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Women with early bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) have greater Alzheimer’s disease (AD) risk than women in spontaneous/natural menopause (SM), but early biomarkers of this risk are not well-characterized. Considering associative memory deficits may presage preclinical AD, we wondered if one of the earliest changes might be in associative memory and whether younger women with BSO had changes similar to those observed in SM. Women with BSO (with and without 17β-estradiol replacement therapy (ERT)), their age-matched premenopausal controls (AMC), and older women in SM completed a functional magnetic resonance imaging face-name associative memory task shown to predict early AD. Brain activation during encoding was compared between groups: AMC (n=25), BSO no ERT (BSO; n=15), BSO+ERT (n=16), and SM without hormone therapy (n=16). Region-of-interest analyses revealed AMC did not contribute to functional group differences. BSO+ERT had higher hippocampal activation than BSO and SM. This hippocampal activation correlated positively with urinary metabolite levels of 17β-estradiol. Multivariate partial least squares analyses showed BSO+ERT had a different network-level activation pattern than BSO and SM. Thus, despite being approximately 10 years younger, women with BSO without ERT had similar brain function to those with SM, suggesting early 17β-estradiol loss may lead to an altered functional brain phenotype which could influence late-life AD risk, making face-name encoding a potential biomarker for midlife women with increased AD risk. Despite similarities in activation, BSO and SM groups showed opposite within-hippocampus connectivity, suggesting menopause type is an important consideration when assessing brain function.

Introduction 17β-estradiol loss is related to Alzheimer’s disease (AD) risk factors, including disordered sleep and associative memory decrements. Women have higher risk for AD than men, and those with mid-life 17β-estradiol loss due to surgical menopause, including bilateral salpingo-oophorectomy (BSO) before age 48, have even higher risk. We wondered whether sleep and associative memory in women with BSO (mean age 44–46) would be comparable to those with spontaneous/natural menopause (SM; mean age 57), and whether 17β-estradiol-based hormone therapy (ET) might mitigate these effects. Methods We assessed sleep using the average of three nights of portable polysomnography (Temec) in women with BSO either taking ET (BSO+ET; n=16), or not (BSO; n=18), and in older spontaneously menopausal women (SM; n=14). Using EEG (Fp1-Fp2), we obtained sleep staging automatically (Neurobit Technologies). Participants also completed a face-name associative memory task during functional magnetic resonance imaging. Recognition accuracy and brain activation during encoding were measured. Results BSO exhibited reduced sleep efficiency compared to BSO+ET. For BSO, there was no relationship between percent of total sleep time in N3 and hippocampal activation during associative encoding, even though percent of total sleep time in N3 was negatively associated with hippocampal activation during associative encoding in BSO+ET. For all groups, including BSO, lower latency to consolidated N3 correlated with better associative memory accuracy. There were no group differences in associative memory accuracy. In contrast to BSO, SM showed significantly longer latency to consolidated N3 than BSO+ET. Conclusion Younger women with BSO have comparable sleep to older women in SM. In younger women with BSO, ET improves sleep efficiency. Further, while associative memory may be disrupted by increased latency to consolidated N3 in all women, BSO and BSO+ET showed similar associative memory accuracy and latency to consolidated N3. Only BSO+ET exhibited a significant correlation between hippocampal activity during associative encoding and time spent in N3, indicating that ET may support the negative relationship between N3 and hippocampal function. Overall, ET in younger women with BSO potentially ameliorates poor sleep and associative memory decrements. Support (if any) Alzheimer’s Association/Brain Canada Foundation: AARF-17-504715; Wilfred and Joyce Posluns Chair in Women’s Brain Health and Aging

Background 17β‐estradiol loss is related to Alzheimer’s disease (AD) risk factors, including disordered sleep and associative memory decrements (Gervais et al., 2017; Rentz et al., 2017). Women have higher risk for AD than men, and those with mid‐life 17β‐estradiol loss due to surgical menopause, including bilateral salpingo‐oophorectomy (BSO) before age 48, have even higher risk (Rocca et al., 2007). Our learning objective was to investigate whether sleep and associative memory in women with BSO (mean age 44‐46) would be comparable to those with spontaneous/natural menopause (SM; mean age 57), and whether 17β‐estradiol‐based hormone therapy (ET) might mitigate these effects. Method We assessed sleep using the average of three nights of portable polysomnography (Temec) in women with BSO either taking ET (BSO+ET; n=16), or not (BSO; n=18), and in older spontaneously menopausal women (SM; n=14). Using EEG (Fp1‐Fp2), we obtained sleep staging automatically (Neurobit Technologies). Participants also completed a face‐name associative memory task during functional magnetic resonance imaging. Recognition accuracy and brain activation during encoding were measured. Result BSO exhibited reduced sleep efficiency compared to BSO+ET. For BSO, there was no relationship between percent of total sleep time in N3 and hippocampal activation during associative encoding, even though percent of total sleep time in N3 was negatively associated with hippocampal activation during associative encoding in BSO+ET. For all groups, including BSO, lower latency to consolidated N3 correlated with better associative memory accuracy. There were no group differences in associative memory accuracy. In contrast to BSO, SM showed significantly longer latency to consolidated N3 than BSO+ET. Conclusion Younger women with BSO have comparable sleep to older women in SM. In younger women with BSO, ET improves sleep efficiency. Further, while associative memory may be disrupted by increased latency to consolidated N3 in all women, BSO and BSO+ET showed similar associative memory accuracy and latency to consolidated N3. Only BSO+ET exhibited a significant correlation between hippocampal activity during associative encoding and time spent in N3, indicating that ET may support the negative relationship between N3 and hippocampal function. Overall, ET in younger women with BSO potentially ameliorates poor sleep and associative memory decrements.

Background: Women with early ovarian hormone deprivation due to bilateral salpingo-oophorectomy (BSO; ovarian and fallopian tube removal) are at risk for later life Alzheimer's disease (AD), but estradiol therapy (ET) may be protective (Rocca et al., 2007). Working memory (WM), temporarily maintaining and manipulating information in mind, depends on structural integrity of fronto-parietal brain regions (Burzynska et al., 2012). WM declines have been observed in midlife women with BSO not taking ET (Gervais et al., 2020), however, structural brain-WM relationships in this midlife population remain unexplored. This study aimed to: 1) Investigate fronto-parietal cortical thickness and gyrification (folding) changes in younger women after early BSO and their relationship to WM, and 2) Explore whether ET ameliorates these changes. Method: Women with early BSO taking ET (BSO+ET: M±SD age = 45±5.1; n = 26), or not taking ET (BSO: M±SD age = 46±5.0y; n = 26) were compared to premenopausal, age-matched controls (AMC: M±SD age = 44±2.9y; n = 42) from Toronto and Montreal, Canada, and Linköping, Sweden. T1-weighted scans were acquired on Siemens Prisma/Philips 3T scanners. WM was measured using Digit Span Backwards (Wechsler, 1945) maximum span and Digit Ordering Task (Petrides et al., 1993) errors. Average cortical thickness and gyrification of fronto-parietal regions were calculated from CIVET (Ad-Dab'bagh et al. 2005), adjusting for scanner and past cancer treatment.Result: Linear models showed no group differences in cortical thickness or WM. However, they showed BSO had significant hypogyrification (reduced cortical folding) in the supplementary motor area (SMA), part of the posterior prefrontal cortex, compared to AMC (adjusted for brain volume; FDR-corrected p = 0.028). BSO+ET had intermediate

Background Women with bilateral salpingo‐oophorectomy (BSO; removal of ovaries and fallopian tubes) prior to age 50 have increased Alzheimer’s disease (AD) risk (Rocca et al., 2007), but the neural mechanisms for this are unclear. Abilities involving manipulation/maintenance aspects of working memory (WM) decline post‐BSO, and this effect may be reduced by estradiol‐based hormone therapy (ET; Gervais et al., 2020). Considering decline in manipulation/maintenance aspects of WM in AD (Germano & Kinsella, 2005), we aimed to understand the relationships between brain structure and WM after BSO. Method Women with BSO taking ET (BSO+ET: M±SDage = 44.92±5.11, n = 26) or not taking ET (BSO: M±SDage = 45.62±5.04, n = 26) were compared to age‐matched premenopausal controls (AMC: M±SDage = 43.71±2.92, n = 42) recruited from Toronto, Montreal, and Linköping. T1‐weighted structural magnetic resonance imaging scans were acquired. Voxel‐based morphometry measures of gray matter volume were obtained (CIVET pipeline, Ad‐Dab’bagh et al., 2005). Digit Span Backward (DSB) and Forward (DSF) subtests (Wechsler, 1945) were administered to assess manipulation/maintenance and updating/maintenance aspects of WM, respectively. Multivariate Behaviour Partial Least Squares (McIntosh & Lobaugh, 2004) was used to compare the correlation between performance (DSB and DSF) and volume between groups. Result There were no group differences in DSB/DSF total span performance. AMC did not show a significant relationship between volume and WM (Figure1A). For BSO and BSO+ET, gray matter volume in key WM regions, including bilateral supplementary motor area, inferior temporal gyrus, superior and inferior frontal gyri, left precuneus, and right cuneus, was negatively associated with DSB performance (Figure1B warm colours), while hippocampal volume was positively associated with DSB performance (Figure1B cold colours). These relationships were strong for BSO (R = ‐0.78), while BSO+ET (R = ‐0.37; moderate correlation) showed an intermediate phenotype between BSO and AMC (R = 0.14; small correlation). Conclusion Manipulation/maintenance aspects of WM and regional volume relationships depended on menopause status and ET. Without ET after BSO, successful WM performance correlated more strongly with hippocampal volume, which is usually the case for high memory load WM tasks (Geva et al., 2016). Even when memory changes are undetected by standard neuropsychological tests, brain‐behaviour relationships may prove a useful tool for assessing early changes in individuals at increased AD risk.