Our observation that ApoE2, ApoE3, and ApoE4 differentially activate APP transcription and Aβ-synthesis reveals a striking parallel to the contribution of these genetic ApoE variants to AD risk, suggesting that the differential activation of Aβ synthesis by ApoE2, ApoE3, and ApoE4 may contribute to their role in AD pathogenesis. However, we do not mean to imply that the differential efficacy of ApoE2, ApoE3, and ApoE4 in activating APP transcription and Aβ-synthesis is the only mechanism by which these genetic isoforms influence AD risk. In recent years, major progress was achieved in the understanding of APP cleavage by α-, β-, and γ-secretases, and plausible hypotheses describe how these proteases may contribute to AD pathogenesis and how rare missense mutations in APP and γ-secretase may cause familial AD (De Strooper and Karran, 2016; Goedert, 2015). How APP transcription is regulated, and what differentiates the APP gene from the closely related APLP1 and APLP2 genes that are not linked to AD, is much less clear. Genetic variations in the APP promoter correlate with AD risk (Lahiri et al., 2005; Brouwers et al., 2006),
