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
- 1Faculty of Agricultural and Food Sciences, University of Milan, Milan, Italy
Abstract
BackgroundStudies indicate that the apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for Alzheimers 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.
MethodsIn 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.
ResultsOver 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.
ConclusionIn 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.
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BibTeX
@misc{heidari2026apoe,
title = {{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}},
author = {A. Heidari and M. Aghajani},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.27.26364131},
url = {https://www.medrxiv.org/content/10.64898/2026.09.27.26364131v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - 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
AU - A. Heidari
AU - M. Aghajani
PY - 2026
DA - 2026/09/27
PB - medRxiv
DO - 10.64898/2026.09.27.26364131
UR - https://www.medrxiv.org/content/10.64898/2026.09.27.26364131v1
AB - BackgroundStudies indicate that the apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for Alzheimers 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. MethodsIn 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. ResultsOver 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. ConclusionIn 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.
ER -