Aβ and Aβ-related genes in AD. Aβ is produced by sequential cleavage of APP by β-secretase (BACE1) and γ-secretase. γ-secretase is a multi-protein complex, of which PS1 or PS2 is the catalytic core. After being produced, Aβ is secreted outside the cell and binds to various isoforms of ApoE. These Aβ-binding ApoE isoforms will allow Aβ to undergo metabolism in different pathways, e.g., clearance via BBB, degradation by Aβ-degradating enzymes (IDE or neprilysin), deposition or trafficking into the cell. The affinity of ApoE4 to Aβ is lower than that of ApoE2 or ApoE3. While ApoE2 and ApoE3 help Aβ to be cleared by transport or degradation, ApoE4 mainly induce Aβ to aggregation, implicating it to be a high risk factor for AD. There is a feedback existing in vivo to keep proper Aβ levels. When Aβ is generated, AICD is released, which is translocated into the nucleus and initiates the transcription of neprilysin. Increased neprilysin protein will degradate Aβ and hereby reduces Aβ to a proper level.