Effects of APOE on tau propagation and tau-mediated neurodegeneration. Despite the lack of definitive evidence suggesting direct interactions between apoE and tau, a series of studies have shown that APOE can modulate tau pathology. Tau aggregation varies across APOE genotypes, with ε4 cases presenting the highest levels and ε2 the lowest. Tau propagation and subsequent seeding could be mediated through apoE receptors capable of internalizing tau, such as LRP1, HSPGs, and SORL1. LDLR overexpression has also been seen to protect against tau-mediated neurodegeneration by reducing extracellular apoE levels. With regard to tau-mediated neurodegeneration and neuroinflammation, both appear to be exacerbated in APOE ε4 brains compared with APOE ε2 or APOE ε3, whereas APOE removal results in a decrease in both.