Scientists point to high concentrations of amyloid-beta in the brain as the chief culprit in Alzheimer’s disease. But they don’t know whether the increased amounts of this peptide arise from its overproduction or from a failure of the body to dispose of an excess.
In the July Nature Medicine, researchers describe a test that enables them for the first time to track amyloid-beta production and clearance in cerebrospinal fluid in people.
While other researchers have used spinal taps to provide a snapshot of amyloid-beta concentrations (SN: 2/18/06, p. 102: Available to subscribers at Looking Ahead: Tests might predict Alzheimer’s risk), measuring the ongoing production and disposal of the peptide could provide insights into the origins of Alzheimer’s and lead to advances in diagnosis and treatment, says study coauthor Randall J. Bateman, a neurologist at Washington University School of Medicine in St. Louis.
He and his colleagues gave six young, healthy volunteers a modified form of the amino acid leucine, a building block of amyloid-beta, and then monitored their cerebrospinal fluid with a spinal tap. After as little as 5 hours of the intravenous leucine drip, the participants’ cerebrospinal fluid showed amyloid-beta that contained some of the modified leucine—a sign that the amyloid-beta was newly produced.
After 9 to 12 hours, when the percentage of amyloid-beta tagged with the modified leucine leveled off, the scientists stopped the leucine drip. They then saw a gradual reduction of tagged amyloid-beta, signaling that the marked peptides were being cleared from the body and replaced.
The rates of amyloid-beta production and clearance were similar. The data indicate that the central nervous system recycles half its supply of amyloid-beta about every 6 hours, says Bateman, who volunteered for the first spinal tap in the study.
The risk of Alzheimer’s rises considerably with age. One hypothesis holds that the capacity to remove amyloid-beta “decreases with age until it reaches a threshold where [amyloid-beta is] produced faster than you can clear it out,” Bateman says.
Now, scientists can apply the new testing method to gauge clearance rates in different age groups. Bateman and his colleagues have begun tests in older people, some with Alzheimer’s disease.
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The new method might also enable doctors to spot imbalances of amyloid-beta production and clearance in people with the earliest stages of lapsing memory, he says.
Meanwhile, drug companies are working to develop agents that stifle amyloid-beta production or hasten its clearance. An accurate measurement of amyloid-beta production and clearance “would be fantastic as a tool for knowing whether the drugs are really working,” says neuroscientist David Teplow of the University of California, Los Angeles School of Medicine.
Until now, Bateman says, the effectiveness of any Alzheimer’s drug could be assessed only by monitoring a patient’s mental performance over months or years. Therefore, the new amyloid-beta analysis might speed testing of novel drugs, he says.