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

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.