The influence of chronological age and menopause status on the functional neural correlates of spatial context memory in middle-aged females

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife – a time when most females experience spontaneous (natural) menopause. Yet, little is known about how menopause status and chronological aging influence the functional brain networks associated with episodic memory. Female-specific investigations of memory-related brain function at midlife are thus warranted to advance our knowledge of how menopause and chronological aging affect cognitive brain aging in middle-aged females. We conducted an event-related task fMRI study of episodic memory for spatial context and used multivariate partial least squares (PLS) to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 middle-aged premenopausal (age range: 39.55 – 53.30 yrs, Mage = 44.41 yrs, SDage = 3.12 yrs) and 41 middle-aged postmenopausal females (age range: 46.70 to 65.14 yrs, Mage = 57.05 yrs, SDage = 3.93 yrs). Behaviorally, both advanced age and postmenopausal status contributed to lower spatial context memory. PLS analysis of the fMRI data indicated that premenopausal, but not postmenopausal, females exhibited a positive correlation between lateral PFC, midline cortical, and angular gyrus activity during retrieval and spatial context memory performance. Also, only postmenopausal females advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal during encoding and retrieval and poorer spatial context memory performance. Our results highlight that both menopause and chronological aging affect episodic memory and related brain function in middle-aged females. Significance Statement This study advances our understanding of how menopause status and chronological age affect memory-related brain function in middle-aged females. Using data driven multivariate partial least squares (PLS) regression for behavioral analysis and PLS correlation for fMRI analysis we found: 1) advanced age and post-menopause status negatively affected spatial context memory, 2) Only premenopausal females exhibited overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy, and 3) age was correlated with reduced encoding and retrieval activity in occipitotemporal, parahippocampal, inferior parietal in only post-menopause, and this was associated with poorer spatial context memory. ### Competing Interest Statement The authors have declared no competing interest.