Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice
Amy Christensen, Ana Carolina Valencia‐Olvera, Helena Xeros, Elizabeth T. Nguyen, Marlene Lopez, Rojan Javaheri, Leon M. Tai, Mary Jo LaDu et al.. Biology of Sex Differences, 2026-08-12
Topic: Amyloid, tau and blood-test diagnosis
Abstract Apolipoprotein E ε4 genotype ( APOE4 ), the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), is associated with sexually dimorphic effects whereby higher risks are generally observed in women. Sex differences can arise in part from developmental processes of sexual differentiation, which yield permanent sex-specific phenotypes that can impact adult trajectories and vulnerabilities to various conditions. We investigated the potential contributions of sexual differentiation to the female bias of APOE4 in driving AD pathogenesis. Specifically, using the EFAD transgenic mouse model of AD that includes knock-in of human APOE3 or APOE4 , we examined the effects of experimental masculinization in perinatal female mice on adult patterns of AD-related pathology relative to control male and female mice. Both female sex and APOE4 genotype were associated with increased levels of β-amyloid pathologies. Masculinization resulted in expected systemic and neural phenotypes in adult animals. The effects of masculinization differed depending upon both outcome measure and APOE genotype. Intermediate phenotypes were the most common response to masculinization, though select aspects of AD-related endpoints, including the numbers of mature amyloid plaques, were reduced by masculinization of APOE4 female mice. These findings suggest that sexual differentiation in early life has modest effects on adult development of AD in females, a relationship that appeared stronger in the context of APOE4 . The results complement prior work establishing roles of sex chromosomes and age-related depletion of sex hormones in the sexual dimorphisms characteristic of AD and provide new insights into the organizational actions of sex hormones and how these interact with APOE genotype.
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APA 7th
Christensen, A., Valencia‐Olvera, A. C., Xeros, H., Nguyen, E. T., Lopez, M., Javaheri, R., et al. (2026). Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00967-w
Vancouver
Christensen A, Valencia‐Olvera AC, Xeros H, Nguyen ET, Lopez M, Javaheri R, et al. Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice. Biology of Sex Differences. 2026. doi:10.1186/s13293-026-00967-w.
BibTeX
@article{christensen2026-93b65e21,
author = {Christensen, Amy and Valencia‐Olvera, Ana Carolina and Xeros, Helena and Nguyen, Elizabeth T. and Lopez, Marlene and Javaheri, Rojan and Tai, Leon M. and LaDu, Mary Jo and others},
title = {{Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice}},
journal = {Biology of Sex Differences},
year = {2026},
doi = {10.1186/s13293-026-00967-w},
url = {https://doi.org/10.1186/s13293-026-00967-w}
}
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Key findings
- Abstract Apolipoprotein E ε4 genotype ( APOE4 ), the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), is associated with sexually dimorphic effects whereby higher risks are generally observed in women.
- Both female sex and APOE4 genotype were associated with increased levels of β-amyloid pathologies.
- These findings suggest that sexual differentiation in early life has modest effects on adult development of AD in females, a relationship that appeared stronger in the context of APOE4 .
- The results complement prior work establishing roles of sex chromosomes and age-related depletion of sex hormones in the sexual dimorphisms characteristic of AD and provide new insights into the organizational actions of sex hormones and how these interact with APOE genotype.
Why it matters
In a mouse model, both female sex and the APOE4 genotype were linked to more β-amyloid pathology, and experimental masculinization had modest effects on some Alzheimer-related outcomes. Because this is an animal study, the results cannot be directly applied to people.
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Study details
- Evidence strengthLow
How this study scored 33/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Biology of Sex Differences) |
| Journal's citation record | 1 / 4 | Biology of Sex Differences: journal h-index 92 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 0 / 6 | Cited 0.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Christian J. Pike: h-index 67 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Southern California: institution h-index 1,521 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Total | 33 / 100 | — |
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