In this chapter, we discuss the current knowledge of the association between APOE polymorphism and synucleinopathies, as well as the diseases’ pathophysiology and main clinical manifestations. Alpha-synuclein regulates the storage of dopamine in synaptic vesicles by influencing the expression and activity of vesicular monoamine transporter 2 (VMAT2) in nigral neurons. ApoE is involved in triglyceride, cholesterol transport, and metabolism and maintains the stability of lipoproteins, playing an important role in repairing and maintaining the integrity of nerves when the nerves are injured. The role of APOE in other synucleinopathies is not completely understood. It has been proposed that the link between APOE ε4 and dementia with Lewy bodies (DLB) could be influenced by the presence of Alzheimer’s disease-related neuropathology, but APOE may be related to dementia through a mechanism that is separate from the amyloid cascade.