NeuroVoices: Robert Alexander, MD, on the Evolution of Antiamyloid Therapeutics in Alzheimer Disease

Antiamyloid monoclonal antibodies have recently demonstrated translational potential after years of limited clinical impact among patients with Alzheimer disease (AD). For example, lecanemab (Leqembi; Eisai) received FDA approval in July 2023 and European Medicines Agency (EMA) approval in late 2024 with certain genetic considerations. Donanemab (Kisulna; Eli Lilly) obtained FDA approval in July 2024, followed by EMA marketing authorization in October 2024. Data from clinical studies indicated that these therapies have effectively reduced cerebral amyloid and modestly slowed cognitive decline in those with early-stage, biomarker-confirmed AD.¹

Findings have also shown that these treatments are associated with notable safety concerns, including amyloid-related imaging abnormalities (ARIA). Prior to initiation of the therapy, risk assessments such as APOE genotyping and evaluation for cerebral amyloid angiopathy or cerebral microbleeds, may be recommended for patients. In terms of research and clinical implementation, researchers recommend that current priorities include biomarker-guided patient selection, ARIA-informed care pathways with shared decision-making, and outcome-driven coverage and pricing strategies.¹ Additionally, researchers advocate for clinical trials to assess combination approaches that integrate antiamyloid therapy with interventions targeting tau pathology.

In a new iteration of NeuroVoices, Robert Alexander, MD, the chief scientific officer at the Banner Alzheimer's Institute, spoke about the shifting landscape of AD treatment at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-4, 2025, in San Diego, California. He talked about how clinical trials are exploring reduced-frequency dosing once amyloid is cleared and next-generation antibodies that show promising safety profiles. Alexander noted increasing patient demand for antiamyloid therapies and emphasized the expanding role of biomarkers in identifying the disease early. In addition, he underscored challenges in translating findings from studies into the clinic and the limitations of PET imaging for routine monitoring.

NeurologyLive: From your clinical perspective, what recent clinical trial findings in AD do you find most promising for changing patient care?

Robert Alexander, MD: There's a few. They're maybe not at the level of findings yet, but I think we're seeing more clinical trial designs looking at different regimens once amyloid has been cleared by one of the approved antibodies. We now have lecanemab, given every 2 weeks, and donanemab, given every 4 weeks. But once the amyloid is removed to whatever the target level would be—which I think we're recognizing is even lower than we had originally thought—now people are looking at if they can just give it every 3 months? Can they give it at less frequent intervals? Which I think is going to be a big advantage for patients.

The other thing we're seeing is this new generation of antiamyloid antibodies. We heard at CTAD about trontinemab, which essentially is gantenerumab but attached to a brain shuttle. You have very rapid clearance and what looks to be a remarkably low rate of the brain edema and hemorrhage or ARIA, associated with this first generation of antibodies. I think that's very promising, especially as the field goes earlier and earlier in terms of intervening.

Right now, the drugs are approved for early AD—patients that have symptoms, either mild cognitive impairment or just mild AD symptoms. But there are studies ongoing now to look at patients that have evidence of brain amyloid but don’t have symptoms yet, and of course in that population you want to have a drug that has a very good safety profile.

How are emerging therapies targeting amyloid, tau, or other pathways shaping the way you approach treatment decisions?

We're seeing much greater uptake, at least at my center, in terms of people requesting and receiving the antiamyloid antibodies. It took a little time to put all the safeguards in place and make sure we had the requisite ability to read all the MRIs and all that. It increased demand, obviously. We’re seeing more widespread use of biomarkers, especially plasma, to understand whether people have evidence of brain amyloid. I think with these new studies like TRAILBLAZER-ALZ 3 or AHEAD, that’s going to be transformative if the drugs work because that opens up a whole new population where we can potentially intervene earlier and maybe have more impact.

What challenges or considerations do you see in translating results from cutting-edge trials into everyday clinical practice for AD?

We're pretty good at using biomarkers to say when we should initiate treatment. We’re not so good at using biomarkers to say when we should stop treatment or go to a less frequent treatment regimen. A lot of the phase 3 studies used PET to make that determination like, when was the amyloid removed? And that's an expensive and not really easily scalable thing to do. I mean, you can't have people in clinical practice have multiple PET scans, even 1 PET scan.

So with the plasma-based biomarkers like p-tau217, you can be pretty sure that someone has brain amyloid, and that makes sense to start treatment. But it does decline with treatment, though only about 30% or 40%, so it doesn't really track very closely with amyloid removal. At the moment, we need better biomarkers, or multiplex biomarkers, or some better understanding of how long we need to treat these people and when we can go into the maintenance regimen. So that's certainly one important thing in terms of translating what was done in the clinical trials to clinical practice.

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

REFERENCES
1. Papaliagkas V. Anti-Amyloid Therapies for Alzheimer's Disease: Progress, Pitfalls, and the Path Ahead. Int J Mol Sci. 2025;26(19):9529. Published 2025 Sep 29. doi:10.3390/ijms26199529