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Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort
Saleh RNM, Hornberger M, Ritchie CW, Minihane AM.. Alzheimer's research & therapy, 2023-01-09
Topic: Brain proteins, microglia and lab models
Background The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT. Methods The analysis used baseline data from participants in the European Prevention of Alzheimer's Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes. Results APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6-10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= -0.555, p=0.035) and left hippocampal volumes (standardized β= -0.577, p=0.028) only in APOE4 carriers. Conclusion HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.
Key findings
- The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results.
- Results APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6-10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively).
- Earlier introduction of HRT was associated with larger right (standardized β= -0.555, p=0.035) and left hippocampal volumes (standardized β= -0.577, p=0.028) only in APOE4 carriers.
- Conclusion HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only.
Why it matters
In the EPAD cohort, APOE4 women who used hormone replacement therapy had the highest delayed memory scores and larger entorhinal and amygdala volumes compared with non-users and non-carriers. Earlier introduction of HRT was associated with larger brain volumes.
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Study details
- Participants1,906
- Effect size61.8%
- Evidence strengthModerate
How this study scored 60/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer's research & therapy) |
| Journal's citation record | 1 / 4 | Alzheimer s Research & Therapy: journal h-index 146 (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 | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2023 — within 6 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,906 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 148 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 29.6 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 5 / 6 | Cited 25.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 3 / 4 | Cited 112 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Anne Marie Minihane: h-index 67 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Edinburgh: institution h-index 1,378 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36624497) |
| Free to read | 2 / 2 | Free to read |
| Total | 60 / 100 | — |
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Read the original
- DOI: 10.1186/s13195-022-01121-5
- PubMed: 36624497
- Original source →
- Free full text: Alzheimer s Research & Therapy →
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
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APA 7th
Saleh, R. N. M., Hornberger, M., Ritchie, C. W., & Minihane, A. M. (2023). Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort. Alzheimer's research & therapy. https://doi.org/10.1186/s13195-022-01121-5
Vancouver
Saleh RNM, Hornberger M, Ritchie CW, Minihane AM. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort. Alzheimer's research & therapy. 2023. doi:10.1186/s13195-022-01121-5. PMID: 36624497.
BibTeX
@article{saleh2023-36624497,
author = {Saleh, R. N. M. and Hornberger, M. and Ritchie, C. W. and Minihane, A. M.},
title = {{Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort}},
journal = {Alzheimer's research \& therapy},
year = {2023},
doi = {10.1186/s13195-022-01121-5},
pmid = {36624497},
url = {https://doi.org/10.1186/s13195-022-01121-5}
}
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