Arresting Alzheimer's

Drugs that fight milder memory loss may prevent its onset

A new front has opened in the battle against Alzheimer's disease. Coming up with a cure for this dreaded form of dementia has proven devilishly hard, since by the time victims develop Alzheimer's, their brains are usually too damaged for any treatment to do much good. So drug companies are increasingly turning their attention to a different class of patients--those who suffer from noticeable memory loss but otherwise function normally. The theory is that treating patients with this condition, known as mild cognitive impairment (MCI), might delay or deter full-blown Alzheimer's.

MCI sufferers show no deterioration in IQ scores but they experience "forgetfulness of a significant nature," such as failing to recall conversations held a short time before, says Dr. Ronald C. Petersen, director of the Alzheimer's Disease Research Center at the Mayo Clinic in Rochester, Minn. This is a more significant memory loss than forgetting a name or where you left the car keys. Within six years of a diagnosis for MCI, some 80% of such patients progress to Alzheimer's.

Consequently, the Food & Drug Administration has signaled its willingness to overhaul its own criteria for judging brain-enhancing drugs. On Mar. 13, an FDA advisory group ruled that experimental Alzheimer's treatments can win approval if they improve memory function in people with MCI, even if they don't alter the course of Alzheimer's itself. This could mean a potential windfall for drug companies. There are currently 4 million Americans suffering from MCI and another 4 million with Alzheimer's disease, says Vincent Simmon, CEO of Cortex Pharmaceuticals Inc. (COR ), a neuroscience company in Irvine, Calif. Those numbers will go up as the baby boomers age. In 2000, 35 million Americans were over 65, and by 2025, there will be 63 million. Alzheimer's strikes about 10% of people over 65.

The National Institutes of Health is leading the way in MCI research. In 1999, its National Institute on Aging announced it would sponsor a three-year, multicenter study of over 700 MCI sufferers ranging in age from 55 to 90. This trial is designed to see if Pfizer Inc.'s (PFE ) leading Alzheimer's drug, Aricept, or vitamin E, can delay the onset of Alzheimer's or other forms of dementia. Other NIH-sponsored trials are testing estrogen and the popular anti-inflammatory drugs that are known as cox-2 inhibitors for the same purpose. If such treatments can delay the onset of Alzheimer's disease for just one year "it could help between 220,000 to 440,000 people and save between $10 billion and $20 billion annually," says Dr. Leon Thal, head of the Alzheimer's Disease Research Center at the University of California at San Diego.

It will be at least three years before the NIH trials produce concrete results, and some scientists are already questioning the value of the Aricept trial.

"Pfizer is dying to use Aricept on MCI," says Harry M. Tracy, publisher of the newsletter NeuroInvestment. "But there is a big question about whether it will work." The drug is one of three Alzheimer's treatments on the market. All of them block the breakdown of a brain chemical called acetylcholine that is important in memory and other intellectual functions. But there is no proof the loss of acetylcholine plays as large a role in MCI as it does in Alzheimer's. And these drugs aren't even that effective against Alzheimer's--they help less than half of all Alzheimer's patients, and then for a period of only a few months or at most two years.

The problem, it seems, is that by the time a patient develops Alzheimer's, the damage is done. The disease is caused by a steady accumulation in the brain, over many years, of an insoluble protein called beta-amyloid. As it accumulates, it forms brain clogging plaque. Victims eventually lose all mental and physical functions, until they die, after about 10 to 12 years.

New drugs in the pipeline aim either to boost the brain's ability to form memories despite the plaque; or to slow the plaque buildup. In the first category are a group of drugs called ampakines, developed by Cortex in partnership with the French company Servier, that increase the activity of brain chemicals important to memory formation. Cortex is testing one of its ampakines in a small study of Alzheimer's patients. The company is planning a larger MCI trial with Servier for later this year.

Improved memory function is also the goal of NeoTherapeutics Inc. (NOET ) in Irvine, Calif. Its lead experimental drug, Neotrophin, stimulates the production and release of growth factors in the brain's memory centers. These growth factors then coax neurons into making new connections with other nerve cells. Neotrophin has been tested in more than 1,000 Alzheimer's patients, with mixed results. Still, NeoTherapeutics President Rajesh C. Shrotriya says: "We believe that Neotrophin could have an effect in normal memory loss." Once the drug is approved for Alzheimer's, he plans to begin testing it in patients with MCI.

END RUN. The formation of memories, though, is a murky process. As researchers in this field feel their way along, they are testing a number of therapeutic approaches intended to aid the development of memories. Memory Pharmaceuticals Corp., a New York neuroscience company, is developing drugs that will help the brain convert transient short-term memories into stable long-term ones. This process, called long-term potentiation, is compromised in the aging brain and in Alzheimer's victims. Axel Unterbeck, president of Memory Pharmaceuticals, says the company has identified several promising drugs and hopes to start trials with Alzheimer's patients in two years.

Memory Pharmaceuticals is also trying to do an end run around the disease, with experimental drugs that enhance the activity, and perhaps the growth, of undamaged neurons in the brain's memory centers. This approach could have wide utility in treating memory problems associated with dozens of diseases, including the normal forgetfulness linked to aging. "It's a very important notion that even if companies succeed in prohibiting amyloid production, the patient will still need treatment of memory problems," says Unterbeck. "We see using one drug that affects disease progression and another that improves function and keeps the patient at home."

Then there are the plaque-attackers. Several groups are working on vaccines that would stimulate the immune system to slough off the plaque deposits that lead to Alzheimer's. The leading candidate is from Elan Corp. (ELN ) in South San Francisco. In one test, Elan's vaccine caused a 70% reduction in amyloid plaques in the brains of mice genetically engineered to develop Alzheimer's. Elan, in partnership with American Home Products, is now running early-stage safety trials of its vaccine in people with advanced Alzheimer's disease. "If the immunization works in Alzheimer's patients, we will move to MCI very rapidly," says Dale B. Schenk, vice-president for research at Elan.

Beyond vaccines are efforts by Bristol Myers Squibb (BMY ), Eli Lilly (LLY ), and Elan to develop compounds that block the enzymes that help cause plaque. Other drugs under development are likewise meant to interfere with the process of plaque formation.

In three to five years, there may be more options for treating MCI and new methods for slowing the onset of Alzheimer's. Researchers are also trying to devise ways of detecting who is at risk for Alzheimer's years before it becomes apparent. In the end, the best chance of "curing" Alzheimer's may be targeting simple forgetfulness.

By Naomi Freundlich in New York

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