APOE ε4 Carrier Status and Cognitive Decline in Mild-to-Moderate Alzheimer's Disease: A Linear Mixed-Effects Analysis of the Placebo Arm of EXPEDITION 1

Background: Studies indicate that the apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for Alzheimer's disease (AD), and individuals with this allele are at increased risk of developing AD, there remains debate regarding whether APOE {varepsilon}4 carriers experience more rapid cognitive decline over time compared to non-carriers. This study assessed this question using linear mixed-effects models applied to the placebo arm of EXPEDITION 1, a phase 3 clinical trial evaluating solanezumab in patients with mild-to-moderate Alzheimers disease. Methods: In this study we utilized data from 370 participants in the placebo group of the EXPEDITION 1 trial. After excluding 27 participants with undefined APOE genotype, all models and analyses were applied to the remaining 343 participants (686 ADAS-Cog14 observations) to determine whether APOE {varepsilon}4 carriers exhibit a faster rate of decline over the 80-week follow-up period. Five nested linear mixed-effects models with a participant-specific random intercept were fitted, and also a complementary change-score analysis was done. Results: Over 80 weeks, ADAS-Cog14 worsened by an average of 7.01 points. Carriers did not decline faster than non-carriers (additional decline 1.31 points; 95% CI -1.22 to 3.83; p = 0.310), and the change-score analysis showed the same pattern. Carriers had worse ADAS-Cog14 scores overall, but this difference was no longer significant after adjustment for baseline CDR-SB. Conclusion: In this cohort, APOE {varepsilon}4 carrier status was related to disease severity at baseline rather than to the rate of cognitive decline over 80 weeks.