Impact of Estradiol and Alzheimer’s Biomarkers on Hippocampal Connectivity in Midlife Women

In the US, 4.1 million women aged 65 years or older are living with Alzheimer’s disease (AD) dementia. Improved understanding of risk and protective factors for AD in women is a public health priority, as women comprise two-thirds of those living with AD and there is no cure for the disease. It is therefore important to identify sex differences in AD pathology, especially early in the course of disease, and recognize the potential variations in pathogenesis associated with major AD risk factors such as apolipoprotein E e4 (APOE4) carrier status. Attempts to identify factors contributing to sex differences in AD have pointed to midlife changes in sex steroid hormones, namely estrogens, during the menopause transition. Surprisingly little is known about the brain changes that occur in women in association with changes in estrogen. To address that gap, I have a growing body of innovative research studies showing estrogen-related changes in brain functional connectivity during memory tasks. Broadly, the data show that endogenous levels of the estrogens estradiol and estrone are associated with differences in brain connectivity, particularly in the hippocampus, a brain area critical in AD pathogenesis. Importantly, these differences are related to memory performance in midlife women. This dissertation has extended this work to functional connectivity, and to the field of AD, by examining apolipoprotein E e4 (APOE4) carrier status and blood-based AD biomarkers. The goal was to examine the interactive association of APOE4 and levels of estradiol with hippocampally-mediated memory circuitry in a sample of midlife, postmenopausal women, and assess whether that memory circuitry is associated with AD biomarkers, cognition, or affect. Aim 1 examined the interactive association of endogenous E2 levels and APOE4 carrier status on hippocampal functional connectivity. During encoding, APOE4 carriers with higher levels of endogenous estradiol showed decreased functional connectivity in the left hippocampus and increased functional connectivity in the right hippocampus. During recognition, APOE4 carriers showed increased left and right hippocampal connectivity. In several regions where APOE4 carriers with higher levels of endogenous estradiol showed decreased functional connectivity, APOE4 non-carriers were in direct opposition, showing increased connectivity, indicating a specific disadvantagaeous association of estradiol in APOE4 carriers in those brain regions. Aim 2 examined the extent to which blood-based AD biomarkers associated with endogenous E2 levels and hippocampal functional connectivity in APOE4 carriers versus non-carriers, finding several associations. In APOE4 carriers, right hippocampal connectivity was associated with increased AD pathology, as shown by increased amyloid-beta. In APOE4 non-carriers, right hippocampal connectivity was associated with increased AD pathology, as shown by increased measures of pTau. These findings confirm that brain areas shown to differentially associate with endogenous estradiol depending on APOE4 status are related to AD pathology and that measures of amyloid-beta in APOE4 carriers, and measures of pTau in non-carriers, may be more relevant to understanding the role of estradiol in the AD continuum. Aim 3 assessed the clinical significance of APOE4 effects by examining the extent to which interactive associations of endogenous E2 levels and APOE4 carrier status with hippocampal functional connectivity were associated with cognition and affect. In APOE4 carriers during encoding, more left hippocampal connectivity was associated with higher levels of estradiol, lower global cognition, and fewer symptoms of depression and anxiety. In APOE4 carriers during recognition, more right hippocampus-to-right SFG, a region associated with increased AD pathology, and right ITG connectivity were associated with higher levels of estradiol and poor verbal memory performance. Conversely, in APOE4 carriers during recognition, more right hippocampus-to-right MTG connectivity was associated with higher levels of estradiol and better cognitive performance. In APOE4 non-carriers, many right hippocampal functional connections, particularly during encoding, had strong clinical relevance to memory performance and very few functional connections associated with affect. These results indicate that APOE4 carriers with high levels of endogenous estradiol are less able to engage functional networks beneficial to measures of cognition or affect. Together, findings suggest that estradiol has a distinct, beneficial, effect on hippocampal connectivity and measures of cognition in APOE4 non-carriers that is not found in APOE4 carriers. Hippocampal functional connections that were differentially associated with estradiol depending on APOE4 genotype may have clinical relevance, as many were also associated with AD biomarkers, cognition, and affect. These findings support the theory that estrogens likely contribute to midlife sex differences in AD, and identify brain changes that occur in postmenopausal women in association with endogenous levels of estrogen and APOE4 carrier status.