Subjective cognitive decline (SCD) and possession of the ε4 allele of the apolipoprotein E (APOE) gene are both associated with increased risk for age-related cognitive decline and Alzheimer’s disease (AD). While mechanisms contributing to the increased risk associated with these factors are not well understood, evidence suggests that altered cerebral blood flow (CBF) may play a critical role. There is also evidence that altered CBF and brain structure among APOE ε4 carriers may interact to negatively impact cognition. The current studies utilized arterial spin labeling (ASL) magnetic resonance imaging (MRI) and high-resolution structural scans among cognitively normal older adults to determine the extent to which: 1) SCD modifies the effect of CBF on concurrent memory (Study 1), 2) APOE modifies effects of medial temporal lobe (MTL) CBF and brain structure (cortical thickness [CT], volume [Vo]) on concurrent memory (Study 2), and on 3) memory change (Study 3). Study 1 results showed that those with SCD exhibited positive associations between memory and CBF within the posterior cingulate cortex, middle temporal gyrus, and inferior frontal gyrus, whereas those without SCD displayed negative associations within the posterior cingulate cortex, middle temporal gyrus, hippocampus, fusiform gyrus, and inferior frontal gyrus. Findings suggest that while higher CBF is supportive of memory function in those without SCD, it may no longer support memory in those reporting SCD, likely reflecting neurovascular dysregulation. Results from Studies 2 and 3 demonstrated that, for APOE ε4 carriers, the combination of higher CBF and lower CT in the entorhinal cortex was associated with worse concurrent memory, but lower CBF and lower CT in this same region was associated with greater memory decline. Findings suggest that APOE ε4 carriers experience neurovascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect cognition even in the absence of overt clinical symptoms. Results support the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among ε4 carriers, likely reflecting different stages of neurovascular compensation. More broadly, results add to accumulating evidence supporting the early role of vascular dysregulation in AD risk.