Figure 2.

Genetics of AD implicate both APP and ELN in AD pathogenesis. AD-related causative and risk factor genes and aging disrupt ELN function directly and promote β-amyloidogenesis by altering APP cleavage and turnover directly or by modifying APP metabolism via ELN dysfunction. APP and ELN biology are intertwined via the biologic actions of genes that are responsible for AD risk. The critical roles of βCTF (C99) and Aβ are indicated and discussed further in the text. Of note, the Icelandic APP mutation that lowers risk for AD is believed to act by reducing BACE1 cleavage of APP (216), thus reducing levels of APP–βCTF and Aβ. EE, early endosome; LE, late endosome.