Lower Endogenous Estrogens in APOE4‐Positive Postmenopausal Women Associated with Lower Regional Brain Volumes

Abstract

AbstractBackgroundDuring the menopause transition, levels of estradiol (E2) ecline. Although these changes are likely key determinants of cognition and brain structure during the menopause transition, how they are related to brain volume in women at elevated risk of Alzheimer’s disease (AD) is not known. We predict associations of endogenous E1 and E2 levels to regional brain volumes will depend on APOE4 carrier status, such that the associations between lower levels of E1 and E2 and lower regional brain volumes will be more positive among APOE4 carriers.MethodsParticipants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 191, mean age 59.4 +/‐ 3.4 years, 45 APOE4 carriers, 84.3% white). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Cross‐sectional associations of interest were analyzed with APOE4 genotype (carrier versus noncarrier; excluding APOE2)ormone levels, and their interaction, as predictors and regional brain volumes (33 regions per hemisphere) as outcome measures using lme4 Package in R. Models controlled for, years of education, and body mass index.ResultsNeither APOE4 carrier status nor hormone levels were associated with brain volumes . However, significant interactions were observed between APOE4 carrier status and E2 levels in relation to volume of the right (p<.05) and left isthmus cingulate (p<.01), right and left middle temporal lobe (p<.05), and the left posterior cingulate (p<.05), such that the positive association between E2 and regional brain volumes was more positive among APOE4 carriers (Figure 1). Further, there was a significant interaction between APOE4 carrier status and E1 levels in relation to volumes of the right and left inferior parietal lobe (p<.05), right (p<.05) and left isthmus cingulate (p<.05), left cuneus (p<.05), left precuneus (p<.05), and left lingual gyrus (p<.05)(Figure 2).ConclusionAlthough some of these findings would be expected by chance, results suggest that lower levels of endogenous estrogens may be a risk factor for regional brain volume loss in female APOE4 carriers compared to non‐carriers.Supported by NIH RF1AG053504 and R01AG053504 (Thurston & Maki)