They included unprecedented roles as direct signal-transducing receptors (Hiesberger et al., 1999; Trommsdorff et al., 1999) and regulators of central and peripheral synaptic transmission (Beffert et al., 2005; Choi et al., 2013; Weeber et al., 2002) and have established a strong rationale and mechanistic basis by which ApoE isoforms and ApoE receptors can directly affect synaptic homeostasis, neuronal survival and thus the cognitive impairment and progressive neurodegeneration that underlie LOAD. Here, APOE is linked to Cognitive impairment.