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Biomedicine

Spotting Alzheimer's Disease Early

An experimental tracer detects signs of the disorder in living patients.

A new molecular dye might eventually help diagnose Alzheimer’s disease much earlier, which could prove vital to developing effective treatments and preventative measures. The molecule binds to amyloid plaques, the neurological hallmark of Alzheimer’s disease, and can be detected in the living human brain with PET imaging.  Previously, the only definitive way to detect amyloid in the brain, and hence diagnose the disease, was via an autopsy.

Detecting Alzheimer’s: At left, a brain scan reveals the presence of a molecule designed to bind to amyloid plaques, a sign of Alzheimer’s, (red and yellow indicate high concentrations) in a living patient. At right, amyloid found in an autopsy, the current gold standard for detection, is marked in dark purple.

“Now we can see this Alzheimer’s lesion in living people, and that’s a big step,” says John Morris, director of the Alzheimer’s Disease Research Center at Washington University. Morris was not involved in the study. “Ultimately, we would like to move diagnosis to the preclinical stage [before symptoms appear] and see if we can devise strategies to prevent the brain damage that produces dementia. But it will be years before we get to that stage.”

An advisory committee for the U.S. Food and Drug Administration will meet on Thursday to decide whether to recommend that the new tracer, developed by Avid Radiopharmaceuticals, be approved to help doctors diagnose the disease or to rule it out. Pharmaceutical giant Eli Lilly acquired the company last December. Avid’s tracer is one of several amyloid binding compounds under development, and the first to complete large-scale clinical trials.

Researchers say the most promising near-term use of the tracer, which is detected via positron emission tomographic (PET) imaging, is in drug development. The ability to detect signs of the disease prior to the development of obvious cognitive problems lets pharmaceutical companies test therapies designed to prevent the development of plaques early on. “It’s enormously important for drug development research,” says Paul Aisen, director of the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. Aisen was not involved in the study. “It allows us to test therapies at the stage of disease where they are most likely to be clinically useful—when people have amyloid deposition but not major cognitive dysfunction.”

Pharmaceutical companies are currently using the type of amyloid imaging used in the study to gauge the effectiveness of experimental drugs designed to reduce buildup of the protein. (Whether or not drugs that block the buildup of amyloid improve memory loss is still an open question. It’s also not clear whether the plaque buildup is a cause of Alzheimer’s or an effect of it.)

In the study, published this week in the Journal of the American Medical Association, researchers conducted positron emission tomography (PET) scans of 29 people—15 diagnosed as having Alzheimer’s—living in hospices. Participants agreed to undergo brain autopsies after death. The researchers found that amyloid levels detected during PET imaging correlated closely with levels determined in the autopsy. PET scans of 74 healthy younger people, who were unlikely to have amyloid in their brains, confirmed that the tracer did not detect the protein when there was none.

Despite the successful results, researchers say the clinical impact of the technology is less clear. For one, no disease-modifying treatments are currently available for Alzheimer’s. “We don’t want to spend billions of dollars diagnosing Alzheimer’s when we cannot do anything about it,” says Michael Weiner, professor of medicine, radiology, and psychiatry at the University of California, San Francisco. Weiner was not involved in the study. “But when there are symptoms, patients and families want to know what’s causing it.”

Aisen says he is concerned that the technology could be overused. “Virtually everyone over the age of 40 is worried about memory, and it’s not easy to distinguish the normal memory decline of aging from early Alzheimer’s,” he says.

While preliminary research suggests that people with very mild memory problems who also have amyloid in the brain are more likely to develop full-blown Alzheimer’s, it’s still unclear what the presence of amyloid in healthy people means, or how doctors should use this information. Scientists are using Avid’s tracer and similar amyloid imaging tools to examine this question.

“Physicians and patients and families may interpret a positive amyloid scan as meaning someone has Alzheimer’s,” says Aisen. “When in fact, even if it turns out that amyloid in the brain is the earliest stage of the disease, it may be more than a decade between deposition of amyloid and clinical manifestation of the disease.”

Both Aisen and Morris say the best clinical use might be to rule out Alzheimer’s in the absence of amyloid buildup. Age-related dementia can have a number of causes—some of them treatable—and about 15 to 20 percent of people diagnosed with Alzheimer’s are found on autopsy not to have the disease.

The National Institute on Aging and the Alzheimer’s Association are working on new guidelines for diagnosing the disease. These guidelines will incorporate amyloid imaging and other techniques, such as detection of amyloid in cerebrospinal fluid.

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