APOE ε2 is associated with increased tau pathology in primary tauopathy

Na Zhao, Chia-Chen Liu (), Alexandra J. Ingelgom, Cynthia Linares, Aishe Kurti, Joshua A. Knight, Michael G. Heckman, Nancy N. Diehl, Mitsuru Shinohara, Yuka A. Martens, Olivia N. Attrebi, Leonard Petrucelli, John D. Fryer, Zbigniew K. Wszolek, Neill R. Graff-Radford, Richard J. Caselli, Monica Y. Sanchez-Contreras, Rosa Rademakers, Melissa E. Murray, Shunsuke Koga, Dennis W. Dickson, Owen A. Ross and Guojun Bu ()
Additional contact information
Na Zhao: Mayo Clinic
Chia-Chen Liu: Mayo Clinic
Alexandra J. Ingelgom: Mayo Clinic
Cynthia Linares: Mayo Clinic
Aishe Kurti: Mayo Clinic
Joshua A. Knight: Mayo Clinic
Michael G. Heckman: Mayo Clinic
Nancy N. Diehl: Mayo Clinic
Mitsuru Shinohara: Mayo Clinic
Yuka A. Martens: Mayo Clinic
Olivia N. Attrebi: Mayo Clinic
Leonard Petrucelli: Mayo Clinic
John D. Fryer: Mayo Clinic
Zbigniew K. Wszolek: Mayo Clinic
Neill R. Graff-Radford: Mayo Clinic
Richard J. Caselli: Mayo Clinic
Monica Y. Sanchez-Contreras: Mayo Clinic
Rosa Rademakers: Mayo Clinic
Melissa E. Murray: Mayo Clinic
Shunsuke Koga: Mayo Clinic
Dennis W. Dickson: Mayo Clinic
Owen A. Ross: Mayo Clinic
Guojun Bu: Mayo Clinic

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by modulating amyloid-β pathology. APOE ε4 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 ε2/ε2. We also show that in humans, the APOE ε2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE ε2/ε2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE ε2 status may influence the risk and progression of tauopathy.

Date: 2018
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DOI: 10.1038/s41467-018-06783-0

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