Authors
Madia Lozupone, Vittorio Dibello, Rodolfo Sardone, Roberta Zupo, Fabio Castellana, Ilaria Bortone, Luisa Lampignano, Michela Di Matteo, Giuseppe Moramarco, Flora Dellegrazie, Antonio Daniele, Vincenzo Solfrizzi, Francesco Panza
Published in
Expert opinion on emerging drugs. Jun 20, 2026. Epub Jun 20, 2026.
Abstract
The amyloid cascade hypothesis provided a compelling rationale for Alzheimer's disease (AD) drug development, but many amyloid-β (Aβ)-targeted agents failed to show benefit. The present review article evaluated emerging Aβ-directed therapies, focusing on mechanisms, clinical efficacy, safety, and regulatory progress.
The recent approvals of lecanemab and donanemab offered the first convincing evidence that reducing Aβ burden can modestly slow cognitive decline in early AD. Beyond these first-generation monoclonal antibodies, the pipeline includes next-generation antibodies with enhanced brain penetration (trontinemab), therapies designed also for presymptomatic intervention (remternetug tested for secondary prevention), and novel approaches targeting galectin-3 to disrupt Aβ aggregation and neuroinflammation. Active immunotherapies like UB-311 and small molecules such as ALZ-801, avoiding amyloid-related imaging abnormalities (ARIA), broaden the therapeutic horizon with potentially safer and more accessible options, but with no proven efficacy.
Clinical benefits for Aβ-centric therapies are modest, ARIA pose ongoing safety concerns, and high costs coupled with intensive monitoring limit accessibility. Regulators have begun to restrict approval to genetically defined subgroups according to apolipoprotein E genotype, underscoring the need for precision medicine. Therefore, while Aβ-centric therapies are incremental, they represent essential steps toward combination and precision strategies in the treatment of AD.
PMID:
42322185
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.
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