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 (Aβ) 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 Aβ status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aβ levels (Aβ-, n=2,824) and those with pathological Aβ levels (Aβ+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aβ1-42.

MEASUREMENTS

Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aβ groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aβ 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. Aβ+ participants performed worse versus Aβ- participants on all cognitive composites though the magnitude of the Aβ effect was generally small. The Aβ+/- 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 Aβ+/- effect sizes.

CONCLUSIONS

Cross-sectional relationships between Aβ and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aβ+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aβ status cross-sectionally cannot be generalized to sensitivity to change over time.

Déclaration de conflit d'intérêts

Kathryn V. Papp has received funding from the Alzheimer’s Association and the National Institute of Health. She has served a paid consultant for Biogen Idec and Digital Cognition Technologies. Christopher Randolph receives a small royalty for Repeatable Battery for the Assessment of Neuropsychological Status. Ellen Grober receives a small royalty for the commercial use of the Free and Cued Selective Reminding test. Hany Rofael and Gerald Novak are employees of Janssen Research and Development and may own stock/stock options in Johnson and Johnson. Michael Donohue is married to an employee of Janssen Research and Development who may own stock/stock options in Johnson and Johnson; and has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai. Karin Ernstrom has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai. Rema Raman has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai. Shunran Wang has received research funding from the National Institutes of Health and Eisai. Reisa Sperling has received research funding from Janssen, and has served as a consultant to AC Immune, Biogen, Eisai, Janssen, Roche, and Takeda. H Robert Brashear, Gary Romano, and David Henley were employed by Janssen Research and Development during the time the study was conducted and may own stock/stock options in Johnson and Johnson. Amy E. Veroff is a consultant neuropsychologist to Janssen Research and Development and receives a small royalty for commercial use of some FCSRT materials.