Estradiol and memory circuitry in the postmenopause: Modification by APOE4

Background: Menopause-related declines in endogenous estrogen have been implicated in the higher risk of Alzheimer’s disease (AD) in female APOE4 carriers compared to male APOE4 carriers, but evidence remains inconclusive. Here we examined APOE4 -related differences in the association of endogenous estradiol with patterns of hippocampal functional connectivity (HFC) during memory tasks, and how those patterns relate to AD biomarkers and memory performance. Methods: 172 postmenopausal women (mean age=59.3 + 3.9 years, 83% white, 23.33% APOE4 carriers) enrolled in MsBrain completed functional magnetic resonance imaging (fMRI) during a word memory task comprising encoding and recognition phases. Left and right HFC were determined by generalized psychophysiological interaction (gPPI) analysis. Interactive associations of estradiol levels and APOE4 carrier status ( APOE3 homozygotes versus APOE4 carriers) with whole-brain left and right HFC were analyzed via linear regression. In subsequent regression analyses, patterns of HFC were examined in relation to blood-based AD biomarkers, cognition and affect, stratifying by APOE4 carrier status. Models controlled for age, education, and body mass index, and were cluster-corrected at p<.05. Results: APOE4 status modified estradiol-related HFC to multiple brain areas, primarily frontal and temporal regions. For the encoding phase, higher estradiol levels were associated with lower left HFC and higher right HFC in APOE4 carriers , but with higher/neutral left HFC and lower/neutral right HFC in APOE4 non-carriers. For the recognition phase, estradiol was related to higher right and left HFC in APOE4 carriers and neutral/lower HFC in APOE4 non-carriers. Estradiol-related HFC in midlife women was more strongly related to AD pathology in APOE4 carriers versus APOE4 non-carriers, and it was related to better memory performance only in non-carriers. Conclusion: In women APOE4 carriers, higher estradiol was associated with a maladaptive pattern of HFC, which was in turn associated with an adverse AD risk profile as measured by AD biomarkers. Conversely, in APOE4 non-carriers, endogenous estradiol appears to have a distinct, beneficial, effect on HFC. These results suggest that higher endogenous levels of estradiol associate with an early AD-related decompensation in memory circuitry in midlife women who carry a genetic risk for AD but a more favorable pattern in women without that genetic risk.