Impact of Sex and Menopausal Status on Episodic Memory Circuitry in Early Midlife.
Cognitive neuroscience of aging studies traditionally target participants age 65 and older. However, epidemiological surveys show that many women report increased forgetfulness earlier in the aging process, as they transition to menopause. In this population-based fMRI study, we stepped back by over a decade to characterize the changes in memory circuitry that occur in early midlife, as a function of sex and women's reproductive stage. Participants (N = 200; age range, 45-55) performed a verbal encoding task during fMRI scanning. Reproductive histories and serologic evaluations were used to determine menopausal status. Results revealed a pronounced impact of reproductive stage on task-evoked hippocampal responses, despite minimal difference in chronological age. Next, we examined the impact of sex and reproductive stage on functional connectivity across task-related brain regions. Postmenopausal women showed enhanced bilateral hippocampal connectivity relative to premenopausal and perimenopausal women. Across women, lower 17β-estradiol concentrations were related to more pronounced alterations in hippocampal connectivity and poorer performance on a subsequent memory retrieval task, strongly implicating sex steroids in the regulation of this circuitry. Finally, subgroup analyses revealed that high-performing postmenopausal women (relative to low and middle performers) exhibited a pattern of brain activity akin to premenopausal women. Together, these findings underscore the importance of considering reproductive stage, not simply chronological age, to identify neuronal and cognitive changes that unfold in the middle decades of life. In keeping with preclinical studies, these human findings suggest that the decline in ovarian estradiol production during menopause plays a significant role in shaping memory circuitry.



Maintaining intact memory function with age is one of the greatest public health challenges of our time, and women have an increased risk for memory disorders relative to men later in life. We studied adults early in the aging process, as women transition into menopause, to identify neuronal and cognitive changes that unfold in the middle decades of life. Results demonstrate regional and network-level differences in memory encoding-related activity as a function of women's reproductive stage, independent of chronological age. Analyzing data without regard to sex or menopausal status obscured group differences in circuit-level neural strategies associated with successful memory retrieval. These findings suggest that early changes in memory circuitry are evident decades before the age range traditionally targeted by cognitive neuroscience of aging studies.
Division of Women's Health, Department of Medicine and Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02120, Harvard Medical School, Boston, Massachusetts 02120, Athinoula A. Martinos Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, jill_goldstein@hms.harvard.edu emily.jacobs@psych.ucsb.edu.
Emily G
0000-0003-0001-5096
EG
Jacobs
Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02120.
Blair K
BK
Weiss
Harvard Medical School, Boston, Massachusetts 02120, Athinoula A. Martinos Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129.
Nikos
N
Makris
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Sue
S
Whitfield-Gabrieli
Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island 02903, and.
Stephen L
SL
Buka
Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
Anne
A
Klibanski
Division of Women's Health, Department of Medicine and Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02120, Harvard Medical School, Boston, Massachusetts 02120, Athinoula A. Martinos Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, jill_goldstein@hms.harvard.edu emily.jacobs@psych.ucsb.edu.
Jill M
JM
Goldstein
D000375:Aging / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D008297:Male; D061212:Memory, Episodic; D008593:Menopause / Q000502:physiology*; D011939:Mental Recall; D008875:Middle Aged; D009415:Nerve Net / Q000502:physiology*; D012727:Sex Characteristics; D013647:Task Performance and Analysis
PFC; episodic memory; estradiol; fMRI; hippocampus; menopause
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