Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice
- 1Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191 USA
- 2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612 USA
- 3Department of Biological Science, California State University Fullerton, Fullerton, CA 92831 USA
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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13293-026-00967-w.
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BibTeX
@article{christensen2026effects,
title = {{Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice}},
author = {Amy Christensen and Ana C. Valencia-Olvera and Helena Xeros and Elizabeth T. Nguyen and Marlene Lopez and Rojan Javaheri and Leon M. Tai and Mary Jo LaDu and Christian J. Pike},
journal = {Biology of Sex Differences},
year = {2026},
month = aug,
doi = {10.1186/s13293-026-00967-w},
url = {https://doi.org/10.1186/s13293-026-00967-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice
AU - Amy Christensen
AU - Ana C. Valencia-Olvera
AU - Helena Xeros
AU - Elizabeth T. Nguyen
AU - Marlene Lopez
AU - Rojan Javaheri
AU - Leon M. Tai
AU - Mary Jo LaDu
AU - Christian J. Pike
PY - 2026
DA - 2026/08/12
JO - Biology of Sex Differences
DO - 10.1186/s13293-026-00967-w
UR - https://doi.org/10.1186/s13293-026-00967-w
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13293-026-00967-w.
SN - 2042-6410
ER -