Scientists have found that a promising class of drugs does not exacerbate Alzheimer's disease if treatment is interrupted. The scientists report these findings from the first trial of a new model for testing Alzheimer's treatments.
Scientists at Washington University School of Medicine in St. Louis and Merck n Co. Inc studied the effects of a class of drugs known as gamma secretase inhibitors.
Researchers had worried that these drugs might cause a build-up of proteins linked to Alzheimer's disease and that this build-up could be unleashed in a surge when patients went off the medications. But the new study suggests that they do not.
"This is important because it eases some concerns that have been raised about this potentially useful class of medications," said senior author DR. Randall Bateman, MD.
Gamma secretase inhibitors block proteins involved in the creation of amyloid beta, the main ingredient of Alzheimer's plaques.
Patients cannot continuously take these drugs because nonstop inhibition of the gamma secretase enzyme has harmful side effects.
One study had revealed that when physicians temporarily halted used of the inhibitors in humans, amyloid beta levels in the blood surged.
An animal study suggested cessation of treatment also led to an amyloid beta increase in the brain.
Researchers have been watching for similar effects in current human clinical trials of gamma secretase inhibitors.
The new study used a technique for measuring production and clearance of amyloid beta developed by Bateman and his colleagues at Washington University.
It was the first time stable-isotope-labeling kinetics (SILK) was used in primates.
In a preliminary assessment of normal amyloid beta production and clearance rates, scientists found that the amyloid beta turnover in the subjects, a group of rhesus macaques, was 10 percent per hour.
"This is much closer to the human turnover rate of 8 percent per hour than other animal models. That means we can be more confident that preclinical testing of Alzheimer's treatments in this model will produce results that accurately predict what the effects will be in humans," said co-first author Dr. Kristin Wildsmith.
When scientists gave the animals gamma secretase inhibitors, SILK testing showed that the drugs reduced production of amyloid beta.
When researchers stopped inhibitors, blood levels of amyloid beta increased above normal levels.
But SILK showed there was no increase in amyloid beta levels in the central nervous system.
"It appears that blood testing may not be the best way to monitor amyloid beta levels in the central nervous system," said Bateman.
Brain amyloid beta is a fragment of a larger protein regularly disassembled as a part of normal metabolism.
Wildsmith showed that treatment with gamma secretase inhibitors shifts this disassembly from an amyloid-beta-producing path to an alternative pathway that precludes the production of amyloid beta.
The findings appeared in The Journal of Neuroscience.