APOE ε2 is associated with increased tau pathology in primary tauopathy

Apolipoprotein E (APOE) epsilon 4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by modulating amyloid-beta pathology. APOE epsilon 4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperphosphorylated tau species, tau aggregates, and behavioral abnormalities in mice expressing APOE epsilon 2/epsilon 2. We also show that in humans, the APOE epsilon 2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE epsilon 2/epsilon 2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE epsilon 2 status may influence the risk and progression of tauopathy.