member and the staff are "blind" to the treatment being received.
What should people consider before participating in a clinical trial?
Expectations and motivations. Clinical trials generally don't have miraculous results. The test drug or treatment may relieve a symptom, change a clinical measurement, or reduce the risk of death. With a complex disease like AD, it is unlikely that one drug will cure or prevent the disease. Some people choose not to participate or drop out of a study because this reality doesn't meet their expectations. Others [NF1]participate because they realize that even if the benefit to them may be slight, they are making a valuable contribution to knowledge that will help future patients.
Uncertainty. Some families have a hard time with the uncertainties of participation - not knowing whether the person is on the test drug or the placebo, not being able to choose which study group to be in, not knowing for a long time whether the study was successful or not. Ongoing and open communication with study staff can help to counter this frustration.
Finding the right clinical trial. Some clinical trials want participants who are cognitively healthy or have only mild symptoms because they are testing a drug that might delay the decline in cognitive function. Other trials are interested in working with participants who have more advanced AD because they are testing a drug that might lessen behavioral symptoms, or they are testing new strategies to help caregivers. Even though a participant may not be eligible for one trial, another trial may be just right.
The biggest benefit of all. Many families find that the biggest benefit of participating in a clinical trial is the regular contact with the study team. These visits provide an opportunity to get state-of-the-art AD care and also to talk on an ongoing basis with experts in AD who have lots of practical experience and a broad perspective on the disease. The study team understands and can provide advice on the emotional and physical aspects of the person with AD and the caregivers' experience. They can suggest ways to cope with the present and give insights into what to expect in the future. They also can share information about support groups and other helpful resources.
For more information about AD clinical trials, visit the NIA's Alzheimer's Disease Education and Referral (ADEAR) Center's Clinical Trials Database website (www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials). This website includes a list of clinical trials on Alzheimer's disease and dementia currently in progress at centers throughout the U.S. It also provides information on the phases of clinical trials and how to participate, and explains the drug development process. The site also provides links to other useful websites with related information. For additional information, visit the clinical trials websites of the Alzheimer's Association www.alz.org/professionals_and_researchers_research_programs.asp and the National Institutes of Health www.clinicaltrials.gov.
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