NeuroVoices: Alireza Atri, MD, PhD, on Notable CTAD Trial Presentations, EVOKE Data

At the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-4, 2025, in San Diego, researchers and clinicians gathered to discuss the latest advances in Alzheimer disease (AD) therapeutics and biomarkers. Among the highlights were updates from large clinical trials investigating novel approaches to modifying disease progression, as well as emerging data on next-generation amyloid-lowering therapies. These informative sessions offered insights into both the successes and challenges in translating experimental findings into meaningful clinical outcomes for patients with AD.

In a new iteration of NeuroVoices, dementia expert Alireza Atri, MD, PhD, director of the Banner Sun Health Research Institute, shared his perspective on data presented at the conference including from the phase 3 EVOKE (NCT0477396) and EVOKE+ trials (NCT4777409) which relayed insights on the efficacy of oral semaglutide (Ozempic; Novo Nordisk) in early symptomatic AD.¹ He also reflected on other noteworthy presentations from the 2025 CTAD Conference, including promising developments in monoclonal antibody therapies and advances in biomarker research.

Throughout the conversation, Atri provides a detailed yet accessible overview of the current landscape in AD research. He highlighted the nuances of interpreting clinical trial results, the importance of biomarkers in tracking disease progression, and the potential for combination therapies and lifestyle interventions to complement pharmacologic approaches. Overall, his insights offered a snapshot of the evolving strategies researchers are pursuing to better understand and address the complexities of AD.

NeurologyLive: What was your initial reaction to the top-line data of the EVOKE trials, as well as additional studies that were presented at CTAD 2025?

Alireza Atri, MD, PhD: I’ll disclose that I’ve been involved with the EVOKE and EVOKE+ trials from the beginning. I’m on the steering committee for the clinical trial, and I’ve worked as a consultant with Novo Nordisk for a very long time.

It was obviously disappointing. It was a negative trial—very clearly negative. Not a failed trial, but a very clearly negative trial. These were 2 very large programs, almost 4000 patients with early symptomatic AD in the MCI or mild dementia stages, followed for at least 2 years. About 1000 or more of them were also followed for a third year, but the readout was at 2 years. It was the CDR sum of boxes, and that was clearly negative—the curves really overlapped at that 2-year stage.

It was a very well-designed and well-executed trial. You could see that this was not because of variability in administration or implementation. The dropout, for example, was quite low for a trial of that duration. You could see that the error bars over time were not because of measurement error. In these stages, oral semaglutide with a target dose of 14-mg didn’t really show efficacy over placebo.

In the initial top-line data, there were some interesting findings. There was some movement on certain AD-related biomarkers, although, of course, they did not show any clinical effect. There was also some movement in neuroinflammatory biomarkers related to neurodegeneration. I think it’s going to take a bit longer to figure out what that means. There were blood biomarkers, and there was some movement in those as well, although it was a bit puzzling.

This was really very much an AD population—about 13% or so had diabetes. In EVOKE+, the idea was to see if up to 20% of people enrolled could have significant white matter changes or vascular burden, because the hypothesis with the receptor agonist is that it probably has people were really in that category. So, it was disappointing.

The drug was relatively well tolerated considering the adverse effects, which included some loss of appetite and weight loss—generally in the 4% to 6% range. But overall, it was a clearly negative study. One of the questions is: Is this too little, too late? Could a drug that affects neuroinflammation and brain health have an effect if given earlier, when people don’t yet have significant brain pathology, and potentially have a broader profile—not just AD but also vascular changes? That question remains unanswered. As far as this study goes, in this population, I think the answer is pretty clear: it’s a negative trial.

Besides the EVOKE trials and the data presented on those, what other notable presentations did you feel were important to highlight from CTAD 2025?

On the therapeutic side, there was a fair bit of excitement about next-generation amyloid-lowering, plaque-lowering monoclonals. Right now, we have 2 that are fully approved in the U.S.—lecanemab and donanemab—and they’re slowly making their way into clinical practice. There were some presentations on ALZ-Net, the patient registry, which is really important for understanding what really happens in the real world. Maria C. Carrillo, PhD, the chief science officer at the Alzheimer’s Association, along with some of the principal investigators of ALZ-Net, presented that data. We have some learnings from that registry that will accumulate over time.

The next generation of monoclonals—derived from gantenerumab but now integrated into an iron receptor brain shuttle system—showed interesting data from ongoing cohorts. There was very rapid and high amyloid clearance in patients with AD and biomarker-confirmed high centiloid levels in the MCI or mild dementia stages. In 6 months, there was a significant amount of amyloid clearance. That’s really interesting, to be able to remove amyloid that quickly. Along with that, other biomarkers also moved consistently, which was of interest. These studies aren’t designed for efficacy, but they showed some point effect sizes trending in the right direction.

This drug involves monthly infusions, and the theory is that it bypasses some vascular spaces, potentially causing less amyloid-related imaging abnormalities (ARIA). The ARIA rates were very low—on the order of 3% to 6%—with one macrohemorrhage reported previously. There are also infusion-related reactions, with steroids given as part of the protocol. There was a lot of discussion among participants that this is a promising drug, potentially the next generation of amyloid-lowering therapy, with more rapid clearance and hopefully lower adverse effects.

Regarding biomarkers, Suzanne E. Schindler, MD, PhD, presented some data that could help with staging P-tau 217 for amyloid. Although it’s called a P-tau amyloid marker, it’s very sensitive to amyloid, and potentially could help with staging and understanding whether amyloid positivity is driving symptoms. In the biomarker space, there were also several presentations, including one given by Marissa Denger, PhD, and colleagues, showing consistent findings across different platforms. There’s a solid rational basis for hope that we’re moving quickly in biomarker development and translation across next-generation programs.

Of course, there was also a lot of discussion about combination therapies, which will be necessary because co-pathology is common in dementia syndromes—not the exception. AD often coexists with vascular changes, Lewy body changes, or TDP-43 pathology, so we’ll need pathways to address all of those in the future.

What developments do you anticipate in the field of AD research over the next year?

In the next year, I see progress in biomarkers and multiplex biomarkers, including those for TDP-43, alpha-synuclein, and refinement of tau markers. Second-generation tau-PET is still being studied. Plasma biomarkers are very important, but learning how to interpret and use them effectively will be critical. We have ongoing secondary prevention trials with plaque-lowering monoclonals, both lecanemab and donanemab, which may read out in the next 1 to 2 years.

There’s excitement about moving earlier with combination therapies, vaccines, and secondary prevention. We shouldn’t forget lifestyle interventions, like the worldwide FINGER program and the U.S. POINTER study. These approaches are not mutually exclusive; they’re very important for addressing dementia beyond pharmacologic interventions.

Transcript has been edited for clarity. Click here to view more coverage of CTAD 2025.

REFERENCES
1. Cummings J, Johannsen P, Atri A, et al. evoke and evoke+: Two phase 3 randomised placebo-controlled trials of semaglutide in participants with early-stage Alzheimer’s disease (NCT04777396 and NCT04777409). Presented at: 2025 CTAD Conference; December 1-4; San Diego, CA.