AI-guided patient stratification improves outcomes and efficiency in the AMARANTH Alzheimer’s Disease clinical trial

Delshad Vaghari, Gayathri Mohankumar, Keith Tan, Andrew Lowe, Craig Shering, Peter Tino and Zoe Kourtzi ()
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Delshad Vaghari: University of Cambridge
Gayathri Mohankumar: AstraZeneca
Keith Tan: AstraZeneca
Andrew Lowe: AstraZeneca
Craig Shering: AstraZeneca
Peter Tino: University of Birmingham
Zoe Kourtzi: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Alzheimer’s Disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, we demonstrate that our robust and interpretable AI-guided tool (predictive prognostic model, PPM) enhances precision in patient stratification, improving outcomes and decreasing sample size for a AD clinical trial. The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite reducing β-amyloid. Employing the PPM, we re-stratify patients precisely using baseline data and demonstrate significant treatment effects; that is, 46% slowing of cognitive decline for slow progressive patients at earlier stages of neurodegeneration. In contrast, rapid progressive patients did not show significant change in cognitive outcomes. Our results provide evidence for AI-guided patient stratification that is more precise than standard patient selection approaches (e.g. β-amyloid positivity) and has strong potential to enhance efficiency and efficacy of future AD trials.

Date: 2025
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DOI: 10.1038/s41467-025-61355-3

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