Mayo researchers identify a good predictor for those at greater risk of Alzheimer's disease

Sunday, June 19, 2005

JACKSONVILLE, Fla., June 19, 2005 — By looking at the ratio between two forms of amyloid beta (Aß) protein, researchers at Mayo Clinic believe they have found a way to identify which normal, elderly people might develop Alzheimer's disease (AD) and its precursor, mild cognitive impairment (MCI).

Mayo Clinic scientist Dr. Steven Younkin was among the first to discover that Aß is a secreted protein normally present in blood and spinal fluid. Most Aß is in a form made up of 40 amino acids (Aß40), but a small percentage has 42 amino acids (Aß42). In all people with Alzheimer's, Aß42 deposits in the brain to form senile plaques, which are one of the pathological hallmarks of the disease. Studies conducted at Mayo Clinic on mice genetically engineered to develop AD show that Aß42 declines in both the blood and spinal fluid as it begins to deposit in the brain.

Younkin and Mayo Clinic neurologist Dr. Neill Graff-Radford led a team of researchers who analyzed Aß to determine if it is useful for identifying elderly individuals most at risk for developing AD. "There is a growing consensus that the best way to manage Alzheimer's disease will be through preventive therapy," says Graff-Radford. "To develop and administer preventive therapy, it is essential to develop biomarkers that can be used to identify at-risk individuals in the same way that cholesterol levels are used to identify those at risk for heart disease."

Specifically, the Mayo team looked at the ratio of Aß42 to Aß40 in blood. They took samples from 563 normal volunteers and followed them for two to 12 years. Researchers found that subjects with the lowest ratio of Aß42 to Aß40 were at the greatest risk of getting AD and getting it sooner.

During the course of the study, 53 subjects developed MCI or AD. Those with low plasma Aß42/Aß40 ratios were at significantly greater risk, and they showed significantly greater cognitive decline as measured by the Mattis Dementia Rating Scale, a 144-point cognitive test. Subjects with plasma Aß42/Aß40 ratios in the lowest 25 percent had a significant threefold increase in relative risk for MCI and AD. Subjects whose Aß42/Aß40 ratio was in the lowest 25 percent developed MCI or AD first, followed by those in the second 25 percent. MCI or AD developed considerably later in subjects whose ratios were in the upper half.

"If our findings can be confirmed in additional follow-up studies," says Younkin, "it seems likely that the plasma Aß42/Aß40 ratio can become an important biomarker for developing and implementing a preventive approach to AD therapy." A study to follow 3,000 people for five years is already under way.

Graff-Radford presents results of this study on June 19 at the Alzheimer's Association International Conference on Prevention of Dementia in Washington, D.C.

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Mayo Clinic is a multispecialty medical clinic in Jacksonville, Fla. The staff includes 312 physicians working in more than 40 specialties to provide diagnosis, treatment and surgery. Patients who need hospitalization are admitted to nearby St. Luke's Hospital, a 289-bed Mayo facility. Mayo Clinics also are located in Rochester, Minn., and Arizona. Visit www.MayoClinic.org/news for all the news from Mayo Clinic.

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