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Healthier World with Quest Diagnostics
41 - Empowering primary care in the new era of Alzheimer’s disease diagnostics (25 min)
00:25:34
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welcome to Healthier world with Quest Diagnostics. Our goal is to prompt action from Insight as we keep you up to date on current clinical and diagnostic topics to transform lives and illuminate a path to better health. Imagine being able to evaluate brain amyloid pathology, a hallmark of Alzheimer's disease, with a simple accessible blood test, rather than relying solely on expensive, hard to access PET scans or invasive lung bar punctures. Recent breakthroughs in blood based biomarkers are making this a reality. Today we're discussing a highly accurate multi marker approach that reduces diagnostic ambiguity and helps identify viable candidates for emerging anti amyloid therapies. I'm Dr. Mason Latsko. Joining me to break down the science and the clinical application is Dr. Matt Stroh. Matt is the Director of Medical Science Liaison for Neurology here at Quest Diagnostics and he, along with our excellent scientific and medical teams, have been at the forefront of translating complex neurological data into actionable clinical tools. Matt, thanks so much for joining me today.
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Yeah, of course, thanks for having me. I'm always excited to talk about what our team has been doing to drive this space.
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Great. Well, I'm happy to have you on today. So before we dive into the science of dementia and Alzheimer's disease or ad, can you share a little bit about your background and your role at Quest Diagnostics?
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Yeah, certainly. So I've been with Quest Diagnostics for a little over four years now. I'm an academically trained neuroscientist and I've had a long standing interest in the etiology of complex neurological diseases, much like Alzheimer's disease. I did my PhD at the University of Kansas School of Medicine and a postdoctoral scholarship at Washington University in St. Louis School of Medicine. Prior to coming to Quest, I did a few tours through pharma working in various therapeutic areas such as migraine cardiology and nephrology, developmental epileptic encephalopathies, and of course, Alzheimer's disease. So since I've been at Quest, we have seen the approval of the first disease modifying therapies in AD, as well as a rapid expansion of a blood based biomarker landscape driven by the recent Alzheimer's association guideline updates as well as initiatives to help establish minimal performance standards for these blood based tests. So our team has worked closely and diligently to develop and launch our AED Detect portfolio which focuses on assessing plasma based biomarkers for evaluation and diagnosis of Alzheimer's disease in symptomatic individuals.
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Yeah, and as you talk about witnessing this expansion of Alzheimer's disease biomarkers during your time here at Quest, it really highlights a major shift. Obviously, neurologists have always been at the center of this field, but as these diagnostic and prognostic tools become more accessible, it's completely opening up doors for primary care. Right. PCPs are now able to utilize blood based biomarkers in their own clinics. Can you talk a little bit about about the clinical landscape right now and how this influx of biomarker testing shifts the relationship between primary care and neurology?
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Yeah. So? Well, historically, patients with cognitive complaints would present to their PCP and be referred to a neurologist or memory specialist where they would undergo neurocognitive exams and possibly even undergo a lumbar puncture or a PET scan to look for AD pathology in the brain. And they would subsequently be given a diagnosis of MCI or dementia and be prescribed a medication that provided some temporary symptom relief while they were advised to get their affairs in order. You know, a diagnosis of AD was devastating, a path that often left providers and patients and caregivers feeling hopeless. Now, over the last few years, we've seen large breakthroughs with the approval of two disease modifying anti amyloid therapies and the emergence of blood based tests for AD pathobiology concordant with guideline revisions and even performance criteria for these tests, which set a high bar for the quality and performance of the tests. So the patient journey is changing significantly and early identification and mitigation of risk factors for developing AD is now becoming more and more important. And the diagnostic process is now beginning even earlier with with PCPs shifting to ordering blood based tests and performing some neurocognitive exams prior to referring to a neurologist for potential treatment. We can even see this shift with the recent FDA clearance of a PTAL181 triage test intended to help PCPs rule out AD during their differential.
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Absolutely. And having P Tau 181 to help triage patients is gonna be pivotal to identify at risk patients. And we'll definitely get more into the weeds with the biomarkers. But even with the right tools, one of the biggest challenges is often untangling the terminology because the symptoms overlap so much. Right. Can you break down the clinical differences between normal age related cognitive decline, mild cognitive impairment, AKA mci, general dementia and even Alzheimer's disease or ad?
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Yeah, so I think this is one of the most common misconceptions among the at risk populations. Alzheimer's disease and the associated cognitive decline is not a normal part of aging. That said, as we age, our ability to quickly think and remember, adapt and execute our cognitive tasks does decline. In general, we can expect a slight decline in cognitive functioning and speed because of age, but we shouldn't see impairment that impacts an individual's activities of daily living, something that we in the field refer to as ADLs, which is what we see in clinical AD patients with MCI or dementia levels of impairment. This is where there's a distinction. Individuals diagnosed with mild cognitive impairment can still function independently, but they have detectable and persistent cognitive issues that can make things a bit more difficult. So when a patient progresses to severe cognitive issues that fully interfere with their ability to lead and manage an independent life, then we say that those individuals have dementia.
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Great. I think that was a really important distinction and really well explained. So now let's zoom back in and talk more specifically about Alzheimer's disease, which is, of course, the most common form of dementia. Because we now have these tools to actively rule in and rule out this specific disease, it's important to understand exactly what we're testing for. So, first, can you describe the pathophysiology of Alzheimer's disease? What is actually happening in the brain? And then we'll jump into specific biomarkers.
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Yeah. Well, as for the pathophysiology of the disease, it's incredibly complex. Right. Even after all of the decades of work, we surprisingly still don't fully understand the etiology or what actually kicks off the start of these pathological processes that lead to AD dementia. What we do know is that AD has two primary biological hallmarks in the brain. It's actually how we define the diagnosis of the disease, and those are amyloid plaques and tau neurofibrillary tangles. Now, these insoluble amyloid plaques are composed of short, sticky extracellular fragments of a protein called the amyloid precursor protein, or app. And the fragment length can vary by a few amino acids. So, you know, 40, 41, 42, 43. But a primary component of the plaques that a lot of us have heard about is the amyloid beta 42 fragment, or a beta 42. The other hallmark, tau tangles, are intracellular paired helical fragments of the microtubule binding protein called tau, often appearing as tangled strands within neurons affected by the disease. And in the AD disease process, tau becomes hyperphosphorylated, making it stickier and more likely to seed and create these filaments within the cells, leading to basically a traffic jam, toxicity, and eventually cell death. We actually evaluate some of these phosphorylated forms of tau as a marker of ongoing disease pathobiology.
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Right. So ultimately we're looking here at tau tangles and amyloid plaque. And with a tau tangles, we're primarily focused on phosphorylated tau that clusters together and essentially mush up the brain and block cell signaling. And with the amyloid, we're really looking at an increase in a beta 42 fragments inside the brain that interfere with neural connections. So knowing that P, tau and amyloid are two specific proteins driving Alzheimer's disease, can a provider just pick one to measure? Is looking at just one of these Paul marks enough to accurately predict Alzheimer's disease?
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So, I mean, this is a great question. It's one that we get often, and I'll go back a little bit and say that, you know, AD is in a group of neurodegenerative diseases known as tylopathies. So we describe AD as an amyloid dependent tauopathy. That is to say that the disease is biologically defined by the presence of both amyloid and tau. And in fact, the progression of the spread of tau throughout the brain is actually dependent upon the presence of amyloid. It's something that we call the amyloid dependent transition. So a combination of amyloid plaque and the tau tangles leads to impaired synaptic transmission and eventually cell death, which obviously affects cognition. So we need to verify that both amyloid and tau are present and consistent with AD pathology in order to confirm the diagnosis. Now, it's really important to note that what I just described is what we call the amyloid hypothesis, which has been the leading hypothesis for the cause and targeted treatment for AD for a long time. While it's very, very clear that amyloid and tau are key hallmarks and critical components of the AD disease process, the amyloid hypothesis has fallen short in explaining a few critical underpinnings to the disease that we would still like to understand. Other major contributing factors like altered immunological and microglial function, even changes in mitochondria and bioenergetics, and even glutamate metabolism. So. But still, amyloid and tau are absolutely key in diagnosis of ad, which is why they are the biomarkers that we focus on.
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Yeah. So let's zoom into that a little bit. Now, we understand that tau and amyloid are key hallmark features of Alzheimer's disease pathobiology. Maybe not the only features, but certainly the primary ones. So let's talk about how your team and others have helped to translate those hallmark proteins into blood based biomarkers. That can help healthcare professionals understand if their patient is truly at risk.
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Well, we've had the tools to rule in and rule out the disease using biomarkers for over a decade now. However, they required painful procedures like an LP and lumbar puncture, or even very costly technology that exposed patients to radiation like amyloid PET scans. So, as you might imagine, this has led to some serious debate and friction in the scientific and medical communities and has ultimately pushed recent guidelines from the Alzheimer's association to pivot to a biological basis for the disease in diagnosis and management. So this leads us to where we are today, which is in the middle of a massive shift to blood based biomarkers for evaluating and diagnosing individuals with high clinical suspicion of ad. So we look at a few specific biomarkers, including that amyloid beta, a beta 42, as well as a shorter fragment, a beta 40, which helps kind of standardize. We combine those and look at a ratio of 42 over 40. So what we've observed is that in individuals who go on to develop Alzheimer's disease, what we see is in the blood, the 42:40 ratio actually goes down. And it goes down as a result of those 42 length proteins getting sticky and depositing in the brain, while the 40 stays relatively stable. So using that knowledge, we can then see who is on the trajectory or is more likely to have amyloid positivity in their brain by simply looking at their blood. We also look at another marker called P Tau217, which is phosphorylated Tau217. Remember I spoke earlier about how tau can be phosphorylated at a number of different sites and, you know, a lot of research has gone into identifying which sites really correlate well with different profiles or different aspects of the disease. So P Tau217 is a really great marker for detecting and confirming amyloid pathology in Alzheimer's disease. And, you know, we've probably heard about P Tau 181 as well. P Tau 217 is kind of the new kid on the block. I always like to make the joke and make the comparison. For those that are Lord of the Rings Fans, P Town 181 is Gandalf the Gray. He's been around for a long time. There's been a lot of research on it. But P Tau317 is Gandalf the White. It's much newer, it's slightly more powerful, and it's still comparative in its ability to detect amyloid pathology in the 80 grain. So basically, our team has recently published a paper on the clinical validation and performance of the combined power of this a beta 4240 ratio, the P Tau 217 levels and ApoE 4 to predict a patient's likelihood of being positive on an amyloid PET scan. So what we did was we took plasma from a clinically well defined group of patients who had amyloid PET scans and were known to be either cognitively normal, have mild cognitive impairment or mci, or who had full blown AD dementia. And we looked at their 4240 ratio and their P Tau 217 levels, as well as how many copies of APOE 4 they were carrying. And we developed an algorithm that we can use to predict how likely a patient is to be positive on an amyloid PET scan. So I won't get too into the weeds about this, but by combining only the 4240 ratio and the P Tau 217 and looking at those individuals with a high clinical suspicion of ad, those people that had a MCI or Alzheimer's disease diagnosis, we were able to achieve excellent diagnostic performance using this method with a 91% sensitivity and 91% specificity, and only about 15% of patients getting what we call an indeterminate score, meaning that we were unable to predict one way or another whether or not they were positive or negative. When we add in a patient's APOE4 allele count to that algorithm, we achieved the same sensitivity and specificity, 91% and we were able to improve the number of patients receiving an indeterminate score to about 7%. So pretty significant improvement there. We're still working on publishing some of our real world evidence data that we will be presenting at AAIC this summer, which means it's actually still embargoed, so I can't speak to that yet. It is very exciting. But what I can say is that we looked at the distribution of high, indeterminate and low likelihood scores across over 4,000 samples that came through our laboratory from physicians ordering the test all over the nation. And what we found was that the rates of high, indeterminate and low likelihood scores coming from real world use in the clinic were nearly spot on with what we had found in our test cohort for the study.
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That's really interesting, both that the model aligns so well with what we actually see in real world patient data, and also that adding APOE4 allele count into the mix does improve the indeterminate rate in the likelihood score. Presumably there are several different biomarkers that you could have added to the score to see if it improves. Why specifically focus on APOE 4?
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Well, APOE 4 is the most significant genetic risk factor for late onset Alzheimer's disease. And in fact, those individuals that have APOE4 homozygosity or are carrying two of the APOE4 alleles are actually at a 15 fold risk of developing Alzheimer's disease. In addition to that, with the recent approval of the disease modifying therapies, lecanemab and Donanemab on the label and in the trials for those drugs, there was assessment of risk for something called aria, which, which is amyloid related imaging abnormalities, which is a side effect of the drug that was documented. I won't get into that too much, but essentially APOE 4 status was considered to be a risk for developing ARIA on those drugs. So when qualifying for or being put on those drugs, APOE4 status is something that the clinician needs to know.
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Yeah, that makes a lot of sense. Understanding that genetic risk factors really complete the picture for Alzheimer's disease pathology. So let's move from specifically talking about the biomarkers back to what a PCP might actually be seeing in clinic. If we look at the workflow right from the beginning, when a patient presents with cognitive impairment, how should a healthcare professional approach that workup? And how do they balance running these advanced tests for Alzheimer's disease against looking at other potential culprits that might be causing the decline?
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Yeah, so for the pcp, it's important to first really assess whether a patient presenting to them with cognitive issues could have reversible causes of cognitive impairment, such as hormonal or nutrient imbalances or deficiencies, or other causes like major depressive disorder or possibly even medication induced cognitive issues. I know I've gone through significant periods of stress and even had declines in mental health that could very closely mimic some of the cognitive issues seen in individuals with dementia. And I would be considered very low risk for AD or other neurodegenerative causes of dementia. So we call these secondary causes of cognitive impairment and have developed tests to help streamline the provider's differential and rule these in or out. Now, if the provider is able to rule out secondary causes of cognitive impairment, then it's important to consider whether they may be at risk or would be an individual with high clinical suspicion of having Alzheimer's disease. And they do this by assessing the patient's age and medical history, evaluating the patient's blood for biomarkers indicative of AD like we were just talking about, and of course, assessing their cognitive function in the clinic with a neurocognitive examination like an MMSE test or an oca. So if the cognitive exam suggests impairment, that meets the thresholds for MCI or dementia. And of course, if the biomarkers agree, this should ultimately prompt the provider to refer to a neurologist for further evaluation and hopefully possibly treatment. Now, for those who are comfortable with this space and the developments that have been ongoing with the blood based testing for ad, it's also possible to combine and streamline this process by including an AD rule out test such as the recently FDA cleared P Tau181 blood test while they're still exploring the secondary causes of cognitive impairment. Now, as I mentioned earlier, there can be significant overlap in the clinical presentation of two diseases with very different etiologies. This is why evaluating biomarkers in a patient's blood can really help tease apart what's going on in the patient's brain and help direct a patient toward precise treatments targeted towards their specific disease pathology. In other words, we're essentially entering into an era of precision and personalized medicine. I don't want to be reductionist and paint a picture that everything is clear cut mixed dementia, including vascular contributions and comorbid conditions. It's ever present in these populations and the PCP and neurologists alike, they should really still consider all possible contributing factors before moving forward. I'd also like to take a moment to ensure that the audience understands that regardless of my excitement and the groundbreaking work being done with the concerted efforts across multiple industries, dementia and neurodegenerative disease is still extremely complicated and difficult. While we're working diligently, tirelessly even, there is a lot that we don't know and a lot that we still need to understand before we can develop a patient journey that is as simple as we would like it to be. But we're making great strides in that direction.
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Very true, ever evolving field. But I really think that was a fantastic framework for providing a complete and streamlined patient care approach for the primary care setting. And to summarize, PCPs can rule out reversible secondary causes of cognitive impairment with the option of simultaneously running the FDA cleared P Tau181 blood test and potentially a neurocognitive exam to screen for early risk. If those initial results or clinical suspicion point toward Alzheimer's disease, they can then follow up with a more comprehensive panel like the Amyloid Beta 4240 in the P Tau 217 ratio, with the option of adding the APOE testing into that panel or refer that patient directly to a specialist. So as we wrap up today, what are some key final takeaways that you want our listeners to walk away with?
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You know, as our understanding of AD matures, it's becoming more evident that early identification and intervention is absolutely critical in modifying the course of the disease progression. So this is why we're working to develop and launch blood based biomarker tests that make it easier to evaluate and track a patient's brain health. Increasing wait times for appointments with specialists is providing impetus for PCBs to become more vital in the early steps of the patient journey. PCPs are on the front lines of that effort, meaning that the fighting AD starts before a patient even sets foot in a neurologist's office. Really, the first provider to hear reports of worrisome cognitive issues from a patient, and often reports from loved ones, is usually the pcp. So they are the first touch point for the patient's journey when cognitive issues really begin. In addition, there are various risk factors associated with the development of AD that the PCP identifies and manages, including diabetes, cardiovascular disease, and even components of a patient's lifestyle. So overall, I think it's important that providers understand that precision medicine is coming, which ultimately means that the individual patient will likely end up with a tailored and customized treatment based on their specific pathological profiles, which we get by heavily integrating biomarkers into clinical practice. It's an exciting time, really.
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Yeah, it really is. Thank you so much for coming on and discussing this with me. It's been a great conversation.
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Yeah, it's been my pleasure. I'm really excited to see where we are in five years, as I remember where we were five years ago, and there's been a lot of progress. You know, it's a very formative time for both the patients and providers alike, and I'm grateful to have a front row seat to watch it all unfold.
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That's a wrap on this episode of Healthier World with Quest Diagnostics. Please follow us on your favorite podcast app and be sure to check out Quest Diagnostics Clinical Education center for more resources, including educational webinars and research publications. Thank you for joining us today as we work to create a healthier world, one life at a time.