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Join us for an enlightening discussion with neurologist Amy E. Sanders as we explore the evolution of biomarkers in diagnosing and monitoring Alzheimer’s disease and other dementias. We’ll delve into the significance of blood-based biomarkers, their potential to revolutionize early detection and treatment, and the challenges of integrating these advancements into clinical practice. Discover how these innovative tools are transforming dementia care, offering hope for earlier intervention and more precise prognoses.
Amy E. Sanders is a neurologist.
She discusses the KevinMD article, “How biomarkers are advancing dementia detection and care.”
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Transcript
Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today, we welcome Amy Sanders. She’s a neurologist, and today’s KevinMD article is “How Biomarkers Are Advancing Dementia Detection and Care.” Amy, welcome to the show.
Amy Sanders: Thank you so much, Kevin. It’s my pleasure to be here.
Kevin Pho: So let’s start by briefly sharing your story and journey.
Amy Sanders: Well, my story is actually a bit unusual because when I finished college, I didn’t go to medical school. I went to graduate school at Columbia University and was going to be a historian of modern Western Europe. I got as far as passing my orals, but when I had to become sort of self-sustaining, it became harder and harder for me to convince myself that people would really, really be interested in how Otto von Bismarck used the Prussian railway system as a way to begin unifying Germany.
It’s a really good dissertation topic, and I hope somebody writes it someday, but it was not for me. When I first went to college, I had been pre-med, but I had been very, very, very bad at it. When you get a D in organic chemistry and another one in calculus, they don’t let you go to medical school. So, I became a history major and went to graduate school in history, but I couldn’t sustain it.
Then I had to have a very, very long think about what I was going to be when I grew up. I was in my thirties by this time, and I decided to go full circle. Columbia had a post-baccalaureate pre-medical program, and they let me do that. I got one medical school to accept me, and that was all it took. When I went to medical school, I knew that I was going to be some kind of doctor from the neck down, and I was not going to be ENT—no offense to ENT practitioners out there; it just wasn’t my scene. Neck anatomy is so complicated and way over my head.
So, it was either going to be psychiatry or neurology. At that time, I was very captivated by things that were tangible, and neurology has all of those pathways. I just ate that up. But then I wound up becoming sort of the most psychiatrically oriented neurologist you’ve probably ever encountered because my area of specialization in neurology is cognitive decline and dementia. In neurology in general, there’s a big overlap with psychiatry, but I think in my area of neurology, that overlap is perhaps at its most notable. So, that’s sort of my story.
Kevin Pho: All right. You wrote this KevinMD article about how biomarkers are advancing dementia detection and care. For those who didn’t get a chance to read your article, tell us what it’s about.
Amy Sanders: Yes. It is about biomarkers, which have been around for a very long time in dementia. I’m currently working for a telemedicine dementia practice called Sunday Health, based out of Washington, D.C., and in that area. We see patients—older adults—with cognitive decline and dementia. That’s how I’ve always practiced, mostly in academic medicine until recently. Now, I work for a startup, but the issues are the same.
For most of my career, and I began practicing in 2008, dementia neurology was kind of this quiet little backwater. We didn’t have disease-modifying treatments, and we looked jealously at multiple sclerosis because they had all these disease-modifying treatments. We didn’t have great biomarkers that we could use to track disease. So, we were jealous of the epileptologists who had a lot of medications. We just didn’t have much. We had counseling—that’s pretty much what we had.
Now things are completely different. We have disease-modifying treatments—the initial ones—and we have biomarkers that now, and this is what’s so exciting, are going to become less expensive and more accessible. A biomarker just means some sort of biological entity that we use to measure physiological activity in the body. Every time you go to your doctor’s office, they take your blood pressure. Well, that’s a kind of biomarker. They may check your hemoglobin A1C, the famous test that assesses how sugary one’s red blood cells have been for the past three months—that’s also a biomarker.
In dementia, for a long time, codified in the 2001 American Academy of Neurology practice parameter for evaluating older adults with cognitive impairment, we’ve always been instructed to check some basic screening labs: a vitamin B12 level—too high, not a problem; too low, it can cause all kinds of mischief, including cognitive impairment—and thyroid function. Too much thyroid makes people very anxious and jittery. Too little thyroid can cause cognitive impairment.
We’ve done that for ages, but what does that do? It tells us there’s no metabolic issue that we could ameliorate to make things maybe a little better, but it didn’t tell us anything about the diagnostic processes that were going on.
Amy Sanders: For a long time, we have had PET imaging that can look at both amyloid and tau. It can see them both. Amyloid is now minimally clinically available—you have to sign your patient up in a registry to get an amyloid PET. Tau PET is still in the purview of research. CSF examination for biomarkers has been around for a long time, but it requires people to have a lumbar puncture, and that’s typically now done in the interventional radiology suite. So, they also get a hefty dose of ionizing radiation.
Wouldn’t it be better if people could just go and have a blood test? That is now what we have—sort of. We’re in the nascent phase of this, but we can now check to see if people have genetic markers that increase their vulnerability to developing Alzheimer’s disease. We can check to see if there’s a clinical hint that they are depositing abnormal amyloid protein into their brain tissue because that amyloid protein is less visible in the peripheral circulation.
We can do a blood test to check for the ratio of abnormal to normal amyloid protein. When that ratio drops, we think it means that people are depositing amyloid protein into their brains. We can also check for several different isoforms of phosphorylated tau protein. These tests are frequently referred to online—in the digital wild west of the internet—as diagnostic tests. That’s a bit of a misnomer. They certainly help clarify my diagnostic thinking, but they are not per se diagnostic—or at least, we don’t yet understand them well enough for them to be per se diagnostic.
What they do provide is a much more precise picture of what is going on. For example, if somebody has elevated levels of both p-tau 217 and p-tau 181—those are the ones most commonly checked these days—it probably indicates there is also amyloid pathology going on. Additionally, we now have tests to assess whether there is neurodegeneration.
For example, I recently saw a gentleman who I believe has vascular dementia. I sent him off to have all of these labs drawn because if they come back essentially negative, that will reinforce my clinical thinking that he has vascular dementia—which, by the way, is the only non-neurodegenerative dementia. I expect, for example, that his level of neurofilament light chain, a general marker of neurodegeneration, will come back as normal.
Biomarkers are incredibly exciting because they increase the precision of our diagnostic thinking, and they are becoming much more accessible and less expensive. As they say, all boats rise.
Kevin Pho: Now, as a neurologist, what are the clinical scenarios that would make you order some of these blood-based biomarkers? Let’s say I, as a primary care physician, send someone to you who I think may have Alzheimer’s dementia. Once that patient is in front of you, where do these blood-based biomarkers enter the diagnostic approach in your mind?
Amy Sanders: That’s an incredibly important question. Thank you so much for asking it. The Alzheimer’s-specific biomarkers really should not be used in a screening fashion. The current thinking, and my thinking as well, is that specialists like me are the ones who should be ordering these biomarkers.
There is a school of thought suggesting that internists or primary care physicians like you could also order them, but they should not be used as a screening tool. Instead, they should be used once there is some evidence that somebody has cognitive impairment. At that point, you can use the biomarkers to confirm your diagnostic thinking—if the profile comes back with an Alzheimer’s-like appearance—or to rule out a possible Alzheimer’s process, which can be equally important.
It’s also worth noting that these tests are not yet accepted as sufficient evidence to establish eligibility for one of the disease-modifying treatments. For that, one would likely still need a confirmatory head scan or CSF analysis with a lumbar puncture. However, beginning with blood tests is certainly more accessible and less expensive.
Kevin Pho: As a neurologist, would you say you need a clinical diagnosis of some type of neurodegenerative dementia before using these biomarkers?
Amy Sanders: I would say I need a clinical suspicion that I want to work up.
Kevin Pho: If these blood-based biomarkers come back positive, what would your next step be, given the positive result and your clinical suspicion of a neurodegenerative source of dementia?
Amy Sanders: There are several pathways forward once I get a positive biomarker result, and much of it depends on the patient. The patient is always the most important person in the room, and the decision-making should be a shared process.
If the patient appears to have mild cognitive impairment due to underlying Alzheimer’s pathology or is in the mild stages of Alzheimer’s disease, they would preliminarily, at least on the surface, be eligible for monoclonal antibody therapy. These new disease-modifying therapies are very exciting. However, the blood-based biomarkers would be suggestive but not sufficient for eligibility in most places.
In most cases, one would still need a confirmatory amyloid PET scan or lumbar puncture. If those confirmatory tests also rule them in, then they would be eligible for monoclonal antibody therapy. On the other hand, if the patient isn’t interested in pursuing treatment—and I’ve had only one patient so far emerge as possibly interested—the counseling I can provide becomes much more precise.
For example, I can say, “Yes, I think this is Alzheimer’s disease based on your clinical history, your clinical profile, and the results of your neuropsychological testing.” The biomarker analysis bolsters my clinical impression. Being able to provide tangible information gives patients a sense of control and helps them adjust to their new diagnostic situation.
Kevin Pho: How accessible are these tests? Is this something you can order at most labs?
Amy Sanders: Yes, Quest has all of the labs that I would typically order available. You sort of order them à la carte. LabCorp actually has something they call the ATN profile. A stands for amyloid, T stands for tau, and N stands for neurodegeneration. I believe you can order the ATN profile at LabCorp.
As it happens, I usually order them piecemeal, à la carte. These tests are now widely available, but I don’t believe they are on the menus of tests that you can just walk into a Quest or a LabCorp and request. They have to be ordered by a physician.
Kevin Pho: You mentioned several blood-based biomarkers, such as phosphorylated tau. How many biomarkers are we talking about? Do they point to different forms of neurodegenerative dementia, or how do they differ in what they measure?
Amy Sanders: You can think of them in a few different categories, or “buckets.” First, there’s a genetic test we now often run. For most of my career, the teaching was not to check someone’s apolipoprotein E (APOE) status because, if it came back showing increased risk, we didn’t have anything to offer them. Now, we do have things to offer, so that test is being run much more frequently. That’s a genetic marker.
Next, there’s the amyloid ratio, which provides an indirect assessment of amyloid. It looks in the peripheral circulation to infer what’s happening in the brain. This ratio, Aβ42 to Aβ40, was actually the first blood-based biomarker I had regular access to—it’s been around for nearly two years.
Then, there’s phosphorylated tau, or p-tau. The “p” stands for phosphorylated, and we look at isoforms such as p-tau 181 and p-tau 217. These biomarkers measure forms of tau protein. Phosphorylated tau is at the center of the famous neurofibrillary tangles in Alzheimer’s disease. These tests give us a sense of whether active Alzheimer pathology is happening.
Amyloid is an extracellular biomarker, while tau tends to be intracellular, so it’s a bit trickier. That’s why I prefer to have two values when assessing tau.
Finally, there are two additional markers: glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL). GFAP, which is a marker of inflammation, is actually a better biomarker in plasma than in CSF. It can indicate that something is starting to happen. NFL, or neurofilament light chain, is a general marker of neurodegeneration.
So, when I’m trying to determine whether this is an underlying Alzheimer pathology, that’s the suite of biomarkers I typically run. This field is evolving rapidly, though, and biomarkers for other neurodegenerative conditions are slowly emerging. For example, we can now perform skin biopsies to detect certain types of Parkinsonian syndromes. There’s a lot of activity in this area, and neurology is no longer a dusty backwater—it’s like downtown Midtown Manhattan these days.
Kevin Pho: Do you see a future where some of these biomarkers might be used more in a screening setting? Is that on the horizon?
Amy Sanders: That’s a good question, and the short and truest answer is, “I don’t know.” I suspect that eventually, we might have the equivalent of a hemoglobin A1C—a biomarker that indicates the earliest possible sign that something is happening. We don’t yet know which of the existing markers that might turn out to be, but I think it’s an entirely likely scenario in the future.
Kevin Pho: As a primary care physician, if a patient comes to me after reading about these biomarkers—perhaps in The New York Times—and wants me to order these tests, how should I respond? What questions should I ask next?
Amy Sanders: That’s a great question. I would first ask whether the patient has any symptoms. If there are symptoms, we need to examine those before making decisions about biomarker testing. Next, ask about family history. A profound family history might warrant a different conversation. For instance, you might at least check their APOE status, though you probably wouldn’t proceed with the other biomarkers at this point.
That said, I’ve had patients come in and say, “I’d like you to run my ATN profile.” I was shocked the first time that happened—someone knew the lingo months ago! In her case, we eventually did order a workup.
If you’re in primary care, it’s a good idea to have a cognitive neurologist—or someone experienced with these biomarkers—on hand for consultation. We’re all still learning how to interpret these markers, and having access to an expert can make a big difference.
Kevin Pho: Just to be clear, as of today—November 2024—you don’t see a role for these blood-based biomarkers to be used in most primary care settings. Is that fair to say?
Amy Sanders: That is fair to say—it’s my opinion. You could ask someone else, and they might have a different perspective. There are definitely two schools of thought on this topic.
Kevin Pho: We’re talking to Amy Sanders. She’s a neurologist, and today’s KevinMD article is “How Biomarkers Are Advancing Dementia Detection and Care.” Amy, let’s end with some of your take-home messages for the KevinMD audience.
Amy Sanders: Sure. If you’re a clinical practitioner who sees older adults with cognitive impairment, know that these biomarkers are out there. They can help you, but you may want to access the services of an expert to guide you as you begin to experiment and learn about them.
For everyone listening, I cannot stress enough how important brain health is. Yes, it’s great that we now have disease-modifying therapies and biomarkers—blood-based and otherwise—but there is so much you, as an individual, can do to protect your brain.
You get EKGs and echocardiograms for your cardiovascular health. You get colonoscopies. For the love of all that is holy, please get a good brain health examination. Talk to your physician about how best to protect your brain. We know a lot about brain health, but as a profession, medicine has not yet done enough to raise awareness about it. So, I’ll plant the seed: please, get your brain health examined.
Kevin Pho: Amy, thank you so much for sharing your perspective and insight. And thanks again for coming on the show.
Amy Sanders: My pleasure. Thank you for having me.
