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

Abstract

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 ε4 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 ε4 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 ε4 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.

Figure 1. Hypothetical Examples of Potential Effect Sampling Effects on Trial Outcomes

These examples show how random oversampling or undersampling of slow vs fast decliners could affect trial outcomes when rate of cognitive decline is not accounted for during randomization. We depict 2 extreme possible situations of oversampling in order to illustrate the influence of an imbalance between slow and fast decliners compared to a perfect randomization. P = placebo group (reflected by solid line); T = treatment group (reflected by dotted line).

Figure 2. Schematic Overview of Simulation Procedure

CDR-SB = Clinical Dementia Rating scale–sum of boxes; P = placebo group, reflected by solid line; T = treatment group, reflected by dotted line.

Figure 3. Individual Trajectories and Simulated Group Differences for All Outcome Measures in the Total Sample (n = 302)

Left column: Individual trajectories on the Clinical Dementia Rating scale–sum of boxes (CDR-SB) (A), the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-Cog) (C), and the Mini-Mental State Examination (MMSE) (E). Dotted vertical line presents scores at the 18 months time point. Right column: Simulated group differences in change from baseline to month 18 based on the total sample (n = 302) on the CDR-SB (B), ADAS-Cog–13-item version (ADAS-Cog-13) (D), and MMSE (F), including 95% range of effect sizes as indicated by vertical gray lines and effect sizes reported for recent clinical trials as indicated by vertical colored lines (blue = EMERGE; yellow = ENGAGE; green = EXPEDITION-3; orange = DAYBREAK-ALZ; red = IDENTITY-2; magenta = BAPINEUZUMAP).

Figure 4. Individual Trajectories of Decline for Each Outcome Measure After Stratifying on Baseline Risk Factors

Risk factors presented in the different rows for all outcome measures (A = Clinical Dementia Rating scale–sum of boxes [CDR-SB]; B = Alzheimer's Disease Assessment Scale–cognitive subscale [ADAS-Cog-13]; C = Mini-Mental State Examination [MMSE]).

Figure 5. Individual Trajectories and Simulated 18-Month Group Differences for the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) After Stratifying on Risk Factors

Figure 6. Individual Trajectories and Simulated 18-Month Group Differences for the Alzheimer's Disease Assessment Scale–Cognitive Subscale–13-Item Version (ADAS-Cog-13) After Stratifying on Risk Factors

Figure 7. Individual Trajectories and Simulated 18-Month Group Differences for the Mini-Mental State Examination (MMSE) After Stratifying on Risk Factors