APOE modifies the interaction of entorhinal cerebral blood flow and cortical thickness on memory function in cognitively normal older adults

Objective: The epsilon 4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE epsilon 4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether APOE genotype (epsilon 4+ vs. epsilon 4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance. Methods: Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 epsilon 4+, 76 epsilon 4-) between the ages of 64 and 89 (mean age = 73). Results: Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in epsilon 4 carriers with lower entorhinal CT. Conclusions: Findings suggest that older adult APOE epsilon 4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE epsilon 4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in epsilon 4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to epsilon 4 carriers and non-carriers are discussed in the context of neurovascular compensation.