Drs McDade and Cohen discuss ATN (amyloid, tau, neurodegeneration) classification and its use in clinical practice to manage Alzheimer’s disease.
Marwan Sabbagh, MD: We’re going to end this segment talking about the ATN [amyloid, tau, neurodegeneration] classification. We started to mention it before. Dr McDade, can you discuss the ATN classification for categories and individuals based on biomarker evidence of pathology? Do you envision it being applied to clinical practice?
Eric McDade, DO: That’s a great question, and it follows up very nicely on what Dr Cohen was just commenting on. I’ll elaborate on that as it relates to the ATN classification. The ATN classification—A is for amyloid, T is for tau, and N is for neurodegeneration—has evolved for a couple of reasons. One is the recognition that we now have the ability to measure the underlying biological components of Alzheimer disease much better than other neurodegenerative diseases. We have to use the tools that we have available.
This has led to a lexicon change in Alzheimer disease, in which we use the ATN criteria to standardize what we’re talking about, particularly starting at research. When we have a group of individuals who we’re diagnosing with Alzheimer disease, we can use these to group them together: this is a group that has amyloid and tau biomarkers that are abnormal; this is a group that has amyloid, tau, and neurodegeneration that are abnormal. Then we can compare those and use those.
It’s led to this biological component of the disease that will eventually lead to the clinical diagnosis, but those 2 are separate in some sense. We recognize that there’s the biological, pathological, mechanistic, and clinical aspect of it. The ATN criteria were developed to also try to stage based on the likelihood of developing symptoms and risk. Essentially, you have a number of combinations with ATN, and you can use those. If somebody’s amyloid-positive only, this helps you know that they’re probably on the Alzheimer pathway, but this is somebody who’s probably far away from symptoms. That becomes increasingly important in the preclinical or presymptomatic stages of the disease. If they’re amyloid plus tau, they’re probably getting closer to having symptoms. If they have the neurodegeneration component, then there’s a high likelihood that they have Alzheimer disease. We can recognize that clinically because they have the full spectrum of biomarkers that are abnormal.
The interesting thing is that this is an evolution, so it will continue to change. It will need to be updated, because the way that it’s conceptualized is that there are multiple ways of measuring each of these. In amyloid, you can measure in the CSF [cerebrospinal fluid], in the plasma, and by PET. These are not interchangeable, and they give us distinct information. That’s led to some confusion early on. Likewise, with the tau, you can measure in the CSF and from plasma, and you have tau PET as well. With neurodegeneration, that typically relates to MRI and measures of atrophy, but also to FDG-PET scans and some other biomarkers, like neurofibrillary light chains, which we’ve been able to measure for a long time. This is conceptualized for the research component, standardizing it across studies. But because you can get CSF, order a tau or a PET scan, and even order some plasma biomarkers in your clinic, this is moving into the clinical space. In the specialty field, we also use these to help give people an informed diagnosis of what’s causing their symptoms.
I can’t emphasize enough, on 1 of the points that you asked about, the plasma. This is revolutionizing what we do and how we think about Alzheimer disease. This will lead to a much more accessible diagnostic test. Eventually, it will make its way into primary care clinics. In the same way, we expect a primary care physician to understand liver enzyme abnormalities, cholesterol levels and how those relate to stroke and heart disease risk, measures of hemoglobin A1C [glycated hemoglobin] and how that relates to pancreatic dysfunction and diabetes. If we get to this point—in all likelihood, we will—this will allow primary care physicians to play a much larger role. They can start that diagnostic pathway with greater confidence once they understand that they can use these biomarkers.
Right now, they’ve been put in these ATN criteria as strong and powerful research tools that are quickly evolving to have clinical implications. Eventually, we’ll be able to use these to measure long-term therapies and all likelihood that we’ll use in the clinic. In the same way, if you start somebody on a statin, for instance, and you had a cholesterol level up, you follow that up and see how they’re responding. It’s likely that we’ll be able to use these same biomarkers to monitor therapies.
Sharon Cohen, MD, FRCPC: Dr McDade, your comments are appropriate. I like your analogies with other areas of medicine, in which family doctors are empowered to diagnose and monitor treatment to different and important things. Because the plasma biomarkers in Alzheimer disease are complicated, we’re still waiting for validation. We need to share the excitement that we have at the specialist level with our colleagues in family medicine and primary care. But we don’t want to give the message that until they have plasma biomarkers, there’s nothing they can do. I know you agree that we need to energize them with what’s coming and how the field is evolving. But there’s a big role they need to play. Some of the confirmatory stuff is in the specialist’s hands. But let’s not let people go undiagnosed or with vague diagnoses.
Eric McDade, DO: In the nonspecialist neurology clinics, this is where these biomarkers will be beyond the specialty clinics. That’s probably the next stage because of their much more intimate understanding of brain disease, CNS disorders, and how we use things like CSF in multiple sclerosis, and they use those and MRIs routinely. It will get there first. We can use that to educate our colleagues who aren’t memory specialists in neurology. That will continue to spread out as we validate these and prove that there’s a role for these in the diagnosis and in monitoring people on long-term therapies.
Sharon Cohen, MD, FRCPC: Even in the shorter term, the plasma biomarkers might come into primary care as a way of narrowing the funnel. Not being diagnostic but helping the primary care practitioner know whom to refer to a specialist because if we open the floodgates, there may be a lot of people to be seen. There is this stepped rhythm that’s going to happen, but it’s exciting.
Transcript edited for clarity