Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence
- 1Centre for Addiction and Mental Health
Abstract
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.
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BibTeX
@misc{perovic2026associations,
title = {{Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence}},
author = {M. Perovic and L. Gravelsins and M. Wood Alexander and A. McGovern and K. Murphy and J. Rabin and L. A. M. Galea},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.26363120},
url = {https://www.medrxiv.org/content/10.64898/2026.09.16.26363120v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence
AU - M. Perovic
AU - L. Gravelsins
AU - M. Wood Alexander
AU - A. McGovern
AU - K. Murphy
AU - J. Rabin
AU - L. A. M. Galea
PY - 2026
DA - 2026/09/16
PB - medRxiv
DO - 10.64898/2026.09.16.26363120
UR - https://www.medrxiv.org/content/10.64898/2026.09.16.26363120v1
AB - 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.
ER -