Early structural brain markers for Alzheimer’s Disease in women: Brain‐behaviour relationships after ovarian removal

Abstract 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±SD age = 44.92±5.11, n = 26) or not taking ET (BSO: M±SD age = 45.62±5.04, n = 26) were compared to age‐matched premenopausal controls (AMC: M±SD age = 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.