Aò Metabolism and the Role of APOE in AlzheimerâÂÂs Disease

Disturbance of the production and clearance of Aβ in the brain is the main cause of memory and cognition decline and contributes strongly to the development of AD. In human, APOE gene has three isoforms, e2, e3 and e4, with APOE e4 as the most risk gene among them. In the development of AD pathophysiology, ApoE4 is positively associated with Aβ plague formation, but the mechanisms are not clear. In this review, we proposed a hypothesis that the effect of ApoE4 on Aβ possibly involves three processes: 1) ApoE4 can directly interact with Aβ and interferes Aβ clearance. 2) ApoE4 can compete with Aβ for the same receptor, that hinds the cellular uptake pathways of Aβ. 3) ApoE4 also modulates other Aβ degrading proteases like IDE to downregulate Aβ degradation, but the mechanisms needs to be further investigated. These findings suggest that the effect of ApoE in AD pathogenesis is complicated and modulation of ApoE is an attractive strategy for AD therapy.