APOE4 has complex effects on AD pathophysiology through both Aβ-mediated pathway (i.e., indirect effect of APOE4 on hippocampal volume or AD-CM reduction via Aβ accumulation) and Aβ-independent pathways (i.e., direct effect of APOE4 on hippocampal volume or AD-CM reduction not mediated by Aβ accumulation; Huang, 2010). Here, APOE is linked to Alzheimer disease.