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Mass Spec Technique Highly Accurate in Detecting Alzheimer's Protein Marker in Study

NEW YORK – Researchers at Washington University School of Medicine in St. Louis have used mass spectrometry as part of a study to obtain accurate measurements of amyloid beta, a protein biomarker for Alzheimer's, to predict whether the protein has accumulated in the brain.

When blood amyloid levels are combined with two other major Alzheimer's risk factors —age and the presence of the genetic variant APOE4 — people with early Alzheimer's brain changes can be identified with 94 percent accuracy, the study found.

The findings, published Aug. 1 in the journal Neurology, represent a step toward a blood test to identify people on track to develop Alzheimer's before symptoms arise, the researchers said in a statement.

The test may be even more sensitive than a standard test — a positron emission tomography (PET) brain scan — at detecting the beginnings of amyloid deposition in the brain, the researchers said. In their study, they used amyloid PET as the primary reference standard for amyloidosis "because it is a well-established biomarker that is widely used in clinical trials for assessment of brain amyloid burden," the researchers wrote in their paper.

In the study, they used an immunoprecipitation and liquid chromatography–mass spectrometry assay to measure the amounts of two forms of amyloid beta in blood — amyloid beta 42 and amyloid beta 40. Immunoprecipitation involves precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein.

The researchers found in their study that the ratio of the two forms of amyloid beta goes down as the amount of amyloid beta deposits in the brain increases.

The study investigators enrolled 158 adults over age 50 and found that all but 10 were cognitively normal. They measured amyloid beta in 210 plasma samples and conducted a PET brain scan for each adult. They then classified each blood sample and PET scan as amyloid positive or negative.

The researchers found that the blood test from each participant agreed with his or her PET scan 88 percent of the time, results that were promising but not accurate enough for a clinical diagnostic test, the researchers said.

To improve the test's accuracy, they incorporated major risk factors for Alzheimer's. Age is the largest known risk factor, because after age 65 the chance of developing the disease doubles every five years. Further, APOE4, a genetic variant, raises the risk of developing Alzheimer's three- to fivefold. Gender also plays a role because two out of three Alzheimer's patients are women.

The researchers found that including gender did not significantly affect their analysis, but including age and APOE4 status raised the accuracy of the blood test to 94 percent.

They found that the results of some blood tests initially were considered false positives because they were positive for amyloid beta but the brain scan came back negative. However, some of the people tested positive on subsequent brain scans taken an average of four years later, suggesting the blood tests had flagged early signs of disease missed by the scan, the researchers said.

The researchers said that a blood test may become available at doctors' offices within a few years. However, its benefits will be amplified once treatments exist to halt the disease process and forestall dementia, they said.

"A blood-based biomarker would enable more rapid and inexpensive screening of potential participants, particularly for prevention trials, where rates of negative amyloid PET scans are about 70 percent," the researchers said in their paper.

Clinical trials of preventive drug candidates have been hampered by the difficulty of identifying participants who have Alzheimer's brain changes but no cognitive problems. The blood test could provide a way to efficiently screen for people with early signs of disease so they can participate in clinical trials evaluating whether drugs can prevent Alzheimer's dementia, the researchers said.

As part of the study, the researchers analyzed the enrollment process for a prominent Alzheimer's prevention trial called the A4 study, which used PET scans to confirm the presence of early Alzheimer's brain changes in potential participants. They concluded that prescreening with a blood test followed by a PET scan for confirmation would have reduced the number of PET scans needed by two thirds. Unlike blood tests, which cost a few hundred dollars, each PET scan costs upward of $4,000, the researchers said. A single site can only run a few dozen PET brain scans a month, because PET scanners are primarily reserved for patient care, not research studies.

The researchers pointed out that in a limitation of the study, they used amyloid PET and CSF biomarkers as the reference standard for brain amyloidosis, "rather than the true gold standard of neuropathology, because most of the study participants are still alive."