Challenges and opportunities for novel combination therapies in Alzheimer's disease: a report from the EU/US CTAD Task Force.

Following the recent approvals of anti-amyloid immunotherapies as "first-in-kind" disease-modifying agents for Alzheimer's disease (AD), there is an emerging emphasis in combination therapies, given the complex and multifactorial etiopathogenesis and pathophysiology of the disease. The EU/US CTAD Task Force met in Madrid in October 2024, to discuss biological rationale and methodological issues and outline potential directions for future research in combination therapies. The Task Force agreed on the necessity and urgency of advancing combination therapies for AD treatment. As of January 1, 2024, in the drug development pipeline, there were 21 combination trials (13 % of all trials). The combination of anti-amyloid and anti-tau therapies could become a central focus of the field. Combinations involving anti-inflammatory and immune mechanisms with anti-amyloid or other therapies also have promise. To facilitate the development and implementation of combination therapies, collaborations between sponsors and public-private partnerships are essential. Optimizing the likelihood of success primarily requires leveraging the use of biomarkers and a clearer understanding of the biological mechanisms underpinning AD and their interactions, especially those involving amyloid, tau, and inflammation, that lead to cognitive decline and progression.