Finding treatment effects in Alzheimer’s trials in the face of disease progression heterogeneity

Objective: To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer’s disease (AD) trials, using a simulation study. Methods: Individuals with an abnormal amyloid PET scan, diagnosis of MCI or dementia, baseline MMSE ≥ 24, global CDR of 0.5, and ≥ 1 follow-up cognitive assessment were selected from the ADNI database (N=302, age 73±6.7; 44% female; 16.1±2.7 years of education; 69% APOE-e4 carrier). We simulated a clinical trial by randomly assigning individuals to a ‘placebo’ and ‘treatment’ group and subsequently computed group differences on the CDR-SB, ADAS-Cog-13 and MMSE after 18 months follow-up. We repeated this simulation 10.000 times to determine the 95% range of effect-sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE-e4 status, CSF total tau levels) on the variability in effect-sizes. Results: Individual trajectories on all cognitive outcomes were highly variable, and the 9...