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Alzheimer’s Disease May Stem from Protein Clearance Problem

Researchers have discovered that a key protein implicated in Alzheimer’s disease is produced in the brain at a normal rate but is not cleared, or removed, efficiently. The finding may lead to improved tests for early diagnosis as well as a new approach to treating this devastating disorder.

Alzheimer's disease is the most common cause of dementia in older adults, affecting as many as 5 million Americans. In the most prevalent type, late-onset Alzheimer’s disease, symptoms usually appear after age 65.

Alzheimer's disease is marked by dense protein clumps, called amyloid plaques, that form between brain cells. The plaques are made mostly of a protein fragment called beta-amyloid, which is produced by nerve cells and released into the surrounding brain fluid.

Researchers have recently developed ways to measure beta-amyloid levels in cerebrospinal fluid (CSF)—the fluid that bathes the brain. An NIH-supported team led by Dr. Randall Bateman at Washington University in St. Louis developed a procedure to measure beta-amyloid levels over time. In the new study, they measured beta-amyloid production and clearance rates in 12 patients with late-onset Alzheimer's and 12 age-matched volunteers free of the disease.

The participants' CSF was sampled hourly for 36 hours via a one-time lumbar puncture. Throughout the procedure, they were encouraged to stay in bed. During the first 9 hours, the participants received an IV drip containing leucine, a protein building block, that had been labeled with a non-radioactive isotope. By measuring the amount of labeled beta-amyloid by mass spectroscopy over time, the researchers were able to calculate how fast it was produced in the participants’ brains and then how fast it was cleared.

The researchers reported in the early online edition of Science on December 9, 2010, that the beta-amyloid production rate was similar between the 2 groups. However, the clearance of beta-amyloid was about 30% slower in those with Alzheimer's disease than in cognitively normal people.

Prior studies in animals suggest several possible explanations for the slower clearance of beta-amyloid in late-onset Alzheimer's disease. One possibility is that as beta-amyloid accumulates, it acts as a sink for more of the protein, trapping it within the brain. The researchers say that sorting out these mechanisms may help speed the development of new drugs for the disease.

"These findings may help point us toward better diagnostic tests and effective therapies," Bateman says. "The next question is what is causing the decreased clearance rate."

"This study is significant in that it reports the first measurement of beta-amyloid production and clearance in Alzheimer's," says Dr. Marcelle Morrison-Bogorad, director of the Division of Neuroscience at NIH's National Institute on Aging (NIA). "For years scientists believed that it was the overproduction of beta-amyloid that led to its accumulation in the brain. These new findings shift the emphasis to clearance of beta-amyloid. This may lead to development of a diagnostic test as well as identification of new therapeutic targets."