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


Jutten, Roos J. et al. (2021), Finding treatment effects in Alzheimer’s trials in the face of disease progression heterogeneity, Dryad, Dataset,


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 95% ranges of possible effect-sizes at 18 months were broad, e.g. ranging from 0.35 improvement to 0.35 decline on the CDR-SB. Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect-sizes. APOE-e4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability as illustrated by broader 95% effect-size ranges (e.g. ±0.70 points for the CDR-SB).

Conclusions: Individuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a-priori effect-sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.