Amyloid status imputed from a multimodal classifier including structural MRI distinguishes progressors from nonprogressors in a mild Alzheimer's disease clinical trial cohort

Abstract

Introduction: Mild-Alzheimer's disease (AD) subjects without significant Aβ pathology represent a confounding finding for clinical trials because they may not progress clinically on the expected trajectory, adding variance into analyses where slowing of progression is being measured.

Methods: A prediction model based on structural magnetic resonance imaging (MRI) in combination with baseline demographics and clinical measurements was used to impute Aβ status of a placebo-treated mild-AD sub-cohort (N = 385) of patients participating in global phase 3 trials. The clinical trajectories of this cohort were evaluated over 18 months duration of the trial, stratified by imputed Aβ status within a mixed-model repeated measures statistical framework.

Results: In the imputed Aβ-positive cohort, both cognitive (ADAS-Cog14 and MMSE) and functional (ADCS-iADL) measures declined more rapidly than in the undifferentiated population.

Discussion: Our results demonstrate imputing Aβ status from MRI scans in mild-AD subjects may be a useful screening tool in global clinical trials if amyloid measurement is not available.

Keywords: ADAS-Cog14; ADCS-iADL; Alzheimer's disease; Aβ pathology; Aβ-positivity; Clinical decline; Florbetapir PET; MMSE; Structural MRI.