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The interplay between age at menopause and synaptic integrity on Alzheimer’s disease risk in women
Madeline Wood Alexander, William G. Honer, Rowan Saloner, Liisa A.M. Galea, David Alan Bennett, Jennifer S. Rabin, Kaitlin Blackstone Casaletto. Science Advances, 2025-03-05
Topic: Amyloid, tau and blood-test diagnosis
Menopause is a major biological transition that may influence women's late-life brain health. Earlier estrogen depletion-via earlier menopause-has been associated with increased risk for Alzheimer's disease (AD). Synaptic dysfunction also incites and exacerbates AD progression. We investigated whether age at menopause and synaptic health together influence AD neuropathology and cognitive trajectories using clinical and autopsy data from 268 female decedents in the Rush Memory and Aging Project. We observed significant interactions between age at menopause and synaptic integrity on cognitive decline and tau tangles, such that earlier menopause strengthened the associations of reduced synaptic integrity with faster cognitive decline and elevated tau. Exploratory analyses showed that these relationships were attenuated in women who took menopausal hormone therapy. These findings suggest that midlife endocrine processes or their sequalae may influence synaptic vulnerability to AD. Interventions addressing both hormonal factors and synaptic health could enhance resilience to dementia in women.
Key findings
- Earlier estrogen depletion-via earlier menopause-has been associated with increased risk for Alzheimer's disease (AD).
- We observed significant interactions between age at menopause and synaptic integrity on cognitive decline and tau tangles, such that earlier menopause strengthened the associations of reduced synaptic integrity with faster cognitive decline and elevated tau.
- Exploratory analyses showed that these relationships were attenuated in women who took menopausal hormone therapy.
- These findings suggest that midlife endocrine processes or their sequalae may influence synaptic vulnerability to AD.
Why it matters
Among 268 women in an autopsy cohort, earlier menopause strengthened the links between reduced synaptic integrity and faster cognitive decline and higher tau tangles, and these relationships appeared weaker in women who took menopausal hormone therapy. These are observational findings, so they do not show that hormone therapy or any other intervention prevents or treats Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 47/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science Advances) |
| Journal's citation record | 3 / 4 | Science Advances: journal h-index 378 (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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 27 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 9.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 17.2× 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 | 2 / 4 | Cited 27 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Kaitlin Blackstone Casaletto: h-index 42 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Toronto: institution h-index 1,923 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40043118) |
| Free to read | 2 / 2 | Free to read |
| Total | 47 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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 names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Alexander, M. W., Honer, W. G., Saloner, R., Galea, L. A., Bennett, D. A., Rabin, J. S., et al. (2025). The interplay between age at menopause and synaptic integrity on Alzheimer’s disease risk in women. Science Advances. https://doi.org/10.1126/sciadv.adt0757
Vancouver
Alexander MW, Honer WG, Saloner R, Galea LA, Bennett DA, Rabin JS, et al. The interplay between age at menopause and synaptic integrity on Alzheimer’s disease risk in women. Science Advances. 2025. doi:10.1126/sciadv.adt0757. PMID: 40043118.
BibTeX
@article{alexander2025-40043118,
author = {Alexander, Madeline Wood and Honer, William G. and Saloner, Rowan and Galea, Liisa A.M. and Bennett, David Alan and Rabin, Jennifer S. and Casaletto, Kaitlin Blackstone},
title = {{The interplay between age at menopause and synaptic integrity on Alzheimer’s disease risk in women}},
journal = {Science Advances},
year = {2025},
doi = {10.1126/sciadv.adt0757},
pmid = {40043118},
url = {https://doi.org/10.1126/sciadv.adt0757}
}
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