At the Alzheimer Congress 2026, speakers outlined a rapidly evolving but uneven therapeutic landscape for Alzheimer’s disease (AD). Antiamyloid immunotherapies remain central to therapeutic research in AD, and other therapies are attracting interest with varying degrees of success.

During a session reviewing data presented at the 2026 Clinical Trials on Alzheimer’s Disease meeting, Mathieu Ceccaldi, MD, PhD, professor of neurology and head of the Department of Neurology and Neuropsychology at Assistance Publique – Hôpitaux de Marseille, Marseille, and Davide Angioni, MD, rheumatologist at Institut Hospitalo Universitaire HealthAge, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France, summarized recent therapeutic advances.

Sustained Benefit

Real-world cohorts from the US, Israel, China, Japan, and South Korea have consistently demonstrated cognitive and functional benefits. The rate of amyloid-related imaging abnormalities appears to be lower in routine clinical practice than in pivotal trials.

Long-term extension data from TRAILBLAZER-ALZ 2 evaluated participants treated with donanemab or placebo during an 18-month double-blind phase, followed by an 18-month open-label extension in which all participants received the drug.

Cognitive decline curves showed that the gap between participants initially treated with donanemab and those treated with placebo continued to widen from 18 to 36 months. Participants who achieved amyloid clearance on imaging during the double-blind phase maintained an amyloid burden below the positivity threshold of 24 Centiloids during the extension phase. Those initially assigned to the placebo group demonstrated a slowing of cognitive decline after switching to active treatment.

Trontinemab Emerges

Trontinemab, an investigational antiamyloid monoclonal antibody (mAb) developed by Roche, has drawn considerable attention.

Updated data from cohorts 3 and 4 of the phase 1b/2a Brainshuttle AD study of trontinemab showed robust amyloid clearance.

At 28 weeks, 92% of participants receiving the highest dose of 3.6 mg/kg fell below the amyloid-positivity threshold of 24 Centiloids. Reductions were also observed in cerebrospinal fluid (CSF) biomarkers associated with amyloid and tau pathologies compared with baseline.

Preliminary exploratory analyses suggested less cognitive decline on the Clinical Dementia Rating Sum of Boxes (CDR-SB) and Mini-Mental State Examination compared with placebo. Hemorrhagic amyloid-related imaging abnormalities occurred in < 5% of the participants, and a single case of edematous amyloid-related imaging abnormalities was reported during the study period. A phase 3 trial is currently underway to assess its clinical efficacy.

Semaglutide Disappoints

Semaglutide, a GLP-1 receptor agonist widely used for obesity and type 2 diabetes, was evaluated for its potential disease-modifying effects on AD. Phase 3 findings did not demonstrate cognitive benefits.

The evoke and evoke+ trials each enrolled 1840 participants with early stages of AD who were positive for amyloid and failed to demonstrate improvement in cognitive decline at 18 months, as measured by the CDR-SB.

Approximately 10% reductions were observed in CSF biomarkers, including tau proteins, the YKL-40 marker of neuroinflammation, total tau, and neurogranin. The safety profile appeared to be consistent with that observed over several years of use of this molecule for other indications.

Anti-Tau Agents

Bepranemab, an investigational humanized immunoglobulin G4 mAb targeting the mid-region of the tau protein, was evaluated in the phase 2 TOGETHER trial involving 460 amyloid-positive participants with prodromal or mild AD. The study did not demonstrate a reduction in cognitive decline at 80 weeks at doses of 45 and 90 mg/kg.

However, bepranemab is the first mAb to reduce tau protein accumulation in patients with AD. In a 40-week open-label extension, preliminary data through week 128 indicated a lower tau burden in participants treated from baseline than in those initially assigned to the placebo. Participants originally in the placebo group demonstrated a slowing of tau accumulation after crossover. The rates of serious adverse events were comparable between the treatment and placebo groups.

Etalanetug, another anti-tau mAb, was evaluated in a phase 1b/2a open-label study of autosomal dominant AD, with a follow-up period of up to 2 years. Reductions in the tau biomarker microtubule-binding region tau243 (MTBR tau243) and extended MTBR tau243 were observed in both CSF and plasma, with CSF reductions of 78% and 90% at 2 years, respectively. Angioni noted that continued monitoring of this candidate is warranted.

This story was translated from Univadis France, part of the Medscape Professional Network.