CLIA-Certified Alzheimer’s Blood Test Gets High Marks In Global Study

By Deborah Borfitz

April 19, 2022 | A blood test to help clinicians diagnose Alzheimer’s disease is “on the road” to effectively replacing cerebrospinal fluid (CSF) testing and PET scans for detecting Alzheimer’s pathology, according to Randall J. Bateman, M.D., a professor of neurology at Washington University School of Medicine and co-developer of the plasma protein assay. A commercial version of the test, PrecivityAD, is already being used extensively in clinical trials as well to evaluate patients in real-world settings.

It is one of multiple blood-based tests for brain amyloid-β (Aβ) pathology, and the top performer in a head-to-head comparison of eight assays on cognitively impaired participants in the Swedish BioFINDER and Alzheimer Disease Neuroimaging Initiative cohorts (JAMA Neurology, DOI: 10.1001/jamaneurol.2021.3180). Within the United States, it is also the first test available to physicians in the clinic that measures levels of plasma Aβ42 and Aβ40 using immunoprecipitation-coupled mass spectrometry, Bateman says.

For many years the only surefire way to know if someone had Alzheimer’s dementia was through an autopsy. But advances in biomarker research are allowing researchers to see changes in the brain while people are alive, monitor the disease’s progression, and test the effectiveness of potential treatments.

Only five years ago, a blood test was considered the “Holy Grail of Alzheimer’s disease” given the presence of the blood-brain barrier and the multitude of failed attempts, Bateman says. “In fact, the year before we discovered this amyloid beta signature in the blood, one of the leading groups in the world came out and said… [it] can’t be [found] for Alzheimer’s because 30-plus studies have [tried and] failed to do so.”

In 2017, when Bateman and WashU neurology professor David Holtzman, M.D., first reported on their highly precise and accurate blood test, it was met with a lot of skepticism until the work was independently replicated by a Japanese group. Aβ42/40 assays are no longer viewed as a mythical pursuit, Bateman says, shifting attention to questions about their implementation.

Their test has most recently been validated in a study published in Neurology (DOI: 10.1212/WNL.0000000000013211) involving nearly 500 patients across three continents—including some not yet experiencing cognitive declines—providing further evidence that the test should be considered for routine screening and diagnosis. Bateman and Holtzman are inventors on a patent the university licensed to C2N Diagnostics, their startup company that has been marketing the PrecivityAD test since it was certified in 2020 under the Clinical Laboratory Improvement Amendments (CLIA) program.

The PrecivityAD test is intended to provide information aiding medical evaluation and care of patients who already have signs and symptoms of cognitive decline, Bateman says. The test is also available throughout most of Europe based on a CE Mark designation.

The test is not yet covered by most health insurance. Pricing is $1,250 per test, although the company provides a sliding scale discount based on the socioeconomic status of patients, according to Joel Braunstein, M.D., CEO of C2N Diagnostics.

For clinical research purposes, the test’s appeal is that it reduces by more than half the time and cost of enrolling patients into trials using gold-standard PET scans, Bateman notes. The screening phase of studies can be completed in under six months, and the research version of the test runs a fraction of the average $5,000 to $8,000 price tag per PET scan.

Blood samples may also be considerably easier to obtain than invasive spinal taps to analyze levels of Aβ and tau protein, he says. In routine clinical practice, the test could be performed wherever blood draws are taken.

The blood test was found in the latest study to be 84% accurate when compared to PET scan, rising to 88% when combined with the genetic variant APOE4. The figures relative to spinal tap were, respectively, 85% and 93%.

By itself, the blood test is far better at identifying legitimate cases of Alzheimer’s disease than is currently happening in clinical settings, Bateman says. Even among patients diagnosed at advanced medical centers, about one-third are wrongly being told they have Alzheimer’s. In the general community, the misdiagnosis rate is closer to 50%.     

Plaques Matter

While it is possible for individuals to have amyloid plaques in their brain and not have Alzheimer’s disease dementia—the most common form of dementia—the reverse does not hold true, says Bateman. The presence of Aβ plaques is part of the disease definition. As with cholesterol plaque in the arteries, and heart attack and strokes, “one is a pathology that exists in the body and can be measured, and the other is end organ damage.”

In the case of Alzheimer’s dementia, Aβ plaques alone are not what cause the brain to stop working properly, Bateman says. Tau tangles also appear to be required. Plaques start forming in the brain 15 to 20 years before the tangles take over and dementia sets in.

As people live longer, the odds improve that more people with the amyloid plaques will develop Alzheimer’s disease. Conversely, if they die earlier, the disease may never manifest itself despite the plaques.

Among other Alzheimer’s disease blood tests currently in use for research purposes are Eli Lilly’s P-tau217 test that measures a correlate of tau in the blood. It has demonstrably good detection accuracy, says Bateman, and has been deployed in at least a couple of the company’s clinical trials.

The research version of the PrecivityAD test has seen significant uptake over the past few years for screening would-be trial participants and “to enroll more people who are positive [for Alzheimer’s disease] and speed up the enrollment process,” Bateman says. A limiting factor of the test’s use as a diagnostic tool in the clinic is that it is still being evaluated by insurance companies. 

The latest study provides strong evidence that the test works well when performed in different labs following different protocols and across different cohorts and continents, but what payers are more interested in are clinical studies done as part of routine patient care, he continues. Some insurers inexplicably ask why an accurate Alzheimer’s diagnosis even matters and gaining their support hinges on showing the economic value in making the test eligible for reimbursement.

“We are now seeing very favorable feedback from memory care specialists who are incorporating the PrecivityAD test into their routine care of patients experiencing memory concerns,” says Braunstein. “For these clinicians, better diagnostic certainty is translating to clinically meaningful changes in decision-making... [in terms of] medications, fewer unnecessary diagnostic tests, and better overall care management.”