Protection against APOE4-associated phenotypes with the longevity-promoting intervention 17α-estradiol in middle-aged male mice
Cassandra Joan McGill, Amy Christensen, Wenjie Qian, Max Andrew Thorwald, José Arquimides Godoy-Lugo, Sara Namvari, Olivia S. White, Caleb E. Finch et al.. Communications Medicine, 2025-06-10
Topic: Brain proteins, microglia and lab models
The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity and increased vulnerability to age-related declines and disorders across multiple systems. Here, we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles. These findings demonstrate that APOE4 promotes systemic and neural aging phenotypes linked to AD and that 17αE2-mediated healthspan actions show a positive APOE4 bias. Collectively, the findings suggest that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with the APOE4 genotype. People with a particular sequence in a part of their DNA called APOE (named APOE4) are more likely to have a reduced lifespan and have a higher risk of developing some age-related disorders, including Alzheimer’s disease. As expected, we found that mice with the APOE4 sequence showed more signs of aging, but that 17αE2 improved several health-related measures, often with a bigger effect in mice with APOE4. These results suggest that treatments that promote healthy aging may be especially helpful for people with APOE4, potentially reducing their risk for age-related diseases such as Alzheimer’s disease. McGill et al. compare the effects of the longevity-promoting compound 17α-estradiol (17αE2) in male mice carrying the common human APOE3 allele versus the Alzheimer-associated APOE4 allele.
Key findings
- The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity and increased vulnerability to age-related declines and disorders across multiple systems.
- Here, we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles.
- These findings demonstrate that APOE4 promotes systemic and neural aging phenotypes linked to AD and that 17αE2-mediated healthspan actions show a positive APOE4 bias.
- Collectively, the findings suggest that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with the APOE4 genotype.
- People with a particular sequence in a part of their DNA called APOE (named APOE4) are more likely to have a reduced lifespan and have a higher risk of developing some age-related disorders, including Alzheimer’s disease.
Why it matters
In early middle-aged mice with human APOE alleles, 17α-estradiol improved several health-related measures, often with a bigger effect in APOE4 mice. These results suggest that longevity-promoting interventions may be especially helpful for people with APOE4, but this is animal research.
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Study details
- Evidence strengthLow
How this study scored 37/100
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 (Communications Medicine) |
| Journal's citation record | 0 / 4 | Communications Medicine: journal h-index 55 (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 | 4 / 5 | 2025 — within 3 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 | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.0× 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 | 1 / 4 | Cited 4 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 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40494894) |
| Free to read | 2 / 2 | Free to read |
| Total | 37 / 100 | — |
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Read the original
- DOI: 10.1038/s43856-025-00942-3
- PubMed: 40494894
- Original source →
- Free full text: Communications Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
McGill, C. J., Christensen, A., Qian, W., Thorwald, M. A., Godoy-Lugo, J. A., Namvari, S., et al. (2025). Protection against APOE4-associated phenotypes with the longevity-promoting intervention 17α-estradiol in middle-aged male mice. Communications Medicine. https://doi.org/10.1038/s43856-025-00942-3
Vancouver
McGill CJ, Christensen A, Qian W, Thorwald MA, Godoy-Lugo JA, Namvari S, et al. Protection against APOE4-associated phenotypes with the longevity-promoting intervention 17α-estradiol in middle-aged male mice. Communications Medicine. 2025. doi:10.1038/s43856-025-00942-3. PMID: 40494894.
BibTeX
@article{mcgill2025-40494894,
author = {McGill, Cassandra Joan and Christensen, Amy and Qian, Wenjie and Thorwald, Max Andrew and Godoy-Lugo, José Arquimides and Namvari, Sara and White, Olivia S. and Finch, Caleb E. and others},
title = {{Protection against APOE4-associated phenotypes with the longevity-promoting intervention 17α-estradiol in middle-aged male mice}},
journal = {Communications Medicine},
year = {2025},
doi = {10.1038/s43856-025-00942-3},
pmid = {40494894},
url = {https://doi.org/10.1038/s43856-025-00942-3}
}
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