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By Alice Park
August 1, 2019

More than a century after Alzheimer’s disease was first described, there still isn’t a treatment to control the cognitive decline and memory loss that are the hallmarks of the neurodegenerative condition. The drugs that are available can alleviate some of the disease’s symptoms, but don’t work to address the root cause of the brain disease. And recent studies of promising drug therapies have failed to show much benefit for patients.

One challenge in developing a treatment for Alzheimer’s lies in that by the time symptoms occur, brain neurons have already been damaged, perhaps beyond repair. And once neural connections are compromised, they aren’t likely to reform or rebuild. Drug treatments that start after people report declines in their thinking skills may simply be too little too late.

That’s why there’s strong interest in developing a reliable way to identify Alzheimer’s patients as early as possible, years or even decades before their memories start to fade. Researchers are investigating a number of promising markers that appear in the blood that could be useful in tracking Alzheimer’s. Some of the most encouraging of this work centers on amyloid, the protein that is the hallmark of the disease. Current methods of testing for amyloid, including taking samples of cerebrospinal fluid and PET imaging of the brain, are expensive, time consuming and, in the case of the spinal fluid samples, invasive. That limits the number of people who get tested; having a blood test would potentially allow more people at risk of developing Alzheimer’s to learn of their status.

Researchers at Washington University School of Medicine in St. Louis report in the journal Neurology that they have developed such a blood test that may be up to 94% accurate in finding people with early Alzheimer’s brain changes. They had previously reported the results at the Alzheimer’s Association International conference in July, and it’s among the most advanced efforts to bring a blood-based test to the clinic.

While everyone makes amyloid, in some, the protein is produced in abnormally copious amounts that clump together and form plaques in the brain, which experts believe start to strangle nerves and sever their critical connections to each other. Having amyloid plaques in the brain is a requirement for an Alzheimer’s diagnosis, so the researchers developed a test that could pick up amyloid levels in the blood.

The team, led by senior author Dr. Randall Bateman, professor of neurology, and first author Dr. Suzanne Schindler, associate professor of neurology, documented the ratio of two fragments of amyloid protein, called a-beta 42 and a-beta 40 to each other; the fragments form when the parent protein is normally chopped by enzymes. In people who develop Alzheimer’s, however, for some reason the resulting fragments start sticking together, and aren’t cleared from the brain. As more amyloid aggregates in the brain to form plaques, less of it, particularly a-beta 42, is available to circulate in the blood, so the ratio of the two forms to each other is a proxy for how much is being pulled into clumps in the brain. The lower the ratio, the more plaques are forming in the brain.

To detect the circulating amyloid, researchers used mass spectrometry, a technique that separates out compounds in a sample by vaporizing them and then shooting them with an electron beam to create specific ionic signatures that identify specific molecules or proteins. The technique can record the amount of a-beta 42 and a-beta 40 from a blood sample.

In this study, the team took samples from 158 people over the age of 50, most of whom were cognitively normal at the start of the study, and followed them for about four years to see which participants developed Alzheimer’s. To verify the amyloid levels found in the blood test, the volunteers also had a PET scan of their brains and provided samples of cerebrospinal fluid, near the start and then again near the end of the study period.

The blood samples were collected within 18 months of the first amyloid PET scan, and 88% of the time, the blood test matched the scan.

That’s not accurate enough to use as a test to identify people at-risk of Alzheimer’s, so the team then combined the blood test with other well-known risk factors, such as the presence of a genetic factor called ApoE4, and age. When these additional factors were considered, the combination matched the PET scan 94% of the time.

Previous efforts, including one by a group of Japanese researchers, to develop a blood test have compared the blood results to PET imaging, but for the first time, the Washington University researchers also tracked the blood test and PET scan results over time. They found that people who had negative amyloid PET scans at the start of the study but positive amyloid blood tests had a 15-fold higher risk of having a positive PET scan by the end of the study.

In other words, the blood test may be picking up very early changes in amyloid, that weren’t detectable on the brain scans. “Typically, with a one-time reading, we would have called those people false positive on the blood test and said it was a failure of the test,” says Schindler. “But the test wasn’t a failure, and those weren’t false positives but rather the blood test was more sensitive than the amyloid PET in picking up early changes of Alzheimer’s.”

Schindler says the test is not perfect yet, and needs more refinement and validation in larger groups of patients. But the research team has already worked with other patients in Australia and Europe and found similarly accurate results.

Using the blood test in a doctor’s office to identify those at the highest risk of developing brain changes linked to Alzheimer’s may still be a few years away. But Maria Carillo, chief science officer at the Alzheimer’s Association, says that in the immediate future, the test could be a huge help in ensuring that the right patients—those with higher levels of amyloid—are taking part in trials of new drug treatments for the disease.

Big questions about a blood test for detecting Alzheimer’s still remain, including how experts will set the threshold for “normal” and “high” levels of amyloid or other proteins in the blood. Making such a determination will be “complicated,” says Schindler, since while the presence of amyloid is necessary for an Alzheimer’s diagnosis, not everyone who harbors amyloid plaques necessarily develops the disease. But having a reliable way to track changes in people’s amyloid levels would be a start.

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