Evaluating emerging amyloid-β centric drugs for the treatment of Alzheimer's disease.

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. Alzheimer’s disease (AD) is a growing global health problem, with no cure currently available. Most existing treatments only relieve symptoms and do not slow the underlying disease process. One of the earliest and most important biological changes in AD is the buildup of amyloid-β (Aβ), a protein that forms plaques in the brain. For this reason, many new drugs have been designed to remove Aβ or prevent it from accumulating. In recent years, several Aβ–targeting therapies have shown that they can successfully reduce amyloid plaques in the brain. These include monoclonal antibodies given by infusion or injection, vaccines that stimulate the immune system, and oral drugs designed to block the formation of toxic Aβ species. Some of these treatments have reached late-stage clinical trials, and a few have received regulatory approval in certain regions. However, while these drugs clearly reduce amyloid levels, their effects on memory and daily functioning are modest, especially when used after symptoms have already appeared. In addition, treatment can be associated with side effects such as brain swelling or small brain bleeds, requiring frequent medical monitoring, costly for healthcare systems. Most evidence so far comes from carefully controlled randomized clinical trials, and real-world experience remains limited. Current research is therefore shifting toward earlier treatment, including prevention in people at high risk, improved drug delivery methods, and combination approaches that also target other disease processes such as tau pathology, inflammation, and vascular or metabolic changes. New blood-based biomarkers are also making it easier to diagnose AD earlier and to select patients more precisely. Overall, Aβ–centered therapies represent an important scientific advance, but they are unlikely to be sufficient on their own. Future progress in AD treatment will depend on better understanding how amyloid may interact with other brain changes, identifying the right patients at the right time, and developing safer, more affordable, and more comprehensive therapeutic strategies.