The Evolving and Emerging Role of Plasma Biomarkers in Diagnosing and Monitoring Alzheimer Disease

Inge Verberk, PhD

Over the past few decades, the understanding of Alzheimer disease (AD) has shifted from a symptomatic focus to a biologically driven framework. Previously, AD was diagnosed based on observable symptoms like memory loss, often confirmed post-mortem through amyloid plaques and tau tangles. However, advancements in biomarker research have introduced objective indicators that track the underlying disease processes, such as amyloid-ß (Aß) accumulation and tau protein phosphorylation, detected through methods like cerebrospinal fluid analysis and brain imaging. These biomarkers have revolutionized our ability to diagnose and monitor AD in its early stages, even before symptoms appear.

At the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, plasma biomarkers were once again a prevalent topic, with several presentations focusing on the evolution and application of these emerging indicators. Inge Verberk, PhD, a research associate at the Amsterdam University Medical Center, sat down with NeurologyLive^® during the meeting, addressing several key questions surrounding the use of plasma biomarkers in AD research and clinical practice.

In the interview, Verberk discussed the potential of emerging biomarkers, such as p-tau 217, and the challenges in translating research findings into clinical settings. She also highlighted the importance of standardization in testing methods and the need for further studies to address factors like pre-analytic handling and comorbidities. Additionally, Verberk touched on the complexities of interpreting biomarker results and the importance of understanding when and how these biomarkers should be used in clinical practice.

NeurologyLive: Which are the most prominent biomarkers currently available?

Inge Verberk, PhD: A lot of attention is going to plasma p-tau217 at the moment. This is a biomarker that shows a huge increase in Alzheimer's disease compared to healthy people or people with other kinds of dementia. This is a very promising biomarker, for example, if you want to select patients for eligibility for treatments. It's a very promising biomarker. If you measure plasma p-tau217 over time, this is also probably predictive of who is going to progress in their disease. But there are also some leads to novel biomarkers that might be able to improve this prediction further. One example that's coming up a lot here at the conference is the MTBR tau protein. There's a plasma assay, very recently published by the group of Randall Bateman et al., and it seems very promising. It's a mass spec technology, so we have some work to do to translate that to amino acids to really make it clinically feasible to use such a biomarker. It seems promising, since it tracks well with tau PET pathology, and tau PET tracks well with clinical symptoms. This might be something that changes along the continuum of Alzheimer's disease.

How do we take plasma biomarkers and translate them from research to clinical settings?

That's a very important topic, and there's a lot of studies and debates about that, well, here at the conference at the AD/PD. What needs to be done is a lot of work on standardization. We need to be able to compare the different immunoassays that are out there, choose the best immunoassay, or maybe there will be multiple immunoassays in the end that we can really use for routine implementation, along with all the regulatory IVD-R certifications that are needed for that. But also, for example, we work a lot on pre-analytics, so understanding if we handle the samples a bit differently prior to the measurements, will that change your plasma levels? We do see that certain steps in this handling process can really impact the levels. That's something to standardize, but also to understand when we shouldn’t maybe use a plasma test. For example, people with chronic kidney disease, you see that levels are different for plasma p-tau 217. That would indicate that if you would test plasma p-tau 217 in such a person, you could likely have a misdiagnosis if you use a threshold. You should also understand when and when we cannot use a plasma test. What to do with patients that have a bit increased levels of p-tau 217, but not as high as to reach the threshold? Are they progressing to Alzheimer disease? Who are those patients in this middle, intermediate group, so to say? There's still a lot to do, but we can be very optimistic, and also just start applying it in routine clinical practice. I know more and more labs and hospitals are starting to do that and also just see in the real world, how does this marker work?

Are there misconceptions or lesser knowns about plasma biomarkers that the clinical community should be aware of?

For example, those comorbidities, I think, are important. There can also be some assay-related things that we don't fully understand yet. For example, we see occasionally very high p-tau 217 levels that are not explained by kidney dysfunction or by Alzheimer disease if you compare it to, like, a gold standard, like CSF or PET. There are still things that we don’t understand. Every test has false positives and false negatives, even a pregnancy test can have that. There are still a lot of things to understand. What we mainly would like to understand first, before we really roll it out all over a country, is, for example, how is the positive predictive value or how is the a priori risk of having Alzheimer disease? How does this affect the performance of such a plasma test and the thresholds that we set? For example, if you move to general practitioners' offices, how reliable are the thresholds that we have? More studies are definitely needed to define that before we fully trust them.

Do you feel as though it is necessary to see a correlation between biomarkers and clinical outcomes, and should that kind of be the standard going forward for all clinical trials within Alzheimer disease?

I do believe so. If you're treating a biological disease, you should have a biological readout. You should be able to understand if something's happening with the biology, and that can inform on, well, maybe how the disease will progress if you remove some sort of pathology. It makes a lot of sense to have biological readouts also. The clinical readouts are maybe still a bit too crude. I know there's also development ongoing, for example, in digital clinical readouts. Once those get improved and become more sensitive to change, maybe that should also go hand in hand. Biology changes first. Pathology or a disease is there that causes the symptoms. If you are able to modify the disease course, you should, in theory, be able to modify the clinical course also. Biology comes first.

Are there any ways we can get more creative with AD clinical trials?

An important or interesting topic is that there's a lot of heterogeneity within Alzheimer's disease also, and now that with clinical trials, we are starting to target different kinds of targets. I also think it's important to look at what kind of patient you have. A big part of Alzheimer's Center research is also on defining AD subtypes. The work of Betty Tijms and Peter Fischer has identified really distinct clinical or biological subtypes of Alzheimer's disease. Starting from biology, if you have a different kind of mechanism that’s more present in your patient, maybe a different kind of treatment would be more optimal? Maybe that also helps in understanding how quickly this patient would progress and also fine-tuning the clinical readouts that you have. If you know my patient progresses really quickly and that one goes a bit slower, maybe that's not what you would see on a group level. If you have slow and fast progressors, and then you even it out, more or less.

Are there any therapeutic mechanisms we should be paying more attention to?

I'm not sure if I should be sitting in the chair of really the fundamental researchers here that are working on those treatments. The disease is multifactorial. Focusing on synapses, focusing on, I mean, all the aspects, I guess. I can imagine that at a certain point, we just need a cocktail of therapeutics that target together to complete Alzheimer's disease, and not only amyloid or only tau.

Transcript edited for clarity. Click here for more AD/PD 2025 coverage.