The Interplay Between Apolipoprotein E4 and the Autophagic–Endocytic–Lysosomal Axis

Since its discovery as a genetic risk factor for Alzheimer’s disease, the APOE4 allele has been linked to the majority of the pathological findings associated with the disease progression. These include abnormalities of the endocytic, autophagic, and lysosomal machineries, which begin at the most early stages of Alzheimer’s disease development. Considering that these three vesicular systems share common features and, in fact, comprise an interconnected cargo-trafficking and degradation network, some of the effects of APOE4 are interrelated, while others are system-specific. In turn, APOE4-driven impairments of endocytosis, autophagy, and lysosomal activity influence various aspects of Alzheimer’s disease pathology, ranging from Aβ generation and clearance to neuronal loss and cognitive deficits. This review discusses the detrimental effects of APOE4 on the endocytic–autophagic–lysosomal axis in the context of Alzheimer’s disease, as well as the various mechanisms underlying them.