When combined with genetic risk factors, test up to 93% accurate at identifying people at risk of Alzheimer’s dementia

Neurologist Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology, inspects a mass spectrometry machine at Washington University School of Medicine in St. Louis. Using mass spectrometry, Bateman and colleagues have developed a blood test that is up to 93% accurate at identifying people at risk of Alzheimer’s dementia. CREDIT: Matt Miller/Washington University

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 published in the journal Neurology [1].

“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. “As new drugs become available, a blood test could determine who might benefit from treatment, including those at very early stages of the disease.”

Low-cost, easily accessible blood test for Alzheimer’s

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 analyses 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 enrol 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.

CLIA certification

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.

What’s important about this study?

The current study shows that the blood test remains highly accurate, even when performed in different labs following different protocols, and in different cohorts across three continents.

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.”

Reference:

[1] Li Y, Schindler SE, Bollinger JG, et al. Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology. First published Dec. 14, 2021.
doi: https://doi.org/10.1212/WNL.0000000000013211.

Jeff Tabor, associate professor of bioengineering in Rice’s Brown School of Engineering (Credit: Jeff Fitlow/Rice University)

In an important step toward the clinical application of synthetic biology, Rice University researchers have engineered a bacterium with the necessary capabilities for diagnosing a human disease.

The engineered strain of the gut bacteria E. coli senses pH and glows when it encounters acidosis, an acidic condition that often occurs during flareups of inflammatory bowel diseases like colitis, ileitis and Crohn’s disease.

Rice University researchers engineered a strain of the gut bacteria E. coli to detect gastrointestinal acidosis. The organism produces fluorescent molecules that allow researchers to see it with standard optical equipment. Under normal conditions (left) it produces molecules that glow red. When it encounters acidic conditions (right), it glows green, and the brightness of the glow reflects the level of acidity. (Image courtesy of Jeff Tabor/Rice University)

Researchers at the University of Colorado (CU) School of Medicine used the Rice-created organism in a mouse model of Crohn’s disease to show acidosis activates a signature set of genes. The corresponding genetic signature in humans has previously been observed during active inflammation in Crohn’s disease patients. The results are available online in the Proceedings of the National Academy of Sciences.

Colours that show up in the toilet

Study co-author Jeffrey Tabor, whose lab engineered the pH-sensing bacterium, said it could be reprogrammed to make colours that show up in the toilet instead of the fluorescent tags used in the CU School of Medicine experiments.

“We think it could be added to food and programmed to turn toilet water blue to warn patients when a flareup is just beginning,” said Tabor, an associate professor of bioengineering in Rice’s Brown School of Engineering.

Over their 3.5 billion-year history, bacteria have evolved countless specific and sensitive genetic circuits to sense their surroundings. Tabor and colleagues developed a biohacking toolkit that allows them to mix and match the inputs and outputs of these bacterial sensors. The pH-sensing circuit was discovered by Rice Ph.D. student Kathryn Brink in a 2019 demonstration of the plug-and-play toolkit.

pH sensor

PNAS study co-authors Sean Colgan, the director of the CU School of Medicine’s mucosal inflammation program, and Ian Cartwright, a postdoctoral fellow in Colgan’s lab, read about the pH sensor and contacted Tabor to see if it could be adapted for use in a mouse model of Crohn’s disease.

“It turns out that measuring pH within the intestine through noninvasive ways is quite difficult,” said Colgan, the Levine-Kern Professor of Medicine and Immunology in the CU School of Medicine.

So Brink spent a few weeks splicing the necessary sensor circuits into an organism and sent it to Colgan’s lab.

“Normally, the pH in your intestines is around seven, which is neutral, but you get a lot of inflammation in Crohn’s disease, and pH goes to something like three, which is very acidic,” Tabor said.

Colgan and colleagues have studied the genes that are turned on and off under such conditions and “needed a tool to measure pH in the intestine to show that the things they were observing in in vitro experiments were also really happening in a live animal,” Tabor said.

Biological tool

“Colonizing this bacterial strain was the perfect biological tool to monitor acidosis during active inflammation,” Colgan said. “Correlating intestinal gene expression with the bacterial pH sensing bacteria proved to be a useful and valuable set of biomarkers for active inflammation in the intestine.”

Tabor said he believes the pH-sensing bacterium could potentially be advanced for human clinical trials in several years.