Dedifferentiation of memory-related brain function as a potential early biomarker of Alzheimer’s disease in asymptomatic older women: Results from the PREVENT-AD Cohort

AbstractLate-onset Alzheimer’s disease (AD) disproportionately affects women compared to men. Episodic memory decline is one of the earliest and most pronounced deficits observed in AD. However, it remains unclear whether there are sex differences in episodic memory-related brain function in cognitively intact older adults at risk of developing AD. In the current study, we used task fMRI to test for sex differences in episodic memory-related brain activity and brain activity-behavior correlations in cognitively intact older adults with a family history of AD from the PREVENT-AD cohort study in Montreal, Canada (Mage=63.03±3.78; Meducation=15.41±3.40). Importantly, we tested women and men who were matched in age, body mass index, years of education, and proximity to the age of parental AD onset. We used data-driven task-based multivariate partial least squares (PLS) analysis to identify sex differences in brain activity during the successful encoding and retrieval of objects and their associated spatial context. We used behavior PLS to examine sex differences in the correlations between brain activity and memory performance at encoding and retrieval. Our results suggested no significant sex differences in behavioral performance on the memory task. Yet, we observed sex differences in task-related brain activity and in brain activity-behavior correlations during the encoding of object-location associative memories and object-only item memory, and the retrieval of object only item memories. Specifically, subsequent object-location associative retrieval associated with encoding related activation of caudate, cingulate, and middle occipital cortex in women and, additionally, of temporo-parietal regions in men. We also found male-specific activations in ventrolateral prefrontal cortex (PFC) and insula during associated with the encoding and retrieval of object-only information. Moreover, whereas activity in ventrolateral PFC, posterior cingulate, and inferior parietal regions during encoding supported subsequent performance in women, activity in these regions during retrieval supported object-location associative memory in men. Similarly, we found that activity in ventrolateral PFC, precuneus, parahippocampal, anterior cingulate, and occipital regions during retrieval supported general memory performance in women but object-only retrieval in men. Our findings suggest functional dedifferentiation of episodic memory-related brain activation and performance in women compared to men. Follow up analyses should test for sex differences in the relationship between brain activity patterns and performance longitudinally, in association with risk factors for AD development.