"I Can't Remember"

Drugs to stave off age-induced memory impairment may be on the horizon

"We are who we are in good measure because of what we have learned and what we remember."

-- Nobel Laureate Dr. Eric R. Kandel

The 76-year-old California lawyer appears to be the very model of healthy aging. C.L., who asked that his name not be used, hikes two miles up a nearby mountain four times a week, is always reading two or more nonfiction books at a time, and boasts that his waist and chest measurements haven't changed since he was 25. This take-charge guy expects a lot of himself. But for the past six years, his memory hasn't measured up. He occasionally forgets a name, he loses his train of thought when there are distractions, and he has walked away from six pairs of expensive sunglasses. "People who are very well-trained intellectually notice when they begin to lose that ability to grab onto every word, every concept," he says. "It's like a significant part of your life is erased."

C.L. yearns for some kind of treatment -- and his determination sends a powerful message to the drug industry. Although he is functioning very well for his age, he lobbied hard to enter a clinical trial for an experimental memory drug developed by Cortex Pharmaceuticals Inc. (COR ) of Irvine, Calif. The compound, called CX516, is in Phase 2 clinical trials for people who suffer from frequent short-term memory lapses, a condition called mild cognitive impairment (MCI). It is an ominous diagnosis, even though the condition doesn't interfere significantly with daily living, because it can be an early warning sign of something much worse. Every year some 15% of people with MCI go on to develop Alzheimer's disease.

HUMAN TRIALS.

  C.L. took nine capsules of CX516 daily for 12 weeks this spring. The impact was immediate. "At the start of the trial, I could remember less than five words out of a list of 20. By the second week, I could get 14 out of 20. There was a very, very appreciable enhancement." He has since finished his part in the study and says it was "heartbreaking" to go off the drug. "I've been thinking of some other way to get it, and I don't give a damn if it's legal or illegal."

If he waits a few years, C.L. should be able to solve his problem legally. At least 60 pharmaceutical and biotech companies around the world are working on novel memory pills. Some 40 are in human trials, and the first of these could be on the market within the next few years. These drugs aim to do far more than relieve the occasional "senior moment." Neuroscientists are hoping that any pill that improves memory in the elderly will also protect against Alzheimer's disease, the diagnosis old people fear most.

"Within five years, we will have treatments that slow the rate of decline or even delay the onset of Alzheimer's by five years or more," predicts Dr. Leon J. Thal, chairman of the Neurosciences Dept. at University of California-San Diego. The drug industry is spending billions of dollars to come up with such a pill, and it's not hard to see why. In 10 years, all 77 million baby boomers will be 50 or older, and as many as 25% of them may develop some form of dementia. They do not, however, show any interest in going gently into that good night. As Harry M. Tracy, publisher of the newsletter NeuroInvestment, notes: "This is a generation that does not accept decline."

FINAL FRONTIER.

  It's also a generation that is approaching the danger zone. The brain reaches its maximum weight by age 20 and then slowly starts shrinking, losing 10% of its volume over an average lifetime. It's virtually inevitable that mental glitches will show up by the time we are eligible for senior-citizen discounts, and people are noticing. Surveys have found that 75% of people over 50 believe they suffered memory problems over the prior year. Some of these people may be overreacting -- but a large proportion aren't. At least 20 million Americans over 60 have some level of memory impairment short of dementia. Another 4.5 million are victims of Alzheimer's, a progressive brain disease that over the course of a decade destroys memory and other cognitive functions until its victims are virtually helpless. The longer one lives, the greater the danger -- 50% of people age 85 and over end up with Alzheimer's.

Since more of us are living to an old, old age, trend lines for memory loss all point upward. The Alzheimer's Assn. estimates that by 2050 -- when the number of people over 65 will have doubled, to 70 million -- there will be 13.2 million Alzheimer's victims. Run the numbers, and it's obvious that a pill that promises to protect against this terrible malady would dwarf the $1.7 billion a year pulled in by Viagra, that other salve for an aging body.

That such pills are even in the pipeline is something of a scientific miracle. The human brain is medicine's most daunting frontier. Made up of more than one trillion highly complex neurons, it remained obdurately opaque long after the body's other tissues had given up many of their mysteries. But in the past decade, the code has been partially cracked. Using sophisticated imaging technologies, animal experiments, and genetic insights, scientists now have a road map of the complex process that is memory formation.

Products follow knowledge. The first drug able to improve the thinking abilities of people with advanced Alzheimer's disease was approved in Europe last year and is widely expected to win the nod from the Food & Drug Administration this fall. Memantine, developed by the German company Merz, is no miracle cure, and it has shown no effect in Alzheimer's patients in the earliest stages of the disease. But clinical trials demonstrated that the drug allows the most desperately confused patients to live independently for six months to a year longer than they would otherwise, with no debilitating side effects.

Memory clinics are springing up around the U.S.

That's more significant than it may sound: Alzheimer's is the No.1 cause of institutionalization in the U.S. Memantine marks the first big payoff of brain research carried out over the past decade. The three treatments for Alzheimer's now on the market -- Pfizer's (PFE ) Aricept, Novartis' (NVS ) Exelon, and Reminyl from Johnson & Johnson (JNJ ) -- all boost the levels of a brain chemical called acetylcholine, and first appeared in the early 1990s. These drugs can delay the downward trajectory of patients in early stages of the disease for several months, but they do not improve thinking power and can cause nausea, loss of appetite, and frequent bowel movements.

Memantine is a smart bomb by comparison. It targets a cell receptor that controls the intake of glutamate, a neurochemical that scientists believe is responsible for 75% of the communications between brain cells. "Memantine represents real progress, a meaningful therapeutic advance," says Dr. Pierre Tariot, a University of Rochester psychiatrist.

Neuroscientists eagerly anticipate more such advances. Even now, the contours of an enormous memory industry are coming into view. Just look at the herbal supplement ginkgo biloba: Annual sales reached an estimated $500 million in the U.S. last year, although clinical trials have disproved claims that it can boost memory. The three Alzheimer's drugs now available had combined U.S. sales of more than $1 billion, despite their shortcomings. Memory clinics are springing up around the nation, headed by everyone from top-ranked neurologists to New Age practitioners, while bookstore shelves are stuffed with how-to guides on memory maintenance.

A CURE IN CURRY?

  Even the federal government is in on the act. The cost of caring for Alzheimer's victims in the U.S. will total over $100 billion this year, making the disease a top priority of the National Institutes of Health. It is sponsoring a dozen or more clinical trials of potential memory enhancers in the hopes that something, anything, will be found that can delay the slide into dementia. Anti-inflammatory treatments such as aspirin and Celebrex are particular favorites for study, because inflammation in the brain is a hallmark of Alzheimer's disease. Vitamin E also has attracted interest in the hope that it may protect brain cells from damaging molecules called free radicals that course through the blood and batter healthy cells.

Plenty of other potential remedies are being tested as well, among them estrogen, blood-pressure medications, cholesterol-lowering drugs, memory exercises, and special diets -- including curry (because India has the lowest incidence of Alzheimer's in the world).

Most experts, though, believe that a drug specifically designed for memory loss will be far more effective than any jerry-built treatment -- and more lucrative for the inventor. Medical experts estimate that about 8 million people in the U.S. over age 50 suffer from mild cognitive impairment, and drugmakers do not plan to stop there. Any pill that wins FDA clearance for cognitive impairment will surely be tested against the next gradation of fuzzy thinking: age-associated memory impairment. The signs of this condition include the occasional misplacing of car keys or failure to recall a well-known name. As many as 12 million Americans suffer from such lapses.

Are "smart pills" for younger people next?

If a pill that treats such minimal memory loss wins FDA approval, it's not hard to imagine the next step down this slope. A drug that can stave off age-associated memory impairment will surely appeal to the enormous cohort that the medical establishment refers to as the "worried well."

These healthy, well-functioning individuals share a common fear: that forgetting a name every now and then is the first step toward dementia. "About half of my patients are around 50 and self-referred because they are just worried," says Dr. Gayatri Devi, director of New York Memory & Healthy Aging Services, a Manhattan-based clinic. "Because their functioning seems impaired, some of them come in convinced that they have Alzheimer's."

Next in line for memory pills could be college students seeking to improve test scores. Drug developers all insist they have no interest in selling memory pills to the young and healthy, but that may not matter: There is already evidence that even nimble memories can be improved. In a groundbreaking study published last year, Peter J. Whitehouse of Case Western Reserve University gave nine healthy aircraft pilots -- mean age 52 -- a daily dose of Aricept, Pfizer's drug for mild Alzheimer's. They were matched with another nine pilots who received placebos. After 30 days, the Aricept pilots were measurably better able to perform a set of complex flight-simulator tasks than the placebo group.

Far more tests will be needed to determine if Aricept, or any other drug, would have the same effect in a larger population. Besides, given its unpleasant side effects, it's unlikely Aricept would ever become a popular "smart pill." Nevertheless, the success of the pilots' study does demonstrate that memory-enhancing pills are possible. It won't be all that easy, however, to push through a medication that tampers with the body's control center, the brain.

PERPETUAL PRESENT.

  "The FDA is going to be very careful about the safety profile of any drug that might be taken by millions of otherwise healthy people," says NeuroInvestment's Tracy. "These drugs have a very high hurdle to leap, much higher than Alzheimer's [medications]." Experimental brain drugs have often failed in clinical trials because of dire side effects. Witness the fate of a promising Alzheimer's vaccine by Elan Pharmaceuticals (ELN ). Development was halted last year, even though the drug was able to reduce levels of the disease in a clinical trial, because some patients died of brain inflammation.

The Elan experience was not the only time that doctors harmed the patient while trying to heal the brain. A breakthrough insight into memory was borne out of an attempt to cure epilepsy that went terribly wrong. In 1953, a Hartford surgeon, in an effort to rid a 27-year-old man of seizures, removed a small structure deep in the brain called the hippocampus. He cured the seizures, but the patient, known as H.M., never formed another memory. He can recall events from before the operation but has no memory at all of a conversation held minutes earlier. He lives in a perpetual present.

H.M.'s tragic case proved that the hippocampus is where fleeting impressions turn into permanent memories. Each sensation that enters the hippocampus, be it a spoken name, some visual impression, or the instructions for a new cell phone, sets off electrical charges inside neurons, the cells that make up the brain. The charge stimulates the cell to release a roiling stew of neurotransmitters, which carry the information across tiny gaps called synapses that connect the neurons to one another. The longer these millions of signals flash back and forth, the stronger the connections become and the more synapses are created -- a single neuron can have as many as 10,000 synapses. Finally, a set of neurons bands together to retain the data, and the brain remolds itself to create storage space.

"Use it or lose it" may apply to memory

The entire process, from the time a number is heard until it is permanently stored, can take hours or even days. As we age, the brain cannot execute this complex dance so quickly. A recent study from the University of Kentucky suggests that the genetic changes behind the mental slowdown may start by age 40, with the results showing up a decade or two later. That doesn't mean we have no choice but to grow continuously dumber. Even while the brain's ability to absorb new information slows, it gets better at storing and calling up information it already has, based on past experience. Age really does beget wisdom.

Continued mental activity might also ward off dementia. Several studies have lent credence to the "use it or lose it" strategy. The most recent, published in June by the Albert Einstein College of Medicine in New York, followed 469 people age 75 or older for five years. Those in the top third of mental activity had a 63% lower risk of dementia than those in the bottom third. Taking part in a single absorbing mental activity one day a week reduced the risk by 7%. However, some scientists wonder if Alzheimer's may have already taken root in the study participants who weren't as mentally engaged, which would explain their lower ranking.

It is almost certainly helpful to start the mental challenges much earlier. Study after study has shown that people with limited or no formal education before the age of 10 are at a higher risk of Alzheimer's later in life. It may be that intensive learning when the brain is young and plastic greatly increases the number of synapses. The brain can call on these reserves as it ages, or in case of injury, such as a stroke. This is when those piano or French lessons your parents forced on you as a child might pay off. "The more synapses you form in your lifetime, the more you can tip the balance in your favor as you age," says Dr. Majid Fotuhi, a neurologist at Johns Hopkins Hospital and author of the book The Memory Cure.

"ACTS OF DESPAIR."

  Unfortunately, memory can slip away from even the best and the brightest. W.D., a 78-year-old doctor in Maryland, retired in 1993 but continued to be very active. Four years ago, he started noticing problems. He would forget where he was going in his car or what restaurant he had just eaten in. "I used to be clear as a bell, and now I have to stop and think about where things are," he says. His doctor ruled out Alzheimer's, but that just makes him wonder what is going wrong. "It's depressing."

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.

By Catherine Arnst

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