Women's brain aging: Effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer's disease

Ann-Marie G. de Lange; Claudia Barth; Tobias Kaufmann; Ivan I. Maximov; Dennis van der Meer; Ingrid Agartz; Lars T. Westlye

doi:10.1002/hbm.25180

Women's brain aging: Effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer's disease

Ann-Marie G. de Lange^*, Claudia Barth^*, Tobias Kaufmann, Ivan I. Maximov, Dennis van der Meer, Ingrid Agartz, Lars T. Westlye

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women's exposure to estrogen may influence their heightened risk of Alzheimer's disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex-hormone exposure and brain aging. We investigated endogenous and exogenous sex-hormone exposure, genetic risk for AD, and neuroimaging-derived biomarkers for brain aging in 16,854 middle to older-aged women. The results showed that as opposed to parity, higher cumulative sex-hormone exposure was associated with more evident brain aging, indicating that i) high levels of cumulative exposure to sex-hormones may have adverse effects on the brain, and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modulations in sex-hormone exposure. In addition, for women using hormonal replacement therapy (HRT), starting treatment earlier was associated with less evident brain aging, but only in women with a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women's brain aging trajectories.

Original language	English
Pages (from-to)	5141-5150
Number of pages	10
Journal	Human Brain Mapping
Volume	41
Issue number	18
Early online date	28 Aug 2020
DOIs	https://doi.org/10.1002/hbm.25180
Publication status	Published - 15 Dec 2020

Keywords

apolipoproteins E
estrogens
neuroimaging
parity
women's brain aging
APOLIPOPROTEIN-E
ESTROGEN EXPOSURE
APOE
AGE
THERAPY
REPRODUCTION
COGNITION
OLDER

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10.1002/hbm.25180Licence: CC BY-NC

Cite this

@article{16da0d3bc560417ca4bcf638459f0f14,

title = "Women's brain aging: Effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer's disease",

abstract = "Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women's exposure to estrogen may influence their heightened risk of Alzheimer's disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex-hormone exposure and brain aging. We investigated endogenous and exogenous sex-hormone exposure, genetic risk for AD, and neuroimaging-derived biomarkers for brain aging in 16,854 middle to older-aged women. The results showed that as opposed to parity, higher cumulative sex-hormone exposure was associated with more evident brain aging, indicating that i) high levels of cumulative exposure to sex-hormones may have adverse effects on the brain, and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modulations in sex-hormone exposure. In addition, for women using hormonal replacement therapy (HRT), starting treatment earlier was associated with less evident brain aging, but only in women with a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women's brain aging trajectories.",

keywords = "apolipoproteins E, estrogens, neuroimaging, parity, women's brain aging, APOLIPOPROTEIN-E, ESTROGEN EXPOSURE, APOE, AGE, THERAPY, REPRODUCTION, COGNITION, OLDER",

author = "{de Lange}, {Ann-Marie G.} and Claudia Barth and Tobias Kaufmann and Maximov, {Ivan I.} and {van der Meer}, Dennis and Ingrid Agartz and Westlye, {Lars T.}",

note = "Funding Information: This research was conducted using the UK Biobank under Application 27412, and received funding from the Research Council of Norway (286838, 273345, 249795, 276082, 250358), the South‐East Norway Regional Health Authority (2015073, 2019107) and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 802998). The permutation testing was performed using resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway. Publisher Copyright: {\textcopyright} 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.",

year = "2020",

month = dec,

day = "15",

doi = "10.1002/hbm.25180",

language = "English",

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journal = "Human Brain Mapping",

issn = "1065-9471",

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T2 - Effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer's disease

AU - de Lange, Ann-Marie G.

AU - Barth, Claudia

AU - Kaufmann, Tobias

AU - Maximov, Ivan I.

AU - van der Meer, Dennis

AU - Agartz, Ingrid

AU - Westlye, Lars T.

N1 - Funding Information: This research was conducted using the UK Biobank under Application 27412, and received funding from the Research Council of Norway (286838, 273345, 249795, 276082, 250358), the South‐East Norway Regional Health Authority (2015073, 2019107) and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 802998). The permutation testing was performed using resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway. Publisher Copyright: © 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

PY - 2020/12/15

Y1 - 2020/12/15

N2 - Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women's exposure to estrogen may influence their heightened risk of Alzheimer's disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex-hormone exposure and brain aging. We investigated endogenous and exogenous sex-hormone exposure, genetic risk for AD, and neuroimaging-derived biomarkers for brain aging in 16,854 middle to older-aged women. The results showed that as opposed to parity, higher cumulative sex-hormone exposure was associated with more evident brain aging, indicating that i) high levels of cumulative exposure to sex-hormones may have adverse effects on the brain, and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modulations in sex-hormone exposure. In addition, for women using hormonal replacement therapy (HRT), starting treatment earlier was associated with less evident brain aging, but only in women with a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women's brain aging trajectories.

AB - Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women's exposure to estrogen may influence their heightened risk of Alzheimer's disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex-hormone exposure and brain aging. We investigated endogenous and exogenous sex-hormone exposure, genetic risk for AD, and neuroimaging-derived biomarkers for brain aging in 16,854 middle to older-aged women. The results showed that as opposed to parity, higher cumulative sex-hormone exposure was associated with more evident brain aging, indicating that i) high levels of cumulative exposure to sex-hormones may have adverse effects on the brain, and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modulations in sex-hormone exposure. In addition, for women using hormonal replacement therapy (HRT), starting treatment earlier was associated with less evident brain aging, but only in women with a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women's brain aging trajectories.

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KW - AGE

KW - THERAPY

KW - REPRODUCTION

KW - COGNITION

KW - OLDER

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