Despite these beneficial effects, the idea of knocking-down APOE expression to improve AD neuropathological hallmarks remains controversial because previous reports have shown that APOEnull animals present with some cognitive deficits, electrophysiological alterations, and functional connectivity changes when compared with wild-type mice (Masliah et al, 1997; Kitamura et al, 2004; Trommer et al, 2004; Yang et al, 2011a; Zerbi et al, 2014). This evidence concerns the gene APOE and Cognitive impairment.