PT  - JOURNAL ARTICLE
AU  - Ann-Marie de Lange
AU  - Claudia Barth
AU  - Tobias Kaufmann
AU  - Ivan I. Maximov
AU  - Dennis van der Meer
AU  - Ingrid Agartz
AU  - Lars T. Westlye
TI  - Cumulative estrogen exposure, APOE genotype, and women’s brain aging - a population-based neuroimaging study
AID  - 10.1101/826123
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 826123
4099  - http://biorxiv.org/content/early/2019/10/31/826123.short
4100  - http://biorxiv.org/content/early/2019/10/31/826123.full
AB  - Estrogen exposure may influence women’s risk of Alzheimer’s disease, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less evidence of brain aging in women with a history of multiple childbirths. Here, we investigated the link between brain aging, estrogen exposure, and APOE genotype beyond the effects of parity in 16,854 UK Biobank women. Machine learning was used to predict brain age based on neuroimaging-derived measures, and the difference between an individual’s predicted and chronological age was used as an estimate of brain aging. Cumulative estrogen exposure was estimated using an index including age at menarche and menopause, BMI, time since menopause, and duration of hormone replacement therapy. Endogenous hormone exposure was approximated by reproductive span, while exogenous exposure was estimated by usage, onset, and duration of hormone replacement therapy and oral contraceptives. Higher cumulative, endogenous, and exogenous estrogen exposure were each linked to higher brain age relative to chronological age. Earlier onset of hormone replacement therapy, particularly before menopause, was associated with less evident brain aging in APOE e4 carriers only, while higher circulating estradiol levels during menopause were linked to more evident brain aging in carriers and less evident brain aging in non-carriers. The results indicate that estrogen exposure and parity may differentially relate to women’s brain aging, and that APOE e4-specific associations between estrogen and brain aging may be of importance for optimizing hormone replacement therapy regimes in perimenopausal women.