"I Can't Remember"

Doctors have no way of predicting who is at risk for such debilitating memory loss. They can't even diagnose Alzheimer's with certainty until after the patient's death: It is then that clumps of rock-hard plaque in the brain can be detected during autopsy. This plaque is caused by the buildup of a protein called amyloid, which slowly destroy neurons, starting in the hippocampus. It is unclear whether amyloid is a cause or a symptom of Alzheimer's, but scientists are fairly certain that it starts accumulating 10 to 20 years before mental decline is evident, by which point it is too late to reverse the process.

The current Alzheimer's treatments are an act of despair," says Dr. Eric R. Kandel, professor of psychiatry at Columbia University. "We have to start [intervening] much earlier if we want to make a difference." Ergo the focus on early memory loss, when the brain may still have a chance to save itself. Success in this area will owe much to the study of animals that likely have far less to remember than humans. It seems that brains of insects, apes, and people work in much the same way. Kandel shared the 2000 Nobel prize for medicine for his breakthrough discoveries about memory that grew out of painstaking work with sea slugs. Kandel's discoveries were amplified by Tim Tully, a fellow of Cold Spring Harbor Laboratories on Long Island, whose research is based on the brains of fruit flies.

Work on these two lowly life forms led to a revolution in the understanding of memory. Kandel discovered that a neurotransmitter called cyclic-amp, or CAMP, plays a key role in strengthening synapses. Camp activates a protein called CREB, which in turn switches on the genes that control the release of neurotransmitters essential to long-term memory. "Think of CREB as a general contractor that organizes the cascade of genes that build memories," says Tully. Once CREB was discovered, Tully went to work designing a strain of fruit flies with the CREB protein permanently activated. The result: flies with photographic memories. The CREB flies could remember how to find sugar water in a specially designed tank after only one try, while average flies would have to go through multiple training sessions.

There is both an offense and a defense drug strategy

Both Kandel and Tully have formed companies to pursue their discoveries, specifically by targeting mild cognitive impairment and age-associated memory impairment. Kandel's firm, Memory Pharmaceuticals Corp. of Montvale, N.J., is the furthest along, with drugs that block the breakdown of CAMP. Memory Pharmaceuticals scored a $150 million partnership with Roche Holdings Ltd. and has six drugs in the pipeline, including one in early-stage human testing. Tully's Helicon Therapeutics Inc., in Farmingdale, N.Y., is still in the lab with drugs designed to boost the activity of CREB and has had promising results in mice.

The renowned reputations of Kandel and Tully have given their companies cachet. But even Tully acknowledges that any memory enhancers developed by Helicon "promise to be only one in this newly emerging sector of the drug industry." Several other candidates are much further along.

Most of these drugs can be divided into two camps, defensive and offensive. They either amplify neurotransmitters that strengthen memory formation or block those that get in the way of that process. Cortex Pharmaceuticals, for example, is investigating a group of drugs called ampakines that amplify the neurotransmitter glutamate, stimulating it to produce more synapses. The furthest along of these is CX516, the drug tested on C.L. In early trials, CX516 boosted memories in healthy 65- to 75-year-old volunteers more than twofold over a placebo group. The drug also improved cognitive performance in a small group of Swedish medical students, an intriguing hint that the drug may work on the young as well as the old. Cortex is conducting a 150-patient clinical trial in patients with mild cognitive impairment, in partnership with Les Laboratories Servier of France, scheduled to finish this year.

The defense strategy is being pursued by Saegis Pharmaceuticals Inc. of Half Moon Bay, Calif. Its drug, SGS742, blocks gaba, a neurotransmitter which can inhibit memory consolidation. The results of a completed Phase 2 trial for MCI have yet to be published, but Saegis Chief Executive Rodney Pearlman says: "We did see a statistical significance over the placebo group."

CHOLESTEROL LINK. There are plenty of existing compounds under investigation as well. One closely watched trial sponsored by the NIH will try to determine if statins, the popular cholesterol-lowering drugs such as Zocor and Lipitor, can slow memory loss. Such a connection makes sense, says Dr. Kenneth Davis, head of the Alzheimer's Disease Research Center at Mt. Sinai Medical Center in New York, because the plaque that clogs arteries in patients with high cholesterol has certain commonalities with the plaque found in the brains of Alzheimer's patients. It will take several years before any of these large prevention trials produce definitive answers. By then, one of the many memory pills in the works could also be available.

At that point, people who suspect declining memory might visit a special clinic where they will take a battery of tests to assess cognitive function. Based on the results, they will be given a set of brain exercises and prescribed a memory drug. "This effort," envisions Tully, "will yield lasting improvements in our abilities to perceive the world around us and remember our contributions to it." It is a vision everyone on the far side of 40 can embrace.

Corrections and ClarificationsIn the table "Memory magic" accompanying this story, the target of Saegis Pharmaceuticals' drug is described incorrectly. It blocks a neurotransmitter that can inhibit memory consolidation.

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