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. Author manuscript; available in PMC: 2023 Apr 20.
Published in final edited form as: Neuron. 2022 Mar 16;110(8):1304–1317. doi: 10.1016/j.neuron.2022.03.004

Figure 1. ApoE cascade hypothesis.

Figure 1.

The cascade starts from the different biochemical and biophysical properties including apoE structure, lipidation, protein levels, receptor binding, and oligomerization. These biochemical/biophysical differences are then propagated to functional effects on cellular homeostasis including cellular stress, endosomal-lysosomal trafficking, as well as lipid dysregulation. Not depicted here, some of these cellular effects can be either cell autonomous in cells expressing abundant apoE (astrocytes and microglia in the brain, hepatocytes and macrophages in the periphery, and vascular mural cells interfacing the periphery with the brain), or non-cell autonomous (e.g., secreted apoE from one cell type binding to apoE receptors on another including neurons). These cellular effects are further relayed to trackable phenotypes at the systems level highlighted by neuroinflammation, vascular dysfunction, and neuropathologies, leading to synaptic dysfunction/loss, neurodegeneration, and eventual age-related cognitive decline and AD.