Do Alzheimer’s patients have high levels of a key brain protein because they make too much of it, or because they can’t clear it from their brains quickly enough?
Scientists at the Alzheimer’s Disease Research Center (ADRC) have developed a safe and sensitive test that may finally help answer this longstanding question.
In addition to helping scientists better understand the origins of this devastating condition, the new test will likely help them improve its diagnosis and treatment.
Researchers from the ADRC studied the production and clearance rates of the brain protein amyloid beta peptide (Abeta) in the human central nervous system.
The scientists’ results were published online June 25 by Nature Medicine.
High levels of Abeta in the brain are a hallmark of Alzheimer’s disease and are believed to be a pivotal cause of the condition. Tests that measure Abeta levels in the cerebrospinal fluid have been available for some time.
However, those fixed assessments of Abeta gave no indication of whether the flood of Abeta in patient’s brains came from an increase in the mechanisms that make the protein or a reduction in the processes that regularly clear it from the brain.
Because Alzheimer’s symptoms take many years to develop, some researchers had assumed that the creation and clearance rates for Abeta were very slow. But the initial test of the new technique, applied to six healthy volunteers, suggests the opposite.
“Abeta has the second-fastest production rate of any protein for which the production rate has been measured so far,” said lead author Randall Bateman, M.D., assistant professor of neurology. “In a time span of about six or seven hours, you make half the amyloid beta found in your central nervous system.”
Ideally, the production and clearance rates stay balanced, causing the overall amount of Abeta in the central nervous system to remain constant.
In the healthy volunteers who were the first test subjects, Bateman found the production and clearance rates were the same.
He is now applying the technique to individuals with Alzheimer’s disease.
Researchers are developing Alzheimer’s drugs that either decrease Abeta production or increase its clearance, Bateman said, and the new test could be very important in determining which approach is most effective.
Prior to the new test, the only way to assess the effectiveness of a new Alzheimer’s drug was to follow the mental performance of patients receiving the treatment over many months or years.
“This new test could let us directly monitor patients in clinical trials to see if the drug is really doing what we want it to do in terms of Abeta metabolism,” Bateman said.
“If further study confirms the validity of our test, it could be very valuable for determining which drugs go forward in clinical trials and at what doses.”
The test may also be useful in diagnoses of Alzheimer’s prior to the onset of clinical symptoms, which occur after the disease has inflicted widespread and largely irreversible damage to the brain.
This study was performed in the laboratories of David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of neurology, and Kevin E. Yarasheski, Ph.D., associate professor of medicine and assistant director of the Washington University Biomedical Mass Spectrometry Resource.
It was also supported by the ADRC, directed by John C. Morris, M.D., the Friedman Distinguished Professor of Neurology.