Alzheimer’s disease has been a challenging health problem for decades, and it remains difficult to diagnose and monitor over time. Before the early 2000s, the only way to confirm a person had Alzheimer’s was by autopsy. Without an easy way to detect definitive markers for Alzheimer’s, doctors would primarily diagnose the disease based on clinical signs, such as confusion and memory loss. Thanks to recent scientific advances, researchers can now identify biomarkers for Alzheimer’s that can aid in diagnosis, but this process often requires expensive and invasive methods, such as brain imaging or collection of spinal fluid.
“A holy grail in the Alzheimer’s research community is to find something that does not require imaging or a spinal tap to diagnose the disease,” said Tim West, Ph.D., vice president of research and development at C₂N Diagnostics. West and his colleagues at C₂N have developed a diagnostic blood test, PrecivityAD™, to address this challenge. The test offers a less invasive, less costly, and more rapid aid in the diagnosis of Alzheimer’s. Emerging data also suggest that the test may help monitor the disease’s progression — as well as patients’ response to treatment — without invasive procedures.
This important advance is thanks in part to NIA’s support for C₂N Diagnostics, with funding that extends back more than a decade. Small Business Innovation Research (SBIR) awards from NIA helped the company move from basic research in an academic laboratory to validation and commercialization of the PrecivityAD™ test. In late 2020, the Clinical Laboratory Improvement Amendments (CLIA) program certified C₂N laboratories to design and offer PrecivityAD™ as a laboratory-developed test to diagnose Alzheimer’s. Now C₂N’s test is available to many doctors across the United States (dependent on state-specific availability reflecting U.S. Food and Drug Administration guidelines). Researchers are also using PrecivityAD™ in clinical trials that test how well new Alzheimer’s treatments work.
From academia to entrepreneurship
David M. Holtzman, M.D., and Randall J. Bateman, M.D., researchers at Washington University in St. Louis, developed the underlying methods behind the PrecivityAD™ test with support from NIA research grants. They wanted to study the brains of people who were both cognitively normal and living with a well-studied biomarker for Alzheimer’s: beta-amyloid protein. Their team created a tagged, detectable molecule that integrates with beta-amyloid proteins in the brain and enables later detection, using a high-powered imaging tool called mass spectrometry.
The research led to a better understanding of Alzheimer’s biology and also helped Holtzman and Bateman recognize the potential for a clinical diagnostic tool. After receiving a provisional patent, partnering with several life science executives, and securing some initial funding from nonprofit organizations, the researchers formed C₂N Diagnostics in 2007.
Within two years, C₂N received its first NIA small business grant. The Phase I SBIR award supported a pilot study to quantify and measure the metabolism of two types of beta-amyloid that are present in brain plaques of people who have Alzheimer’s: beta-amyloid 40 and 42. The team first measured these proteins in spinal fluid. The results demonstrated that C₂N technology could measure metabolism and concentrations of beta-amyloid 40 and 42 accurately in spinal fluid, a key first step in creating a product that could be used to diagnose Alzheimer’s.
These developments were later applied to blood samples for the development of the PrecivityAD™ test. “NIH enabled the foundational element of technology transfer from academic research to product development,” said Joel B. Braunstein, M.D., M.B.A., chief executive officer of C₂N Diagnostics.
Driving clinical confidence
By 2018, C₂N was ready to validate the PrecivityAD™ test as a diagnostic tool. NIA awarded the company small business funding to create a substudy of the Imaging Dementia — Evidence for Amyloid Scanning (IDEAS) study. This validation testing used 686 plasma samples from two independent studies (PARIS-Discovery and MissionAD), which included individuals with mild cognitive impairment or dementia. The research team measured beta-amyloid 40 and 42 levels in these samples and correlated those measurements with beta-amyloid levels detected by brain imaging. The samples from the PARIS study were integral to increasing the confidence that the PrecivityAD™ test could accurately quantify beta-amyloid 40 and 42 in blood, supporting the test’s launch in late 2020 for use in patient care.
There are many practical advantages of the PrecivityAD™ test over traditional diagnostic approaches. Braunstein said that collecting spinal fluid and using brain imaging are well-validated ways to detect beta-amyloid. “But many patients and doctors are not enthusiastic to use these methods because they can be invasive and expensive — if they can access them at all,” he said. For example, an estimated 60 million Americans living in rural areas are many hours away from specialized facilities for brain imaging. “As a blood test, PrecivityAD™ may provide better accessibility, affordability, and convenience in identifying beta-amyloid,” Braunstein said.
The value of NIA small business funding
The building blocks of a successful biotech company, according to Braunstein, are sound science, high integrity, a good team, tenacity, and persistence. And funding is crucial for translational research. “NIH is essential for when you are trying to translate a brilliant idea in the lab into a commercial product,” he said.
NIA’s small business funding helped enable C₂N to optimize the scientific methods that form the basis of the PrecivityAD™ test. In particular, the IDEAS substudy offered access to many patient samples to replicate and validate C₂N’s test. This confidence in the science, made possible through NIA support, led to the successful translation of the PrecivityAD™ test into a clinically validated diagnostic tool that can provide accurate, reliable results.
“The fact that you have a peer-reviewed grant from NIH gives the company credibility,” West added, when considering how small business grants can help attract more seed funding. “Other grant institutions have rigorous review processes, but NIH is the gold standard.”
Looking ahead
The PrecivityAD™ test has already been commercialized as a clinical test to assist in Alzheimer’s diagnosis. And recent studies suggest that PrecivityAD™ may be able to identify beta-amyloid before it shows up in brain imaging. In the future, the science behind C₂N’s blood test may also be useful for detecting other biomarkers for Alzheimer’s, such as tau, a protein that accumulates inside neurons.
Researchers are also using the PrecivityAD™ test in clinical trials to monitor participants’ response to new Alzheimer’s treatments. By lowering the cost and potential barriers to an Alzheimer’s diagnosis, the PrecivityAD™ test holds the potential to help accelerate Alzheimer’s research and improve outcomes for patients.
Braunstein believes the Alzheimer’s field is at a point similar to where cardiology research was when he first started training to be a cardiologist in the mid-1990s. “Since the recognition of lowering LDL cholesterol as a surrogate marker of improved cardiovascular health, you see how much progress has been made in treating heart disease after almost 30 years of innovation,” he said. “Hopefully, for Alzheimer’s disease, the growing availability of robust and quantifiable blood-based biomarkers to gauge an individual’s cognitive health is just the beginning.”
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