Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial

Background Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. Objective To evaluate the association between amyloid (A beta) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). Design Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. Setting The EARLY study was conducted at 143 centers across 14 countries. Participants 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with A beta status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological A beta levels (A beta-, n=2,824) and those with pathological A beta levels (A beta+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid A beta(1-42). Measurements Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between A beta groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between A beta status. Results Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. A beta+ participants performed worse versus A beta- participants on all cognitive composites though the magnitude of the A beta effect was generally small. The A beta+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest A beta+/- effect sizes. Conclusions Cross-sectional relationships between A beta and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The A beta+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to A beta status cross-sectionally cannot be generalized to sensitivity to change over time.

Automated summary

Cognitive composites are commonly used in Alzheimer's disease secondary prevention trials. This study found that individuals with A beta+ status performed worse on cognitive composites, but the effect size was generally small. Memory tests and speed of processing exhibited the largest A beta+/- effect sizes.