Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity

Objective To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study. Methods Individuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score >= 24, global Clinical Dementia Rating (CDR) score of 0.5, and >= 1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 +/- 6.7; 44% female; 16.1 +/- 2.7 years of education; 69% APOE epsilon 4 carrier). We simulated a clinical trial by randomly assigning individuals to a "placebo" and "treatment" group and subsequently computed group differences on the CDR-sum of boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale-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 epsilon 4 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 epsilon 4 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