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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
Heidari A, Aghajani M.. medRxiv, 2026-09-29
Topic: Genetics and APOE
Background Studies indicate that the apolipoprotein E (APOE) ε4 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 ε4 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 Alzheimer’s 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 ε4 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 ε4 carrier status was related to disease severity at baseline rather than to the rate of cognitive decline over 80 weeks.
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APA 7th
Heidari, A., & Aghajani, M. (2026). 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. medRxiv. https://doi.org/10.64898/2026.09.27.26364131
Vancouver
Heidari A, Aghajani M. 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. medRxiv. 2026. doi:10.64898/2026.09.27.26364131.
BibTeX
@article{heidari2026-8aa9046f,
author = {Heidari, A. and Aghajani, M.},
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}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.09.27.26364131},
url = {https://doi.org/10.64898/2026.09.27.26364131}
}
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Key findings
- Background Studies indicate that the apolipoprotein E (APOE) ε4 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 ε4 carriers experience more rapid cognitive decline over time compared to non-carriers.
- Results Over 80 weeks, ADAS-Cog14 worsened by an average of 7.01 points.
- Carriers had worse ADAS-Cog14 scores overall, but this difference was no longer significant after adjustment for baseline CDR-SB.
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Study details
- Study designclinical trial
- Participants370
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 32 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 20 of the 62 points we could judge it on, which is 32 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | Design recorded as “clinical trial”, which our rubric does not rank (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 2 / 4 | 370 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 20 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 20 of the 62 points we could judge it on is 32 out of 100. |
| Total | 32 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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