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Exploring the Technology Behind a Blood Test for Alzheimer's Disease

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Clinicians and research scientists alike are working towards a new paradigm in modern medicine, one that is proactive, and places focus on preventing sickness long before it strikes.

This approach to healthcare will require a deep understanding of an individual's molecular makeup, including their genome, proteome and metabolome. By analyzing this molecular makeup at baseline when an individual is "healthy" and monitoring how it fluctuates in response to specific lifestyle factors, environments and pathologies, the possibility to identify biomarkers will be unlocked – including disease biomarkers.

Technology Networks
recently spoke to Kevin Hrusovsky, founder of Powering Precision Health and CEO at Quanterix, a company which is digitizing biomarker analysis to achieve ultrasensitive measurements of protein biomarkers for a variety of different applications. We were particularly interested in hearing how Quanterix technology is being applied in the pursuit of a biomarker for Alzheimer's disease (AD), a progressive neurodegenerative condition for which diagnosis often occurs after the onset of symptoms.

Molly Campbell (MC): Please can you discuss why the landscape of medicine is shifting from traditional approaches to precision health? What factors warrant this shift?

Kevin Hrusovsky (KH):
Traditional approaches to healthcare and medicine are reactive and are focused on treating disease after it has taken hold. These approaches tend to be based on population averages and don’t account for environmental and lifestyle factors that are often triggers for disease, which can harm individuals and disregards the experiences of marginalized groups. This system is also costly and ineffective.

Precision health is the change we need to move from a reactive “sick care” system to true proactive healthcare. The centrepiece is monitoring an individual’s health at a molecular level – typically by tracking proteins in the blood indicative of health or sickness – to prevent illness, or at least enable earlier detection and diagnosis. The earlier we catch disease and/or get ahead of disease, the more likely we can cure it and the more cost effective it is to treat. By leveraging new technologies for personal health monitoring, a key facet of precision health, we can infuse greater efficiency and precision in drug development toward personalizing treatment for maximum efficacy and minimum toxicity.

MC: Why are blood-based 
biomarkers advantageous when compared to other methods for diagnosing neurological diseases?

Blood-based biomarkers are advantageous when compared to other methods for diagnosing neurological diseases because they enable early detection before symptoms occur. A growing body of research suggests that biomarkers could prove critical to predicting Alzheimer’s disease progression and differentiating the disease from other neurodegenerative disorders.

Leaders in the field of neurodegenerative disease research believe blood tau phosphorylated at threonine 181 (p-tau181) has the potential to revolutionize Alzheimer’s disease research and patient care in much the same way that serum-based Nf-L has for Multiple Sclerosis by empowering regular, less invasive screenings that can be conducted earlier in the disease’s progression.

As a result, biomarkers like p-tau 181 could lead to home sampling to enable early detection, advance identification of potential clinical trial candidates, and consequently, accelerate the development and approval of drug therapies desperately needed to improve outcomes for the millions of people living with Alzheimer’s disease today.

Ruairi MacKenzie (RM): Why has the development of a pre-symptomatic diagnostic assay been a goal of Alzheimer’s research?

The opportunity to focus Alzheimer’s research on detection before symptoms present moves us closer to the reality of developing treatments and therapies aimed at prevention instead of attempting to cure patients who may already be experiencing memory loss, which has been largely unsuccessful. A pre-symptomatic diagnostic assay could result in future treatments that target the disease in its earliest stages, before irreversible brain damage or mental decline has occurred.  

MC: Please can you discuss the development of the Simoa® technology platforms - Simoa® Bead Technology and Simoa® Planar Array Technology? How do they deliver high sensitivity for biomarker detection?

The Simoa technology encompasses two distinct platforms, each with a different technical approach to achieving ultrasensitive measurements of protein biomarkers for different types of applications. Simoa allows researchers to identify single molecules of biomarkers in the blood that are indicative of diseases across therapeutic areas, including neurology, oncology, cardiology, inflammation and infectious disease.

The Simoa science is based upon the isolation of individual immunocomplexes on paramagnetic beads using standard ELISA reagents. The primary difference between Simoa and conventional immunoassays lies in its ability to trap single molecules in femtoliter-sized wells, allowing for a “digital” readout of each individual bead to determine if it is bound to the target analyte or not. The digital nature of the technique allows an average of 1,000-times sensitivity increase over conventional assays with CVs less than 10 percent.

The Simoa Planar Array is a digital ultra-sensitive immunoassay platform for measuring up to 10-plex biomarkers. Its geometry is designed to maximize reaction kinetics and reproducibility within arrays and between wells. By inducing fluid flow streams, or a "vortex" effect, interactions at the molecular level are increased, diffusion-limited gradients are avoided and exquisite assay sensitivity and precision is achieved. The technology enables the performance of up to a 10-plex immunoassay, detecting targets at both acute and baseline levels.

MC: In a clinical environment, there are often large numbers of samples to process and analyze, which can be a challenge. How is the Simoa® technology optimized to deliver high sensitivity and speed for use in the clinical space?

The core differentiator is Simoa’s sensitivity, capable of measuring individual proteins at concentrations 1000 times lower than can be done using other conventional assays.This sensitivity was critical for enabling the findings of this specific study as well as hundreds of others. According to a study published in Nature Medicine, Simoa’s unparalleled sensitivity allowed researchers to see Alzheimer’s disease earlier in the disease cascade to determine that a blood test may be a reliable way to diagnose the disease years before symptoms. The ability to see biomarkers at minute concentrations means that we can not only diagnose sick patients, but also monitor baseline changes in healthy patients, which is the first step in being able to transition today’s sick care into preventative healthcare.

High sensitivity is very important when testing samples, especially for Alzheimer’s disease research. To detect Alzheimer's disease in human plasma, researcher must measure biomarkers at very low concentrations. Simoa technology allows detection of proteins and nucleic acids at the lowest possible levels. The technology also allows researchers to see results in record time and test a large number of samples at once. Results are available within 30 minutes, with subsequent results available every 45 seconds after. It can also test up to 5,000 samples per shift.

RM: If we 
develop this test to the point that Alzheimer’s could be diagnosed 20 years prior to the onset of memory problems, would a diagnosis mean that patients could alter their lifestyle to avoid the worst of the disease? Or does a positive diagnosis already suggest that disease is inevitable?

The primary benefit of early detection is that it creates opportunities to develop new treatments or determine which drugs – perhaps even some that were previously shown to be ineffective – may become relevant if given to patients earlier. Previously, researchers focused on testing people with symptoms, arguably when it is already too late.

At the individual level, early detection also provides patients the opportunity to alter their lifestyle, such as implementing a healthier diet, exercising more and practising memory exercises. While research into whether these lifestyle measures can help prevent the worst of the disease is inconclusive, identifying individuals at risk years before memory problems occur allows researchers to study how lifestyle choices impact the disease. It also gives patients more resources, including time, to make choices when it comes to treatment or preventative care.

MC: Testing for tau appears to be a better indication of burden than testing for amyloid. Does this finding have implications for the amyloid hypothesis, or can it be consistent with that theory?

For decades, the prevailing theory behind the root cause of Alzheimer’s disease has been the amyloid hypothesis, which maintains that the disease evolves from a build-up of a protein fragment called beta-amyloid in the brain. Researchers who subscribe to this theory believe that the disease ultimately stems from biological problems related to production, accumulation, or disposal of this protein.

The amyloid hypothesis could be accurate, but the problem is scientists now view the presence of the protein as a “you’ve-gone-too-far” mile marker. Researchers need to focus on detection and finding a cure for patients before beta-amyloid can be detected. This is why testing for tau is believed to be a better indication of Alzheimer’s disease. Tau can lead to the development of a test that can diagnose the disease before it is too late to treat.

Kevin Hrusovsky was speaking to Molly Campbell and Ruairi MacKenzie, Science Writers for Technology Networks.