The Search for New Treatments

More and more, scientists are able to think about ways to treat, slow, or perhaps even prevent AD at a number of possible points during the years-long continuum of disease progression. This continuum begins with the very earliest disease stage, even before symptoms are evident, moves to the first signs of memory and cognitive problems, then continues through the mild and moderate stages, and ends with the very late stages and the person’s death.

As a result, researchers who focus on developing AD treatments think a lot about the importance of timing:  When would it be best to intervene and what interventions are most appropriate at which time?  These questions are similar to those asked with other conditions, such as heart disease. For example, a physician would prescribe different treatments for a patient who is seemingly healthy but who is at risk of having future heart disease than for a patient who is actually having a heart attack or whose heart disease is well established. The same decision process now can be applied to AD.

It has become clear that there probably is no single “magic bullet” that will, by itself, prevent or cure AD. Therefore, investigators are working to develop an array of options from which physicians can choose. For people who already have AD, the most immediate need is for treatments to control cognitive loss as well as problem behaviors, such as aggression, agitation, wandering, depression, sleep disturbances, hallucinations, and delusions. Safe medications that remain effective over time are needed to ease a broad range of symptoms and to improve a person’s cognitive function and ability to carry out activities of daily living. Scientists also are investigating treatments that combine medications with lifestyle strategies to lessen the risk of developing cognitive decline or AD. Eventually, scientists hope to develop treatments that attack the earliest manifestations and underlying causes of AD, thereby slowing, delaying, or preventing the disease from progressing and damaging cognitive function and quality of life. Scientists use clinical trials to pursue all these goals.

Today, NIA, other NIH institutes, and private industry are conducting many clinical trials of AD interventions (see "Participating in a Clinical Trial" for more about clinical trials). These studies focus on several key areas:

• Helping people with AD maintain their mental functioning
• Managing symptoms
• Slowing, delaying, or preventing AD

HELPING PEOPLE WITH AD MAINTAIN THEIR MENTAL FUNCTIONING
In the mid-1970s, scientists discovered that levels of a neurotransmitter (a chemical that carries messages between neurons) called acetylcholine fell sharply in people with AD. This discovery was one of the first that linked AD with biochemical changes in the brain. Scientists 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. This discovery was an important initial breakthrough in the search for drugs to treat AD.

Four medications, tested in clinical trials, have been approved by the FDA for use in treating AD symptoms. Donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®) are prescribed to treat mild to moderate AD symptoms. Donepezil was recently approved to treat severe AD as well. These drugs, known as cholinesterase inhibitors, act by stopping or slowing the action of acetylcholinesterase, an enzyme that breaks down acetylcholine. They help to maintain higher levels of acetylcholine in the brain. In some people, the drugs maintain abilities to carry out activities of daily living. They also may maintain some thinking, memory, or speaking skills, and can help with certain behavioral symptoms. However, they will not stop or reverse the underlying progression of AD and appear to help people only for months to a few years. The newest approved AD medication is memantine (Namenda®), which 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 will not stop or reverse AD.

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 Mom in the nursing home. We had a great time. Then yesterday, I went to see her again. When I walked into her room, she didn’t know  me. She thought I was her sister.”

“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.”

“Gran hums all the time. She used to be a singer. Is she trying to relive her past?”

As AD begins to affect memory and mental abilities, it also begins to change a person’s emotions and behaviors. Between 70 and 90 percent of people with AD eventually develop one or more behavioral symptoms. These symptoms 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.

The damage of AD affects many different parts of the brain. This presents a problem because even small tasks require the brain to process signals that often involve more than one region of the brain. If this processing is disrupted because of AD, 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, behaviors like the ones highlighted above suddenly make sense or even provide a loving opportunity for caregivers:

For a man who can no longer distinguish between past and present, the anguish caused by the death of a parent may be as real today as it was many years before.

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.

Memories of favorite songs from long ago resurface and provide a compelling link to a happy time in the past.

Behavioral symptoms, often emotional and upsetting, are one of the hardest aspects of the disease for families and other caregivers to deal with. 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 behavioral symptoms occur and are conducting clinical trials on new treatments—both drug and non-drug—to deal with difficult behaviors.

SLOWING, DELAYING, OR PREVENTING AD
AD research has developed to the point where scientists are looking beyond treating symptoms to addressing the underlying disease process. Slowing the progress of AD could do much to maintain the functioning of people with AD and reduce physical and emotional stress on caregivers. Delaying AD’s effects also could help to postpone or prevent placement in an assisted living facility or nursing home, and reduce the financial costs of the disease. Preventing AD altogether is, of course, the ultimate long-term goal.

NIA and pharmaceutical companies support treatment clinical trials that are aimed at slowing, delaying, or preventing AD. The advances in our knowledge about the mechanisms and risk factors associated with AD have expanded the types of interventions under study. These trials are examining a host of possible interventions, including cardiovascular treatments, hormones, type 2 diabetes treatments, antioxidants, omega-3 fatty acids, immunization, cognitive training, and exercise, among others.

For example, NIA funds pilot trials to learn whether treating one or another aspect of type 2 diabetes will affect cognitive health and AD progression. A pilot trial is a relatively small clinical trial that collects initial data on the safety, effectiveness, and best dosage of a potential treatment. This information helps investigators decide which treatments should be tested in larger, full-scale trials. One 4-month pilot trial has examined the effects on AD of administering a nasal-spray form of insulin. This trial is founded on evidence that AD is associated with reduced levels of insulin in cerebrospinal fluid and that treatment with insulin improves memory performance. The trial will provide useful data on the safety, feasibility, and potential effectiveness of this innovative treatment approach. Investigators may be able to use the results to plan future full-scale clinical trials.

Beyond pilot studies, investigators also are conducting full-scale AD clinical trials of various interventions. One of these trials, the Alzheimer’s Disease Cooperative Study (ADCS), is testing whether one omega-3 fatty acid (DHA), found in the oil of certain fish, can slow the progression of cognitive and functional decline in people with mild to moderate AD. During the 18-month clinical trial, investigators will measure the progress of the disease using standard tests for functional and cognitive change. Researchers also will evaluate whether taking DHA supplements has a positive effect on possible physical and biological markers of AD, such as brain atrophy and proteins in blood and spinal fluid. The ADCS is a federally established consortium conducting clinical trials on AD, with sites across the United States and Canada.

Full-scale AD prevention trials are under-way as well. One such trial, Prevention of Alzheimer’s Disease with Vitamin E and Selenium (PREADVISE), is being conducted in conjunction with a National Cancer Institute-funded trial called the Selenium and Vitamin E Cancer Prevention Trial (SELECT). SELECT is evaluating whether taking selenium and/or vitamin E supplements can prevent prostate cancer in healthy men older than 60 years. PREADVISE is evaluating whether these supplements can help prevent memory loss and dementia by protecting brain cells from oxidative damage (see "The Aging Process" for more on oxidative damage). About 6,000 of the more than 30,000 men enrolled in SELECT are participating in PREADVISE.

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