Alzheimer's Researchers Eye Brain Buildup

Tuesday, September 7th 2004, 10:50 am
By: News On 6

WASHINGTON (AP) _ How to prevent a sticky gunk from clogging up, and probably killing, the brain cells of Alzheimer's patients is the newest focus in the fight against the disease.

Half a dozen companies are developing drugs to target the buildup, and researchers are enrolling hundreds of patients to test the lead candidate _ although nobody yet knows if this gunk, called beta-amyloid, is the disease's true culprit.

But it's the chief suspect, and tests of these drugs could finally end a long-standing debate over the cause of Alzheimer's devastating symptoms.

``We have placed our bet on the amyloid hypothesis,'' is the way Dr. Eric Siemers of Eli Lilly & Co. puts it _ a statement that describes much of industry's focus.

The theory is that reducing this brain plaque will finally offer a way to do more than treat just the symptoms of Alzheimer's disease, as today's drugs do. But lest families' hopes get too high, even proponents expect anti-amyloid therapy is most likely to help mild disease, before too many neurons have died.

``If you're trying to control the disease process, you certainly want to treat people as early as possible,'' said Dr. Paul Aisen, a Georgetown University neurologist who is heading the largest U.S. study yet of an anti-amyloid drug, Neurochem Inc.'s Alzhemed.

About 4.5 million Americans have Alzheimer's, a creeping brain degeneration that slowly robs its victims of memory and the ability to reason, communicate and care for themselves. With the aging population, a staggering 14 million may have it by 2050.

No one knows what causes Alzheimer's. Some scientists think fibrous tangles of a protein called tau that builds up inside brain cells kills them.

But the leading theory is that something spurs abnormal production of another protein, beta-amyloid, which forms clumps that coat the outside of brain cells and kills them _ plaque that is the disease's trademark.

Different attempts to attack that plaque:

_Beta-amyloid initially floats in the blood and spinal fluid, until the sticky substance bonds with helper molecules to form chains that build into plaque. Alzhemed essentially coats beta-amyloid, reducing the stickiness so those chains can't form.

It won't help existing symptoms, Aisen stressed. But in small, early stage testing, spinal taps showed Alzhemed users harbored less beta-amyloid, and a handful of milder patients treated for over a year seem to have slowed worsening of their disease, he says.

Consider Libby Monroe, 84, of Bethesda, Md., diagnosed with Alzheimer's in 1999. Her main symptom to date is short-term memory loss.

``I can't say I can recognize any improvement'' since adding Alzhemed to her usual medication, said her husband, Bill Monroe. ``But I can say her gradual loss of memory seems to be quite slow. It's possible the Alzhemed is helping her hold her own to some extent.''

A Phase III study is enrolling about 500 patients around the country and in Canada to try to prove Alzhemed's effects.

_Lilly hopes to halt beta-amyloid formation in the first place. Its drug candidate blocks an enzyme called gamma secretase. The enzyme helps create beta-amyloid by clipping pieces that form it off a larger protein. In early studies, Alzheimer's patients given the still-unnamed drug for six weeks had a 40 percent reduction of beta-amyloid in their blood. Lilly is pursuing additional small studies, but can't yet say when large-scale testing may begin.

_Merck & Co. is trying to block another enzyme, beta secretase, also involved in amyloid formation.

_New York-based Axonyx has Phase III studies under way in Europe of a drug called phenserine. It targets a symptom-causing brain chemical like older Alzheimer's drugs do, but also may have the added boost of somehow lowering beta-amyloid production.

_Wyeth Pharmaceuticals and Elan Corp. have begun early human studies of antibodies, immune system cells created to attack existing amyloid plaque. Elan's earlier attempt at a vaccine to spur patients' own immune system to do the job failed when some suffered serious brain inflammation.

_Harvard researchers are studying whether drugs that remove copper from the body may also remove amyloid.

These approaches require years more research. Meanwhile, there are some steps that may help prevent Alzheimer's, said Dr. Mark Mattson of Johns Hopkins University: Exercise and avoid obesity, high cholesterol and high blood pressure, because the same things that cause heart disease seem to play a role in Alzheimer's.

And keep mentally active, too _ it likely protects brain cells.