Though APOE ε4 carriers remain at significantly greater risk for AD (Corder et al., 1993) due to increased propensity to develop β-amyloid (Castellano et al., 2011; Holtzman et al., 2012) and tau pathologies (Shi et al., 2017), detrimental, age-related effect of the APOE ε4 allele on neuronal network plasticity potential constitutes an independent risk factor promoting earlier age of onset and more rapidly progressing AD symptoms due to limiting the cognitive reserve [reviewed in Yamazaki et al. (2019)]. The gene discussed is APOE; the disease is Alzheimer disease.