Into The Darkness Of The Mind

When Wayne Huizenga of Blockbuster fame bought the Miami Dolphins in 1994, he asked a trusted colleague to write the $127 million check: Gillian Bristol of Ft. Lauderdale, Fla. Bristol handled important financial matters for Huizenga for 26 years, until in early 2000 the math started giving her trouble--not arcane accounting problems, mind you, but simple addition and subtraction. Within months, she was diagnosed with Alzheimer's disease and spiraled rapidly downward. Then in August 2001, her husband, Richard, enrolled her in a clinical trial testing a combination of an FDA-approved drug called Aricept and a European one known as memantine. Gillian finally began stabilizing and has not declined further in the past year. Is that the result of the drug combo or the unpredictable course of the disease? Doctors have no way of knowing. But with the trial long over, Richard continues to buy her both drugs, ordering the memantine from Europe.

Soon he won't have to go to such lengths. In a year of steady progress against Alzheimer's, the biggest concrete development was the FDA's approval of memantine in October. By early 2004 it will be on the market here under the trade name Namenda. It's the first of an entirely new class of drugs and the first approved for moderate-to-severe Alzheimer's--and it comes none too soon. Already 4.5 million Americans have Alzheimer's disease. By 2050, the total could reach 13 million to 16 million. Will we learn to treat or prevent the ailment in time to reduce that toll? Scientists are optimistic, citing potential new treatments and preventive measures.

Namenda is a good start. While earlier drugs boosted low levels of a key brain chemical involved in memory, Namenda protects neurons from excessive stimulation by a second brain chemical that can damage or even kill brain cells. The combined approaches appear to provide the most effective therapy yet. "Now finally we as doctors can tell family members that there is something we can do to slow the disease," says Dr. Barry Reisberg of New York University School of Medicine. But Namenda will not halt the disease's progression. Nor does it address what many scientists see as the actual cause of Alzheimer's--excessive levels of a substance called A-beta, the major constituent of the amyloid plaques that clog patients' brains.

That's why many scientists saw the major development of the year not as Namenda's approval but the revival of vaccine trials against A-beta. Most people had assumed that the quest for a vaccine was dead two years ago, after 18 of 375 patients in a phase-two trial developed brain inflammation. But this fall the FDA cleared Wyeth and Elan Corp. to test a safer, "passive" vaccine. Instead of prodding the immune system to make A-beta antibodies on its own, the new formula will deliver ready-made antibodies. "The problem in the earlier trial wasn't caused by the antibodies but an unrelated side effect of the vaccine," says Dr. Ivan Lieberburg, chief medical officer at Elan. In fact, a group of Swiss scientists reported this summer that among the 30 patients in their portion of the study, those who generated the most antibodies did the best, remaining stable over the next year. By contrast, those who formed no antibodies worsened, and those in the middle declined, but only marginally. If the new vaccine ultimately proves safe, it might eventually be used not only for treatment but also disease prevention in those at highest risk.

But anyone who's truly concerned about developing Alzheimer's can take a simpler preventive measure right now: lose excess weight. A major study this summer found a striking association between obesity in women at age 70 and the risk of developing Alzheimer's 10 to 18 years later. For each one-point increase in body-mass index, the risk of dementia increased by 36 percent. "You don't have to be Twiggy," says epidemiologist Deborah Gustafson of the Medical College of Wisconsin, who worked on the study. "The women at greatest risk were clearly overweight." No one has a definitive explanation. But obesity is the leading risk factor for diabetes, and diabetes doubled the risk for Alzheimer's in two major studies.

Now neurologist Dennis Selkoe and colleagues at Harvard Medical School may have figured out why. The link is an enzyme that breaks down both insulin and A-beta. In the Proceedings of the National Academy of Sciences this year, the scientists showed that mice who were deficient in the enzyme failed to clear A-beta from their brains and also developed insulin resistance. Does the same thing happen in people? Selkoe points out that prediabetic patients, trying to overcome insulin resistance in their tissues, produce abnormally high levels of insulin. If the enzyme is drawn preferentially to the insulin, this would allow A-beta to build up. It's just a hypothesis, but the Harvard team has lab tests, animal studies and genetic screens of 450 Alzheimer's families to back it up.

Either way, the key to controlling Alzheimer's will hinge on early intervention. "Waiting until a patient has Alzheimer's is like waiting for a heart attack to start treating cardiovascular disease," says Peter Lansbury of Harvard's Laboratory for Drug Discovery in Neurodegeneration. With the looming case-load, new treatments can't come soon enough.