Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence
Perovic, M.; Gravelsins, L.; Wood Alexander, M.; McGovern, A.; Murphy, K.; Rabin, J.; Galea, L. A. M.. medRxiv (preprint), 2026-09-20
Topic: Risk, prevention and care in population studies
Implications of menopause hormone therapy (MHT) for cognitive aging remain unclear despite decades of research. Potential reasons include insufficient consideration of MHT type, despite notable pharmacokinetic differences across formulations, and limited attention to individual differences that may exacerbate cognitive risk. We examined late-life neurocognitive outcomes as a function of APOE{varepsilon}4 status, the strongest genetic predictor of Alzheimers disease, and MHT formulation (N=8,741). Results suggest formulation- and domain-specific association between MHT and cognition, with evidence of estradiol-based MHT providing more benefits for APOE{varepsilon}4 carriers relative to conjugated equine estrogens use. Neuroimaging analyses available for a subset of participants (N=930) revealed a consistent pattern of more favourable associations (higher volume, cortical thickness; less white matter damage) in APOE{varepsilon}4 carriers taking estradiol-based MHT. These results reframe mixed MHT findings as an issue of exposure definition and support formulation- and genetic-risk-aware approaches to menopause care.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Perovic, M., Gravelsins, L., Wood Alexander, M., McGovern, A., Murphy, K., Rabin, J., et al. (2026). Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence. medRxiv (preprint). https://doi.org/10.64898/2026.09.16.26363120
Vancouver
Perovic M, Gravelsins L, Wood Alexander M, McGovern A, Murphy K, Rabin J, et al. Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence. medRxiv (preprint). 2026. doi:10.64898/2026.09.16.26363120.
BibTeX
@article{perovic2026-e370555c,
author = {Perovic, M. and Gravelsins, L. and Wood Alexander, M. and McGovern, A. and Murphy, K. and Rabin, J. and Galea, L. A. M.},
title = {{Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.09.16.26363120},
url = {https://doi.org/10.64898/2026.09.16.26363120}
}
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.
Key findings
- Results suggest formulation- and domain-specific association between MHT and cognition, with evidence of estradiol-based MHT providing more benefits for APOE{varepsilon}4 carriers relative to conjugated equine estrogens use.
- Neuroimaging analyses available for a subset of participants (N=930) revealed a consistent pattern of more favourable associations (higher volume, cortical thickness; less white matter damage) in APOE{varepsilon}4 carriers taking estradiol-based MHT.
- These results reframe mixed MHT findings as an issue of exposure definition and support formulation- and genetic-risk-aware approaches to menopause care.
Why it matters
In a large observational study, estradiol-based menopause hormone therapy was linked to more favorable cognitive and brain outcomes in APOE-e4 carriers compared with conjugated equine estrogens. These are associations only, and the authors say formulation- and genetic-risk-aware approaches are needed rather than a general recommendation.
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Study details
- Participants8,741
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 30 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomized / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 28 of the 94 points we could judge it on, which is 30 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 3 / 4 | 8,741 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization 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 | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| 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 Liisa A.M. Galea: h-index 82 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Toronto: institution h-index 1,923 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 4 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 |
| Points | 28 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 28 of the 94 points we could judge it on is 30 out of 100. |
| Total | 30 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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