A blood test developed at Washington University School of Medicine in St. Louis has proven highly accurate in detecting early signs of Alzheimer’s disease in a study involving nearly 500 patients from across three continents, providing further evidence that the test should be considered for routine screening and diagnosis.
The study is available in the journal Neurology.
“Our study shows that the blood test provides a robust measure for detecting amyloid plaques associated with Alzheimer’s disease, even among patients not yet experiencing cognitive declines,” said senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology.
“A blood test for Alzheimer’s provides a huge boost for Alzheimer’s research and diagnosis, drastically cutting the time and cost of identifying patients for clinical trials and spurring the development of new treatment options,” Bateman said.
Developed by Bateman and colleagues, the blood test assesses whether amyloid plaques have begun accumulating in the brain based on the ratio of the levels of the amyloid beta proteins Aβ42 and Aβ40 in the blood.
Researchers have long pursued a low-cost, easily accessible blood test for Alzheimer’s as an alternative to the expensive brain scans and invasive spinal taps now used to assess the presence and progression of the disease within the brain.
Evaluating the disease using PET brain scans – still the gold standard – requires a radioactive brain scan, at an average cost of $5,000 to $8,000 per scan. Another common test, which analyzes levels of amyloid-beta and tau protein in cerebrospinal fluid, costs about $1,000 but requires a spinal tap process that some patients may be unwilling to endure.
This study estimates that prescreening with a $500 blood test could reduce by half both the cost and the time it takes to enroll patients in clinical trials that use PET scans. Screening with blood tests alone could be completed in less than six months and cut costs by tenfold or more, the study finds.
A commercial test based on Bateman’s research was certified in 2020 under the Clinical Laboratory Improvement Amendments (CLIA) program. The CLIA certification program is run by the Food and Drug Administration in partnership with the Centers for Disease Control and Prevention and the Centers for Medicare and Medicaid Services.
Known as Precivity AD, the commercial version of the test is marketed by C2N Diagnostics, a Washington University startup founded by Bateman and his colleague David Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. Bateman and Holtzman are inventors on a patent the university licensed to C2N.
CLIA certification makes the test available for doctors in the United States. It is intended to provide information that will aid the medical evaluation and care of patients who already have symptoms of cognitive decline. A similar certification makes the test available in Europe. The test is not yet covered by most health insurance.
Scientists didn’t know if small differences in sampling methods, such as whether blood is collected after fasting or the type of anti-coagulant used in blood processing, could have a big impact on test accuracy because results are based on subtle shifts in amyloid beta protein levels in the blood. Differences that interfere with the precise measurement of these amyloid protein ratios could have triggered a false negative or positive result.
To confirm the test’s accuracy, researchers applied it to blood samples from individuals enrolled in ongoing Alzheimer’s studies in the United States, Australia and Sweden, each of which uses different protocols for the processing of blood samples and related brain imaging.
Findings from this study confirmed that the Aβ42/Aβ40 blood test using a high-precision immunoprecipitation mass spectrometry technique developed at Washington University provides highly accurate and consistent results for both cognitively impaired and unimpaired individuals across all three studies.
When blood amyloid levels were combined with another major Alzheimer’s risk factor – the presence of the genetic variant APOE4 – the accuracy of the blood test was 88% when compared to brain imaging and 93% when compared to spinal tap.
“These results suggest the test can be useful in identifying nonimpaired patients who may be at risk for future dementia, offering them the opportunity to get enrolled in clinical trials when early intervention has the potential to do the most good,” Bateman said. “A negative test result also could help doctors rule out Alzheimer’s in patients whose impairments may be related to some other health issue, disease or medication.”
lzheimer’s disease (AD) is the most common form of dementia . Globally, nearly 50 million people have AD or a related dementia, yet only 25% of people living with AD have been diagnosed [2, 3]. Currently, AD affects 5.8 million Americans 65 years and older, and by 2050, AD prevalence in the US is expected to increase to 13.8 million .
AD is a progressive, irreversible degenerative condition that affects a person’s memory, cognitive abilities, and personality. AD dementia is associated with increased disease susceptibility in organs outside the brain in ways that can ultimately lead to death. In the US, AD is the sixth-leading cause of death.
With several promising AD-modifying therapies in development, early detection of brain amyloidosis will be imperative for selecting and treating patients. Current AD diagnostic guidelines include tests that detect the presence of brain amyloid-β (Aβ) plaques using either amyloid PET imaging or low cerebrospinal fluid (CSF) Aβ42 levels or Aβ42/40 ratio; biomarkers for dysregulated Aβ metabolism and plaque formation [4–10].
Although amyloid PET imaging and CSF biomarkers have significantly improved the detection of brain amyloidosis, there is still a critical need for safe, lower cost, less resource-intensive, broadly available, blood-based biomarkers that identify the presence or absence of brain amyloid plaques. Herein, we describe the first generation of a Mass Spectrometry (MS)-based blood test that addresses this critical need.
Substantial effort and resources have been devoted to quantifying blood biomarkers (e.g., Aβ42, Aβ40) as potential proxies for brain amyloid plaques [11–24]. Using traditional enzyme-linked immunoassay (ELISA) technology, most prior studies found poor concordance between blood Aβ concentrations and either brain amyloid status or AD .
Recently, mass spectrometry-based technologies have gained traction as highly sensitive and specific methods for quantifying Aβ isoforms in CSF and blood samples [17, 20, 21, 26–31]. These studies found that low plasma Aβ42/40 concentration ratios (or high plasma Aβ40/42 concentration ratios ) are associated with the presence of brain amyloid plaques.
Interestingly, a low plasma Aβ42/40 ratio identified the presence of brain amyloid plaques prior to the onset of a positive amyloid PET scan . During the research and development process, we designed a streamlined, high throughput, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical platform that quantifies plasma Aβ40 and Aβ42 levels and identifies plasma Apolipoprotein E (ApoE) isoform-specific peptides.
To establish proof-of-principle, we tested the robustness, clinical accuracy, and commercial viability of this novel LC-MS/MS assay by evaluating concordance between LC-MS/MS-based measures of plasma Aβ42/40 concentration ratio, ApoE phenotype, and the presence or absence of brain amyloidosis determined using CSF and amyloid PET imaging biomarkers among participants enrolled by multiple memory clinics and academic research centers across the US.
reference link : https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8088704/
More information: Yan Li et al, Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques, Neurology (2021). DOI: 10.1212/WNL.0000000000013211