Advancing Blood Testing for Alzheimer's
What needs to be done in order to build upon the “gold standard” biomarkers for neurodegenerative disease? Dr. Richard Isaacson explains how IND is conducting this rigorous cutting-edge research.
Currently, the gold standard of clinical biomarkers for Alzheimer’s and neurodegenerative disease measure the proteins amyloid-beta and phosphorylated tau (p-tau) in the fluid that surrounds the brain (called cerebrospinal fluid), or brain imaging (via PET scan). These innovations have allowed for great strides in the diagnosis of neurodegenerative disease, given that not too long ago, an autopsy was the only way to definitively diagnose Alzheimer’s.
However, considerable advancements in biomarker research are still necessary to successfully mitigate and prevent neurodegenerative disease in the future. Dr. Richard Isaacson, world-renowned Alzheimer’s researcher, explains how IND is working to improve and expand upon existing biomarkers in order to maximize their impact on public health. He details the many ways in which he and his team are ensuring that the biomarker research at IND is of the highest quality and scientific rigor.
Identification of new biomarkers
While amyloid-beta and tau can often be thought of as the “poster children” of Alzheimer’s disease, additional novel biomarkers are needed to strengthen clinical benefit. Dr. Isaacson states, “I think amyloid and tau are a big part of the story, and I would say even a really important part of the story, but amyloid is confusing.” Although the presence of amyloid in the brain is typically described as a tell-tale feature of neurodegenerative disease, amyloid levels actually increase in all brains with age. In fact, some individuals will present with amyloid plaques throughout their entire brain at the end of their life during autopsy, despite never experiencing cognitive symptoms.
Because of this, Dr. Isaacson shares that to him, “amyloid is a marker, a biomarker of increased risk, but it’s not a definitive marker that a person is going to develop Alzheimer’s disease dementia . . . Yes, the core is certainly amyloid and tau, but there’s a variety of other things.” IND is currently investigating over 120 proteins to discover new markers of neurodegenerative disease beyond amyloid and tau alone.
The curation of a panel of biomarkers
However, the team at IND will not simply be swapping out amyloid and tau for one or two different proteins. Dr. Isaacson explains that he believes “a panel of markers is really the way forward.” Yet, it’s a delicate balance between over-simplicity and over-budget. Dr. Isaacson shares that relying on a single biomarker is not feasible. For example, a form of phosphorylated tau, p-tau 217, has been studied as an independent diagnostic marker for Alzheimer’s disease. Dr. Isaacson explains, “P-tau 217 is a very good test, but not what we’re looking for. We want to understand the whole gamut. We want to understand the full picture.”
However, the more proteins that are being measured, the more expensive the blood test is. Therefore, finding the fewest amount of proteins that provide the greatest amount of information is the goal. Isaacson shares, “We want to figure out which of these 120 markers that we’re looking at are the bare minimum. And if we can find five and do that as a panel...to bring down costs...and put that in to some sort of predictive measurement, that is really critical.”
The use of accurate assays
Another important aspect to consider is that not all blood tests are created equal. Dr. Isaacson explains:
"I would venture to guess that 99% of people...have never heard that LDL cholesterol, the most common one that everyone gets checked, the vast majority of times is an indirect measurement of LDL. In research and in our clinical practice, we measure a direct LDL from a very specific assay, meaning a very specific lab test that was developed by a specific lab. And that's the most accurate...but a lot of these new tests...may not be as accurate. And they may vary from hour to hour, from day to day. And that's not okay on our watch."
This an example of IND’s commitment to collecting consistent and precise data.
Standardization of sample collection
Similarly, the team at IND instituted standardization procedures for blood sample collection to ensure the reliability and reproducibility of their results. All samples are collected in the morning from subjects who have not eaten or exercised that day and have gotten a good night’s sleep. They even go as far as to push the blood draw time back three hours for those who have travel led from the West Coast and are typically on Pacific time. Dr. Isaacson explains that they do this because, “when we're in a research phase and we're in a data validation phase, it's really important to standardize.” The goal is to prevent variability between samples due to technical reasons unrelated to brain health or disease status to ensure that the data are less noisy or inconsistent, and more accurate.
The establishment of dynamic reference ranges If you get standard blood work done, the results from your lab test are compared to a reference range of upper and lower limits that were previously determined to be representative of a healthy population. A lab test is flagged if the results fall outside of these limits and are deemed “abnormal.” One of the challenges of identifying novel biomarkers is establishing appropriate references ranges to differentiate normal from abnormal.
Dr. Isaacson explains:
"Reference ranges for these biomarkers are very new...Today we've literally spent like hours with spreadsheets of all the people in the research study and the cohort that are 'control subjects’, meaning they don't have symptoms, they don't have a family history...even their values were a little bit all over the map. So like, what is a normal reference range?"
And to make things even more complicated, it’s possible that each individual will require personal reference ranges that are established by recording one’s baseline levels before changes take place.
Longitudinal collection of data
This is in part why longitudinal data collection is incredibly important. Tracking changes in biomarker levels over time will be necessary to understand disease progression and treatment efficacy. Dr. Isaacson shares that “single snapshots in time of certain blood tests may be less reliable, but getting this longitudinal data and standardizing it in a really rigorous way is key. ”Overall, this challenging endeavor has the potential to eventually unlock a paradigm shift in how Alzheimer’s and neurodegenerative disease are monitored and treated.
Dr. Isaacson shares:
"IND is really trying to, not just advance the science but also advance the education and I think we're still a little bit of ways away from broad scale adoption, but we're really committed to bringing costs down, increasing access and improving what is the bare minimum we need in science at the lowest possible cost. And how do we scale this in order to make the broadest impact on public health?"
To learn more about IND’s advances in biomarker development, watch our conversation with Dr. Richard Isaacson in the video above.
By Alicia J. Barber, PhD
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