Sex modifies the association between hippocampal blood flow and episodic memory in cognitively unimpaired individuals

Abstract

BackgroundCerebral blood flow (CBF) is disrupted in Alzheimer’s disease (AD) and associated with worse cognition, including episodic memory performance. Sex differences have been noted in both CBF and memory performance in AD; women demonstrate higher global CBF and memory performance than men. However, the effect of sex on the association between CBF and memory performance has not been explored. This study examined whether there were sex differences in the association between memory performance and CBF in AD‐related regions in typically aging older adults.MethodThe study included 119 functionally intact (CDR=0) older adults from the UCSF Hillblom Aging Network (mean age 74.9 (5.7), 51.2% females) who completed a cognitive assessment with brain MRI including T1‐weighted and arterial spin labeling (ASL) in hippocampal and precentral gyrus (as control) regions. Episodic memory was assessed by the California Verbal Learning Test and Benson figure delayed recall. Mean Z‐scores estimated a memory composite score. Memory composites were the dependent variable in regression models testing the interaction between regional ASL and sex as predictors, and age, education, APOE‐ε4, hippocampal volume, and vascular burden composite as covariates.ResultThere were no significant sex differences in levels of hippocampal CBF, but females performed better on the memory composite (p<0.001) than males after adjustment for age and education. We found that sex modified the association between hippocampal CBF and memory performance (figure 1) (p=0.04). Specifically, the positive association between hippocampal CBF and memory performances was stronger in men compared to women. This interaction remained significant after further adjusting for APOE‐ε4, hippocampal volume, and vascular burden. There was no significant sex by CBF interaction on memory performance when examining precentral CBF (p=0.79).ConclusionOur result suggests that sex modifies the association between memory performance and perfusion in brain regions vulnerable to pathological changes in preclinical AD. Specifically, greater hippocampal CBF is positively associated with memory performance in men but not women. Men may benefit more from increased blood flow, possibly reflecting vascular integrity, in hippocampal regions in memory performance than women. This work highlights mechanisms that may be differentially vulnerable by sex differences and inform risk for neurodegenerative diseases.