ArticlemedRxiv : the preprint server for health sciences2025
Evaluation of Amyloid Removal as a Surrogate for Cognitive Decline: Pilot Analysis in Individual-Level Data from the A4 Study of Solanezumab.
Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Amyloid removal has been used as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. The A4 (Alzheimer's Clinical Trial Consortium A4/LEARN) trial's individual-level data supports novel methods to evaluate amyloid's validity as a surrogate for cognitive decline. Methods: In 812 participants, cognitive and functional change was measured using the CDR-SB score. Instrumental-variable analysis estimated the effect of amyloid reduction; mediation analysis quantified solanezumab's cognitive effect mediated by amyloid reduction. Results: Each 10 centiloid reduction due to randomization to treatment was associated with 0.026 higher CDR-SB (95% CI: -0.013, 0.065). 14.6% of solanezumab's effect on cognition was mediated by amyloid reduction (95% CI: -122%, 208%). Discussion: Estimates showing near-zero effects of amyloid reduction on cognitive decline suggest minimal impact of amyloid reduction in populations with little disease progression. Replication in anti-amyloid trials with larger treatment effects could guide treatment and regulatory decisions.
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