NeuroVoices: Nicholas Ashton, PhD, on Advances and Challenges in Alzheimer Disease Biomarkers

Blood-based biomarkers, including plasma phosphorylated tau (p-tau) species and neurofilament light chain, have emerged as reliable indicators of Alzheimer disease (AD) pathology and neurodegeneration.¹ Traditionally, these assays have relied on venipuncture, requiring in-person blood draws, which may limit accessibility for some patients. Capillary blood, collected either as plasma or dried blood spots, has been proposed as a minimally invasive alternative that could enable remote or more frequent sampling, with potential utility for clinical trial prescreening.

A study presented at the recently concluded 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-4, 2025, in San Diego, California, evaluated the performance of 4 capillary blood collection devices for measuring p-tau217 in AD.¹ Conducted by coauthor Nicholas Ashton, PhD, senior director of the Fluid Biomarker Program at Banner Health, and colleagues, the analysis assessed reliability of blood collection, precision of repeated capillary measurements, correlation with venipuncture-derived p-tau217 concentrations, and the ability to distinguish healthy donors from patients with AD. Overall, the results offered practical guidance for implementing capillary blood collection in both clinical trial screening and clinical care.

In a new iteration of NeuroVoices, Ashton reflected on key presentations from CTAD 2025, focusing on AD therapeutics and biomarkers. He noted emerging data on next-generation disease-modifying drugs, including those with improved blood–brain barrier penetration and new administration methods. Beyond amyloid-targeting therapies, he highlighted GLP-1 studies and biomarker findings that may inform future trials. Throughout the conversation, Ashton emphasized the central role of blood and fluid biomarkers in both early-phase and larger clinical studies. Looking ahead, he noted that he expects expanded blood test options, tau- and co-pathology-focused biomarkers, and tools to better guide therapeutic development.

NeurologyLive: What was your reaction to some of the presentations at CTAD 2025 in terms of AD biomarkers?

Nicholas Ashton, PhD: CTAD is a clinical trials conference, predominantly. This has been an exciting space in the AD field, where we’ve had FDA-approved disease-modifying treatments approved in the last few years. Now we’re starting to see more versions of these similar types of drugs, better at crossing the blood–brain barrier. There was more data on trontinemab —how that performs, how that works.

We also got some insights into therapeutics outside of the amyloid hypothesis. Looking at these GLP-1 results, topline results on those, which didn’t look so promising, but biomarker changes which may provide some avenue for additional studies in there, and some information about how they work and what’s the hypothesis around why they would work outside this disease.

A lot of enthusiasm around the current drugs that we have approved—how do they work in the real world, off-label in patients, new versions of these drugs coming in subcutaneous administration rather than these biweekly infusions or monthly infusions. What was important and exciting, from my perspective, is that fluid biomarkers, and particularly blood biomarkers, almost played a central role in all these trials, whether it was early-phase trials or these larger phase 3 studies looking at biomarker changes—were they positive, negative, using them for recruitment.

This was a really exciting time for us, where we wanted to be with these biomarkers making us understand what’s happening with our therapeutics. Some of these are approved for clinical use, some of these blood tests, but now we’re trusting them and using them to inform our therapeutic discoveries and drivers.

Can you expand the implications of these AD biomarkers for clinical care?

One of the most talked-about studies was right on the first day, which is more of a real-world evaluation of how this FDA-cleared test from Fujirebio—this p-tau217 over Aβ42 ratio—how that was performing. I think the takeaway from that was maybe a negative one. I would be a little bit more optimistic.

It didn’t prove that the test didn’t work. What it showed is that the cutoffs suggested were not translatable across cohorts. That’s what the topline results were. For me, from working in a clinical chemistry lab, that’s not surprising. Most labs develop and validate their own cutoffs, and the standardization and stability of cutoffs come with time, and people suggest similar cutoffs, and that’s where the standardization comes from. But generally, labs develop their own cutoffs. Large clinical labs—that’s the norm here.

I wasn’t overly concerned about that. There was a narrative, and I think a justified narrative, that Aβ42 in plasma is unreliable. For many years, we’ve shown, and others have shown, that it’s very susceptible to pre-analytics. It can change with different therapeutic indications—like sacubitril/valsartan (Entresto) increases Aβ levels in the blood—so it wouldn’t be appropriate for those who are on cardiac failure drugs. There are other concerns around why Aβ is not necessarily an ideal choice.

I would say one thing that was quite concerning is that the cutoff suggested on the FDA-clear label and what the Mayo Clinic suggested would work in their sample were very different. Although I said that people come up with their cutoffs, I mean, they should be relatively similar, but that wasn’t the case.

I wouldn’t be overly disappointed by this report. I think it was to be expected, to be honest. In these early phases, labs should know that they have to do their own cutoffs, and that’s what the medical field does. The fact that they were so different would give me pause for thought.

Where do you see the field moving in 2026, in terms of biomarkers and in general?

I think in 2026 we’re going to have a larger number of options for our blood tests in AD. We’re going to see different tests being cleared for use, and I think that’s really going to help us stabilize the field. We’ll have different choices, and labs will be able to access tests that are more appropriate to their infrastructure. So that drives competition, drives down prices—it’s all going to be very positive.

I think we’ve now started to see the emergence of biomarkers more related to tau tangle pathology. So, this eMTBR-tau243 was featured in a number of presentations, and we’re seeing that. So phospho-tau is generally associated with amyloid pathology, and maybe eMTBR-tau243 more associated with tau pathology. So that’s an exciting avenue.

We also saw some proteomic studies of how we understand other co-pathologies. So TDP-43, α-synuclein—they are big parts in other neurodegenerative disorders but play a huge part in AD as well. Having a way to, in vivo, decide whether someone has α-synuclein or TDP present is very important for our trials and drug development, and I think we’re getting closer to being able to do that.

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REFERENCES
1. Moughadam S, Huber H, Montoliu-Gaya L, et al. Head-to-head comparison of 4 capillary blood sampling devices for measuring p217 tau. Presented at: CTAD 2025; December 1-4; San Diego, CA. Abstract P246.