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New Quest Alzheimer's Assay Uses Ratio of Peptides to Improve Test Sensitivity


NEW YORK (360Dx) – A new mass spectrometry-based assay developed by Quest Diagnostics, which measures the ratio between two peptides associated with Alzheimer's disease, is demonstrating increased specificity and sensitivity in diagnosing the ailment in research studies, according to the company.

The test's approach differs from other methods, which often measures the two peptides, amyloid beta 42 and amyloid beta 40, independently. In addition to determining the ratio of those peptides, Quest's test, conducted on cerebral spinal fluid, measures Apolipoprotein E, or APOE proteins, according to Edward Ginns, medical director, neurology at Quest. The assay has been offered since late summer through Quest's Nichols Institute in San Juan Capistrano, California, where it was developed, he said.

Measuring the ratio is significant because a patient's level of Abeta42 changes with progression to Alzheimer's disease, but the level of Abeta 40 varies from person to person but remains constant as the disease progresses, Ginns explained.

"The changes in Abeta40 that we can identify from person to person correlate and make more meaningful the changes that we see in Abeta42," Ginns said.

Understanding an individual's Abeta40 level essentially provides a reference point of how much a person's Abeta42 is changing, explained Nigel Clarke, vice president of special technology at the Quest Diagnostics Nichols Institute, where the assay is performed.

"This gets us around the problem that I don't have a control sample from you when you were 40," Clarke said. "If I can look at my [Abeta42] and my [Abeta40] and if I find that my [Abeta42] is much lower than it should be in ratio compared to my [Abeta40], that ratio has changed and that is an indicator that I'm probably plaquing out the [Abeta42] and moving into Alzheimer's disease."

Abeta42 molecules tend to band together into insoluble clusters over time, Clarke said. "They have the ability to stick on top of each other like shingles, and that's what we refer to as plaquing," he said.

The plaquing eventually kills the cell that it inhabits. Then when the cell dies the body's immune system reacts as if a potential pathogen has killed the cell and begins to fight the perceived pathogen. The immune response causes inflammation and kills more cells in the areas, Clarke explained. This process, over time leads to Alzheimer's disease, he said.

"One of the biggest risk factors of getting Alzheimer's disease is getting old. A person has these plaques and the brain has enough redundancy to cope with it for a while. You don't go into full blown Alzheimer's disease until you are getting to a tipping point where you have lost so much brain tissue that the brain is struggling to be able to rewire," he said. "At some point you lose too much brain tissue and now you are on a downward slope. That's when you go into Alzheimer's disease."

While a person with Alzheimer's disease might have more Abeta42 in the brain, the assay is designed to detect a lower concentration of in Abeta42 in a person's cerebral spinal fluid, Clarke said. That's because the Abeta42 is clustering, or plaquing, in the brain rather than being cleared out of the system through the flow of cerebral spinal fluid, he explained.

To develop the assay, Quest used 400 cerebral spinal fluid samples from University of California, San Diego School of Medicine. The samples, which had been assessed by physicians independently, were initially reviewed in a blinded study. After initially establishing Abeta 42-to-Abeta 40 ratios for each of the samples on a blinded basis, the blind was broken and researchers and statisticians were able to establish a continuum of ratios. A range of ratios for people who had Alzheimer's disease was established, as well as a range for those who did not appear to have the disease, and a range for those who had mild cognitive impairment and were probably heading toward Alzheimer's disease.

The assay also tests for APOE proteins because patients with APOE E4/E4 have an 85 to 90 percent chance of getting Alzheimer's disease in their lifetime, Clarke explained.

The relationship between Abeta42 and Abeta40 has been studied before, Clarke said, noting that he studied the issue 25 years ago while working at the Mayo Clinic.

"We finally got to the point now where our instruments are sensitive enough, and our abilities with automation mean we can make a commercial assay out of this," he said.

While some researchers have studied Abeta42 and Abeta40 levels using an enzyme-linked immunosorbent assay, or ELISA, Clarke said that Quest has invested heavily in developing a large group internally with expertise in mass spectrometry.

"A big selling point on this is that this is done on mass spectrometry," he said. "The ELISAs have a huge amount of variability and people know that."

In addition to working with UC San Diego, which supplied the initial 400 samples, Quest is also working with UCSF School of Medicine, collaborating on several projects related to diagnosing and determining care pathways related to Alzheimer's disease and dementia. One aspect of the collaboration involves accessing and studying more samples of patients who do not have Alzheimer's disease but have comorbidities or other forms of dementia that mimic Alzheimer's disease.

"We want to see how specific our assay is. Can we tell the different between hippocampal sclerosis and Alzheimer's disease?" said Clarke "Preliminary data says we can, but it's not powered enough so we need to go out there and get a bunch more non-Alzheimer's disease patients, as well as a few Alzheimer's patients and a few controls blinded by an independent group."

Quest is currently working with researchers at the medical schools on a research paper on its findings that it aims to publish soon. Clarke said researchers hope to publish a second paper in the future as more data is collected on the specificity of the test in relation to other forms of dementia.

A longer term goal, he said, would be to develop a blood test for the disease, as patients who receive spinal taps are generally already down a care pathway.

"Eventually we would love to be able to have something where you can do it from a plasma test," Clarke said. "Then you'd have a whole sea change, if you could actually identify a person in their 40's or 50s as being of higher risk of going to Alzheimer's disease in the same way you can do it with diabetes."

While there is no cure for Alzheimer's, Ginns noted that there is interest within the medical community in identifying cognitive impairment that leads to Alzheimer's as early as possible.

"In the future, if we are able to identify reliably those that are at high risk for dementia like Alzheimer's, we could start treatment earlier. It's possible that some of the therapeutic interventions that we are currently exploring way down the line in severe dementia might actually have a better benefit earlier in the course where nerve cells are very much functional," he said. "So the challenge there is to have a test that is not just sensitive to change in cognition that could lead to Alzheimer's, but also specific so that we don't misinform an individual and their family that they're going to have a disease that we currently have no cure for at the moment."