Journal article
Consideration of sex as a biological variable over the history of the 5xFAD Alzheimer's Disease mouse model
Biology of sex differences, Vol.16(1), 105
12/17/2025
DOI: 10.1186/s13293-025-00788-3
PMCID: PMC12709748
PMID: 41408378
Abstract
Women are nearly twice as likely to be diagnosed with Alzheimer's Disease (AD) over their lifetime. However, historically, preclinical studies utilizing AD rodent models to define new therapeutic targets in AD treatment have neglected to consider the confounding influence of subject sex leading to a lack of mechanistic insight into the biological underpinnings of sex bias in AD.
Here, we tracked choice of subject sex over the twenty-year history of the 5xFAD mouse, one of the most frequently cited pre-clinical AD models. We analyzed 1,330 primary research articles indexed on PubMed and recorded information provided regarding subject sex and/or as a rationale for not including datasets separated by sex, if noted. Trends were then plotted as a function of time ending in December 2024.
In the last 15 years, the number of published manuscripts on the 5xFAD model omitting information on subject sex has progressively declined. However, the proportion of studies utilizing either males only (29%) or combining data from both sexes (24%) far surpasses studies acknowledging sex as a biological variable (SABV) (< 12%) with no significant changes noted over time. On average, the ratio of male only: female only studies of 5xFAD mice hovered around 2:1. The most frequently cited reason for omitting sex-based analyses was either a lack of sex differences found (29%), accelerated development of plaque burden in 5xFAD females (17%), or the possibility of within- or between-sex variability (15%). Mention of SABV has steadily increased in studies utilizing 5xFAD mice peaking at ~ 30% of manuscripts published in 2024. However, two key confounds in the 5xFAD model, including the potential impact of an estrogen response element (ERE) and parental imprinting in the Thy1 promoter driving transgene expression, have been largely ignored.
The 5xFAD model represents a compelling example of how neglecting to recognize the impact of biological sex on neural function can compromise study design and data interpretation. Given sex-dependent Thy1 promoter regulation may skew phenotypic outcomes, investigators should judiciously interpret sex differences observed in any AD mouse utilizing the Thy1 promoter to drive transgene expression.
Details
- Title: Subtitle
- Consideration of sex as a biological variable over the history of the 5xFAD Alzheimer's Disease mouse model
- Creators
- Julia I Neuharth - University of IowaK Stephanie Hernandez - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, 52242, IA, USAJacob Bernholtz - University of IowaHadley Edwards - Florida Atlantic UniversityAdele Stewart - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Biology of sex differences, Vol.16(1), 105
- DOI
- 10.1186/s13293-025-00788-3
- PMID
- 41408378
- PMCID
- PMC12709748
- NLM abbreviation
- Biol Sex Differ
- ISSN
- 2042-6410
- eISSN
- 2042-6410
- Publisher
- Springer Nature
- Grant note
- Lulu Merle Johnson Recruitment Fellowship / University of Iowa NIH T32NS007421 / NIH HHS
- Language
- English
- Date published
- 12/17/2025
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9985091805402771
Metrics
2 Record Views