Blood protein test helps predict risk of cognitive decline and Alzheimer's disease

Thursday, March 15, 2007

JACKSONVILLE, Fla. — Mayo Clinic investigators have found that measuring amyloid proteins in the blood of the elderly can help predict who is at imminent risk of developing mild cognitive impairments and Alzheimer's disease (AD).

They say their findings, published in the March issue of the Archives of Neurology, is a positive step forward in the quest to develop a simple and inexpensive blood test to help identify people at risk for AD — much as measuring cholesterol identifies those at risk for heart disease.

This amyloid blood test is not yet ready for use, the researcher say, because ongoing studies are still defining its predictive powers, but they say the study suggests that such a test could be useful especially when used in conjunction with other risk factors such as apolipoprotein-E (APOE4) gene and increasing age.

"By itself, the test identified individuals who were three times more likely to develop cognitive impairment or Alzheimer's disease within three to five years," says the study's first author, Dr. Neill Graff-Radford, who heads the Alzheimer's Disease Research Center's Memory Disorder Clinic at Mayo Clinic in Jacksonville, and who has led the work on the blood test. "But when APOE status is also considered, the combination of these factors is strongly predictive."

For example, patients in this study who had both a "positive" amyloid test and one APOE4 gene had a 20 percent chance of developing AD within three to five years Graff-Radford says. In all, 53 of the study's 563 participants developed AD or the mild cognitive impairment that precedes AD.

The study's senior author, Dr. Steven Younkin, a Mayo Clinic basic researcher in Jacksonville, added that an amyloid test will only become useful when preventive therapies are available. "Nobody will want to know if they will develop Alzheimer's disease unless there is therapy that will reduce that risk," he says. "So at the same time that we are perfecting this test, investigators here and at other institutions are developing such therapies.

"Our goal is identify people at risk and offer them a therapy to reduce that risk," he says.

The study is a collaborative effort between researchers at Mayo Clinic in Jacksonville, where much of the basic research needed to develop the test is being conducted, and investigators at Mayo Clinic in Rochester, Minn., which is undertaking a longitudinal study looking for potential biomarkers for AD in thousand of individuals.

Many scientists believe that a significant contributing cause to development of AD is the deposition of sticky amyloid beta (Aâ) fibers in the brain, which then clump together to form the "plaque" that helps disrupt normal thought and memory processes. The most common form of Aâ in a normal brain is Aâ40, but between 5 percent and 20 percent is Aâ42, a slightly longer form of the protein whose shape makes it prone to clinging on to other Aâ fibers.

The genesis of the Mayo amyloid test, or "assay," began in 1995 when Younkin helped show that genes responsible for early-onset forms of AD all increase production of Aâ42, suggesting then that Aâ42 is the central player in the disorder. The Mayo researchers then found that the amount of Aâ42 relative to the amount of Aâ40 in the blood could be a biomarker of eminent disease.

This study is the first to indicate that, indeed, this protein ratio may be useful for identifying elderly, white subjects who are at imminent risk for mild cognitive impairment and AD, the scientists say. They divided blood samples from the patients into quartiles, from low ratio (of Aâ42/Aâ40) to a high ratio, and found that participants in the lowest quartile were three times more likely to develop cognitive impairment and AD compared to patients in the top quartile.

Participants in the lowest quartile reached a 10 percent disease incidence by three years, followed by those in the second quartile, who took about five years to reach that incidence. Those in the third and fourth quartiles took about eight years to reach 10 percent cumulative incidence.

"This suggests that the time course of amyloid beta aggregation and deposition is extended over a period of 10 to 15 years before symptoms occur," Younkin says. In participants who were older than 80, and whose Aâ42/Aâ40 ratio was below the median, the five-year incidence of mild cognitive impairment and AD was 20 percent, and in younger patients, it was about 5 percent, he says.

Additional studies are underway with thousands of participants, and the researchers are keen to understand more about the trajectory of the ratio, Graff-Radford says. "If it is low at age 82, how was it at age 75? We want to go back in time and determine the trajectory of this ratio. This possibly can be done with a larger longitudinal study which is underway."

The study was funded by grants from the National Institutes on Aging, and by the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research program at the Mayo Clinic. Co-authors include, from Mayo Clinic in Rochester: Drs. Ronald Petersen, Bradley Boeve, David Knopman, Robert Ivnik, and Genn Smith; and from Mayo Clinic in Jacksonville: Drs. Julia Crook, John Lucas and Linda Younkin.

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