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Researchers hope to quell a surge of Alzheimer's cases with new diagnostic tools

By Aaron James
Special to The Washington Post
Tuesday, August 24, 2010; HE01

"We have a tsunami coming at us, and we're sitting in a rowboat," says neurologist Richard Mayeux of New York's Columbia University.

The surge that worries Mayeux is Alzheimer's disease: In 2050, 13.5 million Americans may have it, at an annual health-care cost of more than $1 trillion, according to the Alzheimer's Association.

"Alzheimer's could bankrupt Medicare and Medicaid," says Howard Fillit of the Alzheimer's Drug Discovery Foundation.

The impending epidemic, combined with emerging technologies, is driving a transformation in the fight against the disease: Instead of beginning treatment after symptoms appear, the idea is to detect and respond to the disease in the earliest, previously undetectable stages, before it can irretrievably ravage the brain. Researchers say that, based on current estimates of life expectancy, delaying the onset of Alzheimer's by an average of five years could reduce the number of patients by half.

"People take Lipitor because it lowers the risk of heart disease. We want to find the same thing for Alzheimer's," Mayeux says.

The new approach is made possible by recently developed methods to detect and measure Alzheimer's biomarkers, the biological indicators of the disease. New brain-scanning techniques, tests for "suspect" genes and measures of certain telltale proteins in spinal fluid probably won't benefit patients for years, but they're giving researchers a more sophisticated picture of the disease's pathology.

At the Banner Alzheimer's Institute in Phoenix, researchers Eric Reiman and Pierre Tariot are leading the Alzheimer's Prevention Initiative, a collaborative effort by scientists, academics and the pharmaceutical industry. "We want to help launch the era of Alzheimer's prevention research," Reiman says. "It's a true collaboration between stakeholders, the people afflicted, the families and people at risk."

The institute is developing two studies, to begin in 2012, that will treat apparently healthy people who show the highest genetic risk for developing the disease. "They will be more or less free of symptoms when we begin," Tariot says.

The researchers will use brain imaging and cognitive tests to track the impact of experimental drugs. "The hypothesis is that if we give pre-symptomatic people these treatments we should be able to see some evidence of the effects," Tariot says.

One study, to take place in the region around Medellin, Colombia, will focus on 2,000 members of 25 extended families who share a common ancestry and whose members carry a gene that leads some to develop Alzheimer's while they're still in their 40s. Though early-onset Alzheimer's is rare, the underlying mechanisms are thought to be quite similar to those that appear when the disease typically emerges, usually in the 70s and 80s.

For the second study, to be conducted in the United States, researchers will screen 50,000 people ages 60 to 80 to see if they carry two copies of a gene, ApoE4, that evidence suggests is linked to Alzheimer's. Of those who do, Reiman expects 400 to be enrolled in the study.

Half the participants in each study will receive an experimental drug and half will receive placebos; then they will be monitored for two years. If the drug doesn't seem to have a protective effect, the investigators will try another drug, looking for one to help prevent onset. Reiman says they have not yet decided which drugs will be tested.

Ethical questions

Giving experimental therapies to healthy people raises ethical questions. But researchers, physicians and pharmaceutical executives say the urgency of the problem justifies taking a certain amount of risk, which they will disclose to everyone participating in the studies.

"We need to be able to say, 'Here is what we know and here is what we don't know about this drug,' " Tariot says.

New brain-imaging technologies will help the researchers evaluate the drugs' efficacy. For example, Avid Radiopharmaceuticals of Philadelphia has developed a new dye, AV45, that binds with amyloid proteins, which create the plaques in the brain that are Alzheimer's hallmarks. The dye makes the plaques visible on a PET scan.

"This is a compound that sees amyloid in the brain," says Michael Weiner of the Alzheimer's Disease Neuroimaging Initiative, who was not involved with the dye's development but intends to use it in future studies. "Another way of saying it is that it sees Alzheimer's in the brain." Before the advent of amyloid imaging technologies, the only way to see amyloid plaques and therefore obtain a definitive Alzheimer's diagnosis was to do an autopsy after the patient died.

AV45 is not the first amyloid dye, but it represents an important advance because researchers can use it for about two hours before it degrades. Earlier amyloid dyes were limited because their fleeting radioactivity -- they were effective for only 20 minutes -- meant they had to be made on-site and used immediately.

"This tracer can be used much more broadly," researcher Susan Landau of the University of California at Berkeley, says of AV45.

Landau is leading a study that seeks to determine which biomarkers can best predict Alzheimer's. Her work has shown that a particular PET scan, which measures overall brain function, used in conjunction with memory tests, can distinguish which patients with mild cognitive impairment (an early Alzheimer's symptom) will go on to develop Alzheimer's and which won't.

"Overall, in the field, there's the hope that we will be able to predict it before symptoms appear," Landau says.

To date, remedies for Alzheimer's remain frustratingly limited. Once Alheimer's symptoms appear, the disease has already disrupted the brain's communication system of neurons, synapses and neurotransmitters. The drugs so far approved by the Food and Drug Administration include acetylcholinesterase inhibitors such as Aricept, Razadyne and Exelon, which aim to reduce the breakdown of acetylcholine, a key neurotransmitter. Another medication, Namenda, works to reduce the excessive amount of the neurotransmitter glutamate produced by Alzheimer's brains; too much glutamate results in cell death.

These drugs don't cure Alzheimer's; they only treat the symptoms and are effective for a few years, if at all. Some patients report improved memory and cognitive function with the treatments; others see no improvement. More than 150 Alzheimer's drugs are in development.

Building momentum

As enthusiastic as researchers are, they face a long road. Even if they determine which biomarkers are best at predicting the disease and discover drugs that slow the progress of those biomarkers, there's no guarantee that the drugs will arrest the cognitive decline.

Recent experimental drugs have been effective in removing amyloid from patients' brains, for example, but produced no change in their symptoms. That has fueled debate whether the telltale amyloid plaques may be only a sign of the underlying disease, not its cause.

"Amyloid plaques may be like gravestones that signify the end stage of the disease," Tariot says. "The toxicity may have occurred long before the plaques appear."

"Creating knowledge is a long way from making drugs," acknowledges Fillit of the Alzheimer's Drug Discovery Foundation, which invests in start-up biotech firms, existing companies and academic research. It can cost $1.2 billion to bring a new drug to market, Fillit says.

"We give this money for a very specific purpose, and we want specific milestones," Fillit said. "The only way out of this conundrum is to find new drugs."

In a report last year, the Alzheimer's Study Group, a panel co-chaired by former House speaker Newt Gingrich and former senator Bob Kerrey, warned that the Alzheimer's epidemic will progress like the disease itself: slowly. But if we ignore it, the group said, it could have the same disastrous consequences as ignoring the levees in New Orleans or looking the other way as subprime loans subverted the financial system.

The convergence of technological innovation and an enormous population at risk has made Alzheimer's a higher national priority for researchers.

"We're excited about this change of momentum," Tariot said. "We've captured people's imagination and attention."

James, a senior at the University of Nebraska at Lincoln, is a fellow of the News21 program at the Columbia University Graduate School of Journalism. http://columbia.news21.com.

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