Impact of Sex and Menopausal Status on Episodic Memory Circuitry in Early Midlife

Abstract

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 ϭ 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 17␤-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.

Impact of sex and reproductive status on memory circuitry structure and function in early midlife using structural covariance analysis

“…We recently demonstrated significant reproductive age‐related changes in regional brain activity and network‐level connectivity during working memory and encoding in early midlife associated with menopausal changes drawn from the cohort presented here (Jacobs et al, , ). In the current study, we investigated sex differences and reproductive status on structural brain volumes and their associations within the memory circuit.…”

“…We think this lack of volume change is not surprising given that the women in the current study were both healthy and in early postmenopause, and thus, ovarian decline would likely not have a significant impact on brain volumes in this sample. However, covariance analyses may be more sensitive to identifying subtle changes in memory circuitry in early midlife, as in our previous fMRI memory circuitry work on this cohort (Jacobs et al, , ), and therefore more suitable to investigate reproductive hormone‐dependent differences in structural associations within the memory circuit in early midlife.…”

“…Groups were matched on important demographics—such as body mass index, education, parental socioeconomic status, ethnicity, and age (Table ). The sample presented here differs slightly from our previously published fMRI papers (Jacobs et al, ), given that a few subjects had either usable T1 or fMRI scans. Human subjects’ approval was granted by Partners Healthcare and Brown University.…”

Ovarian hormones: a long overlooked but critical contributor to cognitive brain structures and function

“…The difference between inverse hippocampal activation and attenuated hippocampal deactivation can likely be explained by varying task demands and hippocampal connectivity. For instance, postmenopausal women had increased connectivity among the bilateral hippocampi during verbal processing . They also exhibited increased dorsolateral PFC activity during verbal working memory, and only for these postmenopausal women did connectivity between the dorsolateral PFC and hippocampus predict task performance .…”

“…There is also evidence for changes in brain function associated with menopause during verbal tasks and the cognitive control of emotion processing. With respect to verbal processing, hippocampal function seems to be altered among pre‐, peri‐, and postmenopausal women, with postmenopausal women showing the least hippocampal activity during verbal processing and the least hippocampal deactivation during verbal working memory; in both cases, hippocampal activity was related to estradiol . The difference between inverse hippocampal activation and attenuated hippocampal deactivation can likely be explained by varying task demands and hippocampal connectivity.…”