Collectively, our findings establish a mechanistic link between cholesterol accumulation and α-Syn pathology mediated by APOE4 astrocytes and offer therapeutic opportunities for APOE4 carriers with α-Syn pathology in classical synucleinopathies like LBD, as well as in AD with Lewy Bodies and other neurodegenerative conditions. The gene discussed is APOE; the disease is synucleinopathy.