Alzheimer's Cure Elusive Despite Progress

Last Editorial Review: 4/8/2005

Ronald Reagan's struggle shows how far we've come, how far we have to go.

By Daniel DeNoon
WebMD Feature

Reviewed By Brunilda Nazario

Former President Reagan's long struggle with Alzheimer's disease is over at last. But his fight continues.

Sadly, Alzheimer's disease can't yet be cured. Not even for the strongest women and men. Not even with the best medical care on earth. Yet medical progress offers more reason for hope than for despair.

"A world without Alzheimer's disease ... is within our reach," says Sheldon Goldberg, president of the Alzheimer's Association, in a news release mourning Reagan's death.

Anyone who's followed the Reagan family's ordeal -- and that of America's 4.5 million other Alzheimer's patients -- knows what the disease looks like. People affected by Alzheimer's gradually lose their memories. They become disoriented and confused. Their ability to reason or even to think is affected.

What's happening is that brain cells are losing their connection to other brain cells and die. It's not entirely clear why. Thick plaques of a protein called amyloid clog the brain, and brain fibers become hopelessly tangled.

Is amyloid the cause of Alzheimer's disease or the effect of a deeper process? There's only one way to find out: Get rid of the gunk and see whether Alzheimer's patients get better.

A Glimpse of the Future of Alzheimer's

Getting rid of plaque seems like a pipe dream. But that's just what happened to some of the patients enrolled in a clinical trial of an anti-plaque vaccine.

The trial had to be stopped because one in 20 subjects developed life-threatening swelling of the brain. But when some of these subjects died of other causes, autopsies showed something nobody had ever seen before.

"It really does look like this treatment is removing amyloid plaque from the brain," Bill Theis, PhD, recently told WebMD. "In other reports, the people in the trial who made more anti-plaque antibodies had more maintenance of memory function."

Theis, Alzheimer's Association vice president for medical and scientific affairs, promises that this July we'll hear more about the results of this extraordinary trial during the association's annual meeting. However, it's unlikely that the vaccine itself will ever be a realistic Alzheimer's treatment unless somebody figures out how to eliminate its deadly side effects.

Nevertheless, the study results -- and findings from animal studies -- strongly suggest that it's a good idea to attack plaque, says Sam Gandy, MD, PhD, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia.

"I am pretty convinced amyloid is bad even if it is true that another insult is more commonly the initiating factor," Gandy tells WebMD. "I feel confident that removing amyloid is a good idea."

Tomorrow's Plaque Fighters

Gandy says that scientists are in hot pursuit of three anti-amyloid ideas.

First is the anti-plaque antibody approach. Using a vaccine and allowing the body to make antibodies seems too dangerous. But what if you could raise plaque-busting antibodies in the laboratory? Theoretically, you then could find a dose that cuts plaque without killing the patient.

This isn't science fiction any more. Several companies are racing to develop this strategy, known as passive immunization or passive antibody transfer.

"It works in the mouse model," Gandy says. "It should be effective."

The second idea is to keep plaque from forming clumps. Amyloid gets particularly sticky when it combined with two substances: sugars and metals (especially zinc). Drugs that block both of these combinations are in the pipeline. And they work in mice, Gandy says.

The third idea -- and the one closest to reality -- involves new uses for existing drugs. Amyloid doesn't just happen. It's the result of a complex biochemical process. The process stops without a key set of enzymes.

It's recently become clear that some of the cholesterol-fighting drugs called statins block these enzymes. Data from trials of one of these drugs -- Lipitor -- suggest that people taking the drug to treat high cholesterol have a lower risk of Alzheimer's disease. The National Institute on Aging (NIA) is conducting a large clinical trial to see whether another of these drugs, Zocor, actually prevents Alzheimer's.

The NIA is also looking at another class of drugs capable of blocking amyloid production. It's the NSAIDs or nonsteroidal anti-inflammatory drugs -- the same class to which aspirin and ibuprofen belong. One of these drugs, Ansaid, may be particularly effective against amyloid, Gandy says.

If these drugs already exist, why aren't they being used? The reason is that amyloid plaques are notoriously hard to detect until Alzheimer's disease is well under way.

That, too, is changing. Gandy says that new imaging techniques called PET scans will allow doctors to see tiny spots of amyloid.

"This might be useful for very early diagnosis of people getting Alzheimer's disease, decades before symptoms show up," Gandy says. "And it will help with developing prevention drugs, because it will let you see what is going on."

Many people who don't think plaque is the No. 1 bad guy have another villain in mind. These are the tangled fibers in the brains of Alzheimer's patients. It's been hard to work on anti-tangle drugs, because there's no good animal model. But progress is being made, Gandy says.

Today's Alzheimer's Disease Treatments

While waiting for tomorrow, a lot of exciting Alzheimer's treatments are available today.

Currently available drugs slow Alzheimer's process. Patients who were on a sharp decline often stabilize. Today, there are several ways to treat Alzheimer's disease:

  • Aricept, Exelon, and Reminyl. These are the cholinesterase inhibitors. Cholinesterase breaks down an important brain chemical called acetylcholine. These drugs keep this from happening. Unfortunately, this doesn't stop brain cells from dying. About half of the patients who take these drugs see a modest improvement in mental function. (Tacrine, the first member of this class of drugs, now rarely is used because it sometimes causes liver damage.) In April 2005, Reminyl's label was changed to include information about the deaths of 13 elderly patients who were taking the drug during a study. The deaths were due to various causes, including heart attack and stroke.

  • Namenda, approved in October 2003, is the newest kind of Alzheimer's drug. It's called an NMDA receptor antagonist. The NMDA receptor is a kind of dimmer switch that controls the actions of a brain chemical called glutamate. Glutamate plays a major role in learning and memory. Too much of it kills brain cells. Too little makes them grind to a halt. Namenda helps balance glutamate levels.

  • Vitamin E. Everybody's brain is under constant attack from destructive oxygen molecules called free radicals. We've evolved effective ways to fend off these attacks. But Alzheimer's disease and the normal aging process seems to lower these defenses. Antioxidant compounds -- especially vitamin E -- may reinforce this crumbling line of defense.

Other treatments don't affect Alzheimer's disease itself but can help reduce the agitation that often distresses patients and their caretakers. Agitation is the word used to describe the many behaviors that pop up as Alzheimer's disease progresses. These include personality changes, sleep disturbances, delusions, hallucinations, restlessness, and emotional disturbances.

Treatments include:

  • Behavioral interventions. Sometimes it helps to simplify a patient's environment and routine tasks. Patients may need extra rest between stimulating events. Labels or verbal cues can reduce disorientation.

  • Antidepressants.

  • Anxiety-reducing medications.

  • Antipsychotic medications.

Originally published June 7, 2004.

Medically updated April 7, 2005.

SOURCES: Sam Gandy, MD, PhD, director, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia. Bill Theis, PhD, Alzheimer's Association vice president for medical and scientific affairs. News release, Alzheimer's Association. Alzheimer's Association.

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