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Kyoko Konishi, PhD






Massachusetts General Hospital




Kyoko Konishi*, Sarah Aroner, Anne Remington, Harlyn Aizley, & Jill M Goldstein

Principal Investigator

Dr. Jill Goldstein


Longitudinal Impact of Midlife Metabolic Health on Memory Function: Role of Sex and Reproductive Aging

In addition to chronological aging, women undergo reproductive aging in midlife, during which they experience a depletion of ovarian hormones including estradiol. Estradiol is a master regulator of many neurological and physiological functions, including memory circuitry and metabolic function. With menopause, there is a 15-25% decrease in cerebral glucose metabolism resulting in a period of vulnerability in women that may increase susceptibility to neurodegeneration and cognitive impairment. Here, we assessed the longitudinal impact of metabolic health, in relation to sex and reproductive aging, on memory performance and cellular aging in early midlife. Women live a third of their life after menopause and thus, understanding the impact of ovarian decline on the brain is particularly important for women’s health. This work will inform in women, critical windows of vulnerability, mechanistic targets for intervention, identify early in life high-risk populations, and will highlight key differences with aged-matched men.


Menopause and estradiol decline are associated with altered memory circuitry function and decreased glucose metabolism, resulting in a period of vulnerability in some women. Here, we assessed the longitudinal impact of prior metabolic health, in relation to sex and reproductive aging, on memory performance and cellular aging later in midlife. 103 participants (48M:55F) underwent metabolic and memory assessments at ages 40-50 years old. At ages 45-55, the same participants underwent follow-up memory assessments. Generalized estimating equation models adjusting for age and education were used to assess associations between metabolic function and memory outcomes. Models were run both stratified by sex and with the inclusion of an interaction term. We found that at ages 40-50 years old, there was no significant relationship between metabolic health and memory in both men and women (p>0.05). However, women with prediabetic/diabetic levels of HbA1c (>=5.7) at ages 40-50 performed significantly worse on memory tasks 5 years later compared to those with lower levels of HbA1c (β=-6.32, p<0.01) and differed significantly from men (p<0.01). In men, there were no significant associations between HbA1c levels and memory performance. Examining the impact of menopause, we found that women with higher HbA1c levels who transitioned to postmenopause during the follow-up period had the worst memory performance 5 years later (β=-1.22, p<0.01) compared with those who remained in pre/perimenopause (p=0.05). Finally, we found that poor metabolic health was also related to accelerated cellular aging in the form of shorter leukocyte telomere length (β=-0.41, p<0.05), which in turn was related to poor memory performance. Taken together, these results suggest that midlife metabolic health is related to cellular aging and has a greater longitudinal impact on memory performance in women compared to men. Further, results suggest that midlife metabolic health may impact memory decline in women during the transition through menopause.

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