New Blood Test Diagnoses Alzheimer’s-Like Changes in Mice

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Researchers have for the first time used a blood test to identify Alzheimer’s-type changes in living mice. The test, developed by researchers at Washington University School of Medicine in St. Louis and Eli Lilly and Company, predicts the amount of amyloid plaque in an animal’s brain. To date, the only way to definitively diagnose Alzheimer’s disease in humans is by examining a person’s brain after death. The study is published in the March 22 issue of Science.

“We don’t know if this finding in mice will apply to humans,” says David M. Holtzman, M.D., the Charlotte and Paul Hagemann Associate Professor of Neurology and associate professor of molecular biology and pharmacology at the School of Medicine. “If it does, it has the potential to provide a non-invasive means of detecting Alzheimer’s pathology even before clinical symptoms appear.”

Recent studies have revealed physical changes that can begin in the brains of Alzheimer’s patients 10 to 20 years before symptoms arise. For reasons not entirely understood, potentially dangerous amounts of a protein called amyloid-b (Ab) begin to build up in these individuals. If enough Ab clumps together in the brain, it forms amyloid plaques, a key feature of Alzheimer’s disease.

“Brain plaques are somewhat analogous to the plaques characteristic of arteriosclerosis,” explains Hagemann. “If you have a heart attack at age 65, the atherosclerotic process that caused that event probably started decades beforehand. Since we now know that Alzheimer’s pathology starts well before symptoms appear, we’re hoping it may be possible to develop a test that predicts the presence of amyloid plaques and, ultimately, the risk of dementia, similar to performing an angiogram to predict an impending heart attack.”

The team examined 49 mice with a mutation in the gene for amyloid precursor protein (APP) similar to the genetic abnormality found in some families with a strong history of Alzheimer’s disease. All the mice developed varying degrees of plaques within a year. The researchers took advantage of these differences to investigate potential factors that predict the extent of plaque formation.

First, they measured baseline levels of two types of Ab in the animals’ blood, Ab40 and Ab42. The mice then were injected with an antibody called m266, which draws Ab out of the brain and into the surrounding blood without harming the animals, and were then periodically retested for blood levels of Ab. After 24 hours, the researchers examined each animal’s brain tissue for plaques, focusing on two key regions involved in Alzheimer’s disease: the hippocampus and the cingulate cortex.

Before m266 injection, the amount of Ab in the animals’ blood did not correlate to the number of plaques in their brains. But within five minutes of m266 injection, Ab levels increased dramatically and did correlate with the amount of brain amyloid. This suggests that blood Ab levels do not reflect the progression of the disease unless the animal has been given m266.

According to DeMattos, blood Ab levels in humans also do not reflect the amount of amyloid plaques in the brain. “The truly novel finding of our experiment is that a simple injection of m266 altered the metabolism of Ab and unmasked important correlations with brain pathology. Hopefully, we also will be able to alter the metabolism of Ab in humans.”

The team used their data to develop potential models for estimating amyloid levels in the brain. Several factors, including overall levels of Ab after m266 injection and Ab40 levels 24 hours after injection, accurately revealed the extent of amyloid deposition in the brains of these mice. Using these factors, the team developed a rough diagnostic procedure to determine “high” or “low” plaque burden in the animals.

“This has obvious implications for developing a similar blood test for brain amyloid load in humans,” says Holtzman. “Though we will not be able to detect risk in someone who has not begun to accumulate amyloid, we hope to predict the disease well before symptoms appear. Such a test also could distinguish individuals suffering from dementia caused by Alzheimer’s from those with other types of dementia, and may help us evaluate an individual’s response to particular medical therapies.”

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