Thursday, March 5

SILK Blood Test Can Catch Alzheimer's Sooner

The Stable Isotope Labeling Kinetics (SILK™) blood test can catch Alzheimer's years before signs appear. Learn about this important advance for prevention, treatment and research.

Biomarkers in the blood, indicating Alzheimer's, may appear 15 years before there are signs of trouble. If researchers could just use those biomarkers to catch Alzheimer's earlier, they would have a much better shot at finding ways to prevent and treat it.

New technologies are trying to achieve this goal. Leading the pack is the Stable Isotope Labeling Kinetics (SILK™) platform pioneered at Washington University School of Medicine (WUSM) in St. Louis and already marketed by C2N. It includes new technologies that enable a novel approach to measure the metabolism of brain-derived proteins implicated in Alzheimer's disease (AD) and mild cognitive impairment (MCI).

Biomarkers are chemicals in our bodies that are markers for an illness, such as Alzheimer's. Until now, doctors looking for Alzheimer's biomarkers would go through the delicate process of taking cerebrospinal fluid from patients. For the first time, instead of analyzing Alzheimer's proteins in cerebrospinal fluid, it is now possible to detect the same metabolic markers in patients’ blood samples.

This capability has implications for the advancement of new treatments, early prevention, and personal wellness. Alzheimer’s is now one of the major global healthcare concerns. Approximately 44 million people currently have clinical Alzheimer's disease (AD). Millions more have MCI that places them at high risk for progression to clinical AD. The number of cases of AD and MCI are expected to increase sharply in the years ahead due to the aging baby boomer population.

Pharmaceutical companies developing new drugs targeting AD increasingly recognize that early intervention provides the greatest chance of halting or reversing disease progression. Biomarkers are needed to detect this early pathology, which can begin at least 15 years before the onset of any clinical symptoms. At the same time, dynamic biomarkers, like those offered by the SILK™ platform, may also track treatment responses during the pre-symptomatic stages of disease.

Since 2008, C2N has applied the SILK-Aβ® test to measure the kinetics of beta-amyloid in cerebrospinal fluid. The test has served as a primary endpoint in clinical drug studies to demonstrate target engagement and guide dose selection. The SILK-Aβ® isoforms test is also highly sensitive to identifying people with brain amyloidosis (one of the earliest indicators of Alzheimer's), even before amyloid deposits are seen with brain imaging. Still, the more invasive nature of cerebrospinal fluid sampling has impeded the full potential of the SILK-Aβ® method.

“With a simplified SILK-Aβ® test available through blood sampling, we now have an opportunity to validate a unique therapeutic and diagnostic marker,” stated Dr. Joel B. Braunstein, CEO of C2N. “We plan to achieve this validation by collaborating with pharmaceutical companies that are testing their compounds in phase 2 and phase 3 clinical studies, as well as by participating in natural history studies tracking the progression of AD. If successful, we expect to be able to offer a reliable and informative screening test that is also convenient for patients.”

Alzheimer’s Disease & Mild Cognitive Impairment

Currently AD is diagnosed based on clinical assessment by skilled neurologists or based on an amyloid imaging brain scan: there are no approved blood based biomarkers for this disease. Early detection of AD is a major research focus since early detection would pave the way for early intervention. Mild cognitive impairment (MCI) is often a precursor of clinical AD. The disorder is associated with cognition changes that are serious enough to be noticed by the individuals experiencing them or to other people, but the changes are not severe enough to interfere with activities of daily living. Individuals with MCI have a significantly increased risk of eventually developing AD, with approximately 50% of such individuals converting to AD within three years.

SILK-Aβ® Technology

Dr. Randall Bateman and Dr. David Holtzman originally developed the SILK™ technology at WUSM. Scientific American recognized the SILK-Aβ® assay as one of the top 50 new innovative technologies of the year. Similar to a pulse chase assay, the SILK-Aβ® assay relies on in vivo labeling of human subjects with a stable isotope labeled amino acid. The stable isotope labeled amino acid is non-radioactive, safe to the environment and to humans, and is incorporated into newly generated proteins. Using a highly sensitive mass spectrometer, we can measure the incorporation of the stable isotope into Aβ and thereby assess the metabolism of Aβ. This ability is particularly useful for early detection of brain amyloidosis or when assessing the pharmacodynamic effect of drugs that are hypothesized to alter the metabolism of Aβ in humans. With these new developments, we have expanded the use of the assay to measuring Aβ metabolism in plasma.


About C2N Diagnostics

C2N Diagnostics, LLC ( formed in late 2007 by scientific co-founders Drs. David Holtzman and Randall Bateman of Washington University School of Medicine in St. Louis, the Washington University Office of Technology Management, and LifeTech Research, a Maryland-based technology research and commercialization firm ( C2N is commercializing a suite of novel biomarker assays and tools to assist in pre-clinical drug discovery, clinical drug development, and the early detection and assessment of progression of debilitating neurodegenerative disorders. The company’s products include the SILK-Aβ®, SILK-ApoE™, SISAQ-Aβ™, and SISAQ-Tau™ Assays, which rely upon stable isotope labeling and tandem mass spectrometry for the measurement of the kinetics, or in vivo metabolism, and absolute quantitation of brain derived proteins. Beyond AD, products are in development to target Parkinson’s disease, Huntington’s disease, brain injury, schizophrenia and amyotrophic lateral sclerosis, among other conditions.


  1. Is this blood test available to all physicians for their patients?

    1. It is currently being used to test patients who are trying out new medications in clinical trials. It is simultaneously being simplified and tested so that it can be used by all physician and patients in the near future.

  2. Is this test coming to Australia ?

    1. I don't know of specific plans, but they have clearly been working on commercializing the test and expanding its availability.

  3. Any idea how many years it will be before thus test will be widely available to the public?

    1. They have not yet released a specific timeline to the public.

  4. how would we sign up for the trial?

  5. This is a highly sophisticated analytical methodology requiring wildly expensive instrumentation, still in the very early developmental stages and used for experimental purposes to try to determine whether and when different isoforms of Abeta are released into the blood in clinically relevant concentrations. As far as I can tell, there's only one facility capable of working with SILK.

    I'd be dumbfounded if it were ever available to the general public.

    Patients in clinical trials who undergo SILK analysis of CSF and/or blood are admitted to the hospital at 7:00 AM after an overnight fast from 8PM the preceding evening. They are fed carefully controlled low-leucine diets. Intravenous catheters are placed in two veins, one to administer the stable isotope labeled leucine solution, and the other to obtain blood samples. They've also been placing a subarachnoid catheter at the L3-L4 interspace so that CSF could be sampled repeatedly without performing multiple lumbar punctures. Patients stay in bed except to use the bathroom.

    The stable label solution is infused continuously by IV for 9 hours, and the blood and CSF samples are collected hourly for 36 hours.

    All of the samples then undergo a series of steps to isolate and concentrate the protein(s) of interest from other labeled proteins (e.g., by immunoprecipitation), proteolytically cleave the concentrated protein into smaller peptide fragments, and analyzed by liquid chromatography / electrospray ionization tandem mass spectrometry. I don't know how much the instrumentation costs -- I imagine they're built to order, so you don't find prices on -- but I'd hazard a guess in the millions. And they're also very pricey when it comes to maintenance, operation, and repair.

    Now, if you were to "commercialize" this, you could sell reagents (stable-labeled leucine, immunoprecipitation beads designed to isolate the protein(s) of interest, and protocols specific for the type of data desired, and then have centralized labs with the requisite instrumentation do the analyses. That would spread the costs for the instrumentation and skilled technicians over many samples. Provided, that is, that the samples would be stable enough for storage and transport. That's a big potential problem when it comes to Abeta.

    And provided that research does confirm that the analyses will be relevant to the diagnosis of prodromal Alzheimer's (that's going to take years of study and many millions of dollars) and/or to the development of drugs to treat the disease.

    Anyone interested in learning more, see:

    Basic method:

    Studying Abeta isoform metabolism:

    Use in a clinical trial:

  6. Anonymous, if you're interested in participating in clinical trials involving SILK, I'd suggest that you contact Dr Randall Bateman at the Washington University School of Medicine (WUSM) in St. Louis and see what they may have in the pipeline.

    If you're just interested in clinical trials on new drugs to treat Alzheimer's, search the database at


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