The article by Nichols et al1 is an important and useful addition to the literature. To our knowledge, it was the first to examine the effects of apolipoprotein E (APOE) genetic variation using an episodic memory task during functional magnetic resonance imaging across the adult life span. During task performance, they found an age × genotype interaction: in younger subjects, ϵ4 carriers showed less hippocampal activation than ϵ4 noncarriers, whereas the opposite was true for older subjects. A recent review,2 however, highlighted the almost equal distribution of either “underactivation” or “overactivation” in ϵ4 carriers compared with noncarriers during episodic memory functional magnetic resonance imaging studies in both younger and older participants. Therefore, despite the results of Nichols et al, an explanation for the discrepant results in the literature remains elusive. One important consideration of ϵ4 activity on the blood oxygen level–dependent signal is its well-documented effect on resting cerebral blood flow.2 Indeed, patients with Alzheimer disease (AD) early in the disease process show decreased blood flow at rest in the hippocampal complex and posterior cingulate cortex. Furthermore, the ϵ4 allele has been shown to influence functional connectivity at rest among regions that compose episodic memory circuitry.3