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Sex differences in episodic memory in early midlife: impact of reproductive aging

Rentz, Dorene M. PsyD; Weiss, Blair K. BS; Jacobs, Emily G. PhD; Cherkerzian, Sara ScD; Klibanski, Anne MD; Remington, Anne MA; Aizley, Harlyn MEd; Goldstein, Jill M. PhD

doi: 10.1097/GME.0000000000000771
Original Articles

Objective: Few have characterized cognitive changes with age as a function of menopausal stage relative to men, or sex differences in components of memory in early midlife. The study aim was to investigate variation in memory function in early midlife as a function of sex, sex steroid hormones, and reproductive status.

Methods: A total of 212 men and women aged 45 to 55 were selected for this cross-sectional study from a prenatal cohort of pregnancies whose mothers were originally recruited in 1959 to 1966. They underwent clinical and cognitive testing and hormonal assessments of menopause status. Multivariate general linear models for multiple memory outcomes were used to test hypotheses controlling for potential confounders. Episodic memory, executive function, semantic processing, and estimated verbal intelligence were assessed. Associative memory and episodic verbal memory were assessed using Face-Name Associative Memory Exam (FNAME) and Selective Reminding Test (SRT), given increased sensitivity to detecting early cognitive decline. Impacts of sex and reproductive stage on performance were tested.

Results: Women outperformed men on all memory measures including FNAME (β = −0.30, P < 0.0001) and SRT (β = −0.29, P < 0.0001). Furthermore, premenopausal and perimenopausal women outperformed postmenopausal women on FNAME (initial learning, β= 0.32, P = 0.01) and SRT (recall, β= 2.39, P = 0.02). Across all women, higher estradiol was associated with better SRT performance (recall, β = 1.96, P = 0.01) and marginally associated with FNAME (initial learning, β = 0.19, P = 0.06).

Conclusions: This study demonstrated that, in early midlife, women outperformed age-matched men across all memory measures, but sex differences were attenuated for postmenopausal women. Initial learning and memory retrieval were particularly vulnerable, whereas memory consolidation and storage were preserved. Findings underscore the significance of the decline in ovarian estradiol production in midlife and its role in shaping memory function.

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1Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

3Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital, Boston, MA

4Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA

5Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA.

Address correspondence to: Jill M. Goldstein, PhD, Connors Center for Women's Health and Gender Biology, One Brigham Circle, 3rd floor, 1620 Tremont St, Boston, MA 02120. E-mail:

Received 20 May, 2016

Revised 30 August, 2016

Accepted 30 August, 2016

J.M.G. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses and interpretations.

Funding/support: The work of this study was supported by the National Institute of Mental Health (R01 MH090291, J.M.G., PI). Additional support for Dr Jacobs's time was provided by ORWH-NICHD BIRCWH K12 HD051959. The Harvard Clinical and Translational Science Center (NIH UL1 RR025758) provided support for serologic acquisition and evaluations.

Financial disclosure/conflicts of interest: D.M.R. has served as a paid consultant for Eli Lilly, Janssen Pharmaceuticals and Biogen Idec. She also serves on the Neurotrack Scientific Advisory Board as a paid member. These associations are not related to this paper. All other authors have no conflicts of interest.

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© 2017 by The North American Menopause Society.