Evaluation of Amyloid Removal as a Surrogate for Cognitive Decline: Pilot Analysis in Individual-Level Data from the A4 Study of Solanezumab

BackgroundAmyloid removal has been used as a surrogate outcome in Alzheimers disease trials, allowing accelerated approval of aducanumab and lecanemab. The A4 (Alzheimers Clinical Trial Consortium A4/LEARN) trials individual-level data supports novel methods to evaluate amyloids validity as a surrogate for cognitive decline. MethodsIn 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 solanezumabs cognitive effect mediated by amyloid reduction. ResultsEach 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 solanezumabs effect on cognition was mediated by amyloid reduction (95% CI: -122%, 208%). DiscussionEstimates 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.