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UCSD Study Aims to Halt Alzheimer's by Blocking Enzyme


April 28, 2006  |  

Clinical trial to inhibit enzyme may prevent amyloid plaque buildup thought to trigger disease

The Shiley-Marcos Alzheimer’s Disease Research Center at the University of California, San Diego (UCSD) School of Medicine is participating in a national study of a drug designed to block an enzyme that produces plaques believed to trigger Alzheimer’s disease. They are looking for men and women, age 50 or older and who have been diagnosed with Alzheimer’s disease, to participate in the study.

"Our study is focused on the presumed cause of the disease,” said Adam Fleisher, MD, assistant professor in the Department of Neurosciences at UC San Diego and project director for the study. “Rather than treating symptoms of the disease, this drug has the potential to attack the root cause.”

UC San Diego is one of six sites around the country taking part in a double-blind, placebo-controlled study of the agent known as LY450139, which blocks an enzyme called gamma secretase.  The drug is manufactured by Eli Lilly and Company, which is funding the study. Other study sites are in Indianapolis, St. Louis, Philadelphia, Seattle, and Portland.

"There is a theory that accumulation of beta-amyloid in the brain may cause Alzheimer's disease, so if you prevent the amyloid from depositing, you can halt the disease," said Roy Yaari, MD, UC San Diego Geriatric Neurology Fellow and principal investigator of the La Jolla site study.

Gamma secretase is an enzyme that produces beta-amyloid. Beta-amyloid fragments clump together to form dense, insoluble plaques inside the hippocampus – the part of the brain that controls learning and memory – and the cerebral cortex, where sensory and motor information is coordinated.

The plaques formed by beta-amyloid disrupt nerve connections and disrupt signals in the brain, leading to symptoms of Alzheimer's such as confusion, memory lapses, and impaired movement or coordination.

The gamma secretase enzyme is made up of a complex of four proteins, and LY450139 is thought to de-activate it by binding within the complex, although the exact location is still being studied.

The 29-week-long study, set for completion in September, is a Phase II trial involving 45 participants that will determine LY450139's safety, whether it causes any side effects, how much of the drug should be given and how long it can be detected in the blood. Researchers hope to measure levels of biomarkers in blood and spinal fluid that might relate to Alzheimer's disease, changes in the study subjects' thinking and memory, and changes in their daily living activities.

Study participants will be asked to make an initial office visit, followed by visits for treatments every other week for 14 weeks. They then will make two follow-up visits.

In a study published in the Feb. 28 issue of the journal Neurology, LY450139 was shown to reduce blood plasma levels of beta-amyloid by 38 percent in 70 Alzheimer's patients given 30 milligrams of LY450139 for one week, followed by 40 milligrams for five weeks. They reported that the lowest concentration of the protein occurred three hours after a 40 milligram dose was taken. The drug was well tolerated, according to this report.

A study published last summer in the journal Clinical Neuropharmacology found results similar to those in the previous study. In that Phase I trial, researchers found a "dose-dependent" reduction blood plasma levels of beta-amyloid in 37 volunteers taking between 5 and 50 milligrams of LY450139 during a 14-day period. Side effects, which can include headache and abdominal pain, were manageable.

Eric Siemers, MD, a neurologist at Eli Lilly and lead investigator for the Neurology and Clinical Neuropharmacology studies, said his company has been interested in finding therapies for Alzheimer's disease "for a number of years," and that LY450139 is "the first putative disease-modifying drug" to reach the clinical trial stage.

But that doesn't mean a therapy that will stop the cognitive decline caused by Alzheimer's disease is right around the corner, Siemers emphasized.

"The current study is primarily to look at tolerability, and also to confirm the biomarkers effects," he said. "Studies that look at clinical measures of cognitive decline in Alzheimer's disease patients typically require 12 to 18 months of treatment, and hundreds of subjects."

Patients or families looking for more information should call UC San Diego’s Shiley-Marcos Alzheimer’s Disease Research at 858-822-5800.




Media Contact: Debra Kain, 619-543-6163,

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