In the absence of a dementia diagnosis, human APOE4-carriers still display structural and functional differences within regions of the hippocampus and cortex, and cognitive decline compared to age-matched non-carriers (Bookheimer and Burggren, 2009; Filippini et al., 2009; Olofsson et al., 2010; Sheline et al., 2010; Wisdom et al., 2011; Liu et al., 2013; Di Battista et al., 2016), and mouse models show cognitive deficits linked to APOE4 expression without AD pathology (Leung et al., 2012; Peng et al., 2017; East et al., 2018). This evidence concerns the gene APOE and Alzheimer disease.