Stopping a Mind Thief

Today's Alzheimer's treatments cannot preserve precious memories in those assaulted by the disease, but researchers are getting closer to treatments that might.

Perhaps the only thing worse than getting Alzheimer's disease (AD) is watching the disorder ravage the mind of a loved one. AD triggers the progressive death of the brain's neurons, slowly erasing its victims' memories, their personalities, and even their ability to recognize the faces of family and friends.

Age is the single biggest risk factor for AD: One in 10 people over 65 suffer from the disease; by age 85, the incidence is nearly 50%. With 6.6 million Americans expected to reach age 85 or older by 2013, the need for more effective Alzheimer's treatments has never been greater (see "Before We Forget"). Current therapies alleviate the symptoms of AD in only a fraction of patients and do not halt the disease's progression. But scientists are now using their knowledge of the molecular processes that drive AD to develop methods for slowing or stopping the disease.

Four of the five drugs currently approved to treat AD work by boosting the brain's supplies of acetylcholine, a neurotransmitter involved in memory whose concentrations dwindle in people with AD, says William Thies, vice president of scientific and medical affairs for the Alzheimer's Association. These compounds, called cholinesterase inhibitors, stifle an enzyme that breaks down the neurotransmitter.

But the medications don't work for everyone. "About a third of the people on these drugs get a robust response, about a third get some response, and a third get no response," he says. Although researchers would like to do better, even a limited improvement can delay the need for nursing care--which makes a huge difference for families, says Neil Buckholtz, chief of the Dementias of Aging Branch at the National Institute on Aging in Baltimore, Maryland. Cholinesterase inhibitors can also relieve some of AD's more disturbing, behavioral problems, such as psychosis, aggression, and sleep disorders. "These are some of the most difficult symptoms for families to deal with," says Buckholtz.

The fifth drug against AD--approved this month by the U.S. Food and Drug Administration--regulates glutamate, another neurotransmitter involved in learning and memory. Imbalances in glutamate appear to contribute to the memory loss and neuron death characteristic of the disease. Like the cholinesterase inhibitors, the new drug, memantine, doesn't help everyone and doesn't appear to stop disease progression, says Thies. But because memantine works by a different mechanism, he says, "you potentially have an additive effect." Researchers are investigating whether memantine, combined with one of the older drugs, will offer greater benefits than either drug alone.

In the meantime, other scientists are busy pursuing a wide range of new treatments targeting the deposits of amyloid protein that clutter the brains of people with AD. In 2000, researchers at Elan Pharmaceuticals in South San Francisco announced that they had developed a vaccine that clears these amyloid plaques--and prevents memory loss--in mice that had been engineered to overproduce the protein. But last year researchers abruptly halted clinical trials of the vaccine after a few participants developed dangerous inflammation in their brains--a reaction that proved fatal for several volunteers. Despite this setback, autopsy reports suggest that the vaccine removed amyloid plaques from the brain.

These researchers are now working to eliminate the vaccine's deadly side effects. "Vaccines are very complicated," says Thies. It's not uncommon that the first formulation doesn't end up being the final therapeutic choice, he says. He predicts that the improved vaccines will be back in the clinic in the next year or two.

Whereas vaccines enlist the body's immune system to destroy plaques, other experimental drugs tinker with the brain's chemistry to block amyloid from forming in the first place. These compounds inhibit an enzyme that helps clip amyloid from a larger precursor protein. Drug companies are racing to identify and test these so-called secretase inhibitors. Several compounds have made it to early stage clinical trials, but information about these industry-sponsored trials remains tightly guarded.

Another study, published this month in the Proceedings of the National Academy of Sciences, showed that the cancer drug Gleevec cut amyloid concentrations in cultured nerve cells and in guinea pigs. The drug, which indirectly inhibits secretase, isn't suitable for Alzheimer's treatment because it doesn't breach the blood-brain barrier. But the discovery suggests a new pathway that researchers can exploit to subdue secretase and reduce amyloid, says William Netzer, a neuroscientist at Rockefeller University in New York City and one of the study's authors.

Other scientists hope to disarm amyloid by robbing it of its assistants, zinc and copper. Concentrations of these metal ions in the brain rise with age, and the metals appear to induce amyloid aggregation, says neuroscientist Ashley Bush of the Genetics and Aging Research Unit Massachusetts General Hospital in Charlestown. Furthermore, when amyloid couples with metal ions, the aggregates generate highly reactive chemicals that can damage neurons. Removing metal ions from the brain should put the brakes on AD, Bush reasons.

He and pathologist Colin Masters of the University of Melbourne in Australia are testing the theory with clioquinol, an antibiotic that ties up zinc and copper ions. "In vitro, it's very potent at dissolving amyloid, and in a transgenic mice model, it's an extremely potent inhibitor of amyloid deposition," says Bush. Early results from clinical trials of clioquinol look promising: In one preliminary study, the drug slowed the rate of cognitive decline in people with AD.

Unfortunately, even the most promising treatment strategies seem unlikely to completely reverse AD's damage. "Once the brain cells are dead, they're gone. We're not at the point where we can regenerate neurons very well," says Claudia Kawas, a neurologist at the Institute for Brain Aging and Dementia at the University of California, Irvine. For this reason, preventing disease onset remains the Holy Grail. Several large-scale clinical trials are now testing medications that some studies suggest might reduce the risk of developing AD, such as nonsteroidal anti-inflammatory drugs and cholesterol-lowering drugs. Such trials, however, take years to complete. Still, researchers remain cautiously optimistic. "If you consider that 20 years ago there really wasn't much research, we've come a tremendous way," says Buckholtz. "But we have a long way to go." For those struggling to hold on to loved ones with AD, progress cannot come fast enough.

Christie Aschwanden is a freelance writer who hopes she will never forget her adventures living and working in an ancient village in the Swiss Alps.