Papers

Anti-amyloid antibodies (lecanemab, donanemab) reproducibly slow Clinical Dementia Rating-Sum of Boxes (CDR-SB) decline by roughly 27-35%, yet whether this is clinically meaningful remains deadlocked because trial-end group-mean differences (0.45-0.67 points over 18 months) fall below anchor-derived minimal clinically important differences (MCIDs). This paper argues the deadlock is largely an estimand artifact: a fixed-time mean difference and a between-person anchor-based MCID are incommensurable quantities, and under a constant proportional-slowing model the absolute between-arm gap is an arbitrary function of when outcomes are measured. Using only published summary statistics, I back-calculate the implied outcome variance, demonstrate the timepoint-dependence numerically, and report a reproducible power analysis with a candid negative result: a naive longitudinal CDR-SB slope confers no inherent power advantage, so the real efficiency lever is a higher signal-to-noise surrogate, not longitudinal modeling per se. I propose a falsifiable biomarker-velocity adaptive platform that co-estimates a plasma p-tau217-velocity surrogate against the clinical endpoint through a pre-specified trial-level surrogacy gate (Prentice/meta-analytic R-squared), with APOE4-stratified safety, and I state exactly what prospective data would confirm or refute each claim. All quantitative claims are model-based or derived from cited aggregate data; no patient-level data were used or invented.