APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms1. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

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  1. 1.

    , & Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006312 (2012)

  2. 2.

    et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993)

  3. 3.

    et al. β-amyloid burden is not associated with rates of brain atrophy. Ann. Neurol. 63, 204–212 (2008)

  4. 4.

    , , & Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639 (1992)

  5. 5.

    et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-Parkinsonism from Richardson’s syndrome. Brain 130, 1566–1576 (2007)

  6. 6.

    et al. Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 11183–11186 (1994)

  7. 7.

    . et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527–2534 (2004)

  8. 8.

    et al. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol. 133, 839–856 (2017)

  9. 9.

    et al. Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia. Brain 140, 1437–1446 (2017)

  10. 10.

    et al. Apolipoprotein E gene and sporadic frontal lobe dementia. Neurology 48, 1526–1529 (1997)

  11. 11.

    et al. Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc. Natl Acad. Sci. USA 106, 2018–2022 (2009)

  12. 12.

    . et al. Dose dependent effect of APOE epsilon4 on behavioral symptoms in frontal lobe dementia. Neurobiol. Aging 27, 285–292 (2006)

  13. 13.

    et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007)

  14. 14.

    et al. Impaired autophagy in APOE4 astrocytes. J. Alzheimers Dis. 51, 915–927 (2016)

  15. 15.

    et al. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J. Neurosci. 29, 6771–6779 (2009)

  16. 16.

    et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017)

  17. 17.

    et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016)

  18. 18.

    , & APOE genotype-specific differences in the innate immune response. Neurobiol. Aging 30, 1350–1360 (2009)

  19. 19.

    et al. APOε4 is associated with enhanced in vivo innate immune responses in human subjects. J. Allergy Clin. Immunol. 134, 127–134 (2014)

  20. 20.

    et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012)

  21. 21.

    et al. Allele epsilon 4 of apolipoprotein E shows a dose effect on age at onset of Pick disease. Exp. Neurol. 136, 162–170 (1995)

  22. 22.

    et al. Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl Acad. Sci. USA 98, 8838–8843 (2001)

  23. 23.

    et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016)

  24. 24.

    et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016)

  25. 25.

    et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013)

  26. 26.

    et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014)

  27. 27.

    et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015)

  28. 28.

    et al. Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol. 125, 581–593 (2013)

  29. 29.

    et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 8, 1–13 (2012)

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This study was funded by National Institutes of Health (NIH) NS090934 (D.M.H.), P01-AG03991 (D.M.H., J.C.M., A.M.F.), P01-AG026276 (D.M.H., J.C.M., A.M.F.), P50 AG05681 (D.M.H., J.C.M., A.M.F.), the JPB Foundation (D.M.H., B.A.B.), Cure Alzheimer’s Fund (D.M.H.), a grant from AstraZeneca (D.M.H., S.M.P.), NIH AG023501 (W.W.S.), AG019724 (W.W.S.), Consortium for Frontotemporal Dementia Research (W.W.S.), Tau Consortium (W.W.S.), NIH K08 AG052648 (S.S.), NIH AG051812 (O.B.), NS088137 (O.B.), National Multiple Sclerosis Society (5092A1) (O.B.), Nancy Davis Foundation Award (O.B.), Amyotrophic Lateral Sclerosis Association (ALSA2087) (O.B.), and NIH K01 NS096719-01 (G.G.). We thank J. Yu for technical assistance in gene expression analysis; N. Barthélemy for assistance in tau phosphorylation analysis; and S. Schindler for assistance in statistical analysis. Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (NIH Grant U01 AG024904) and Department of Defense ADNI (award number W81XWH-12-2-0012). A full list of ADNI funding information is listed in the Supplementary Information.

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Author notes


  1. Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Yang Shi
    • , Gilbert Gallardo
    • , Kairuo Wang
    • , Joseph Roh
    • , Mary Beth Finn
    • , Hong Jiang
    • , Courtney Sutphen
    • , John C. Morris
    • , Anne M. Fagan
    •  & David M. Holtzman
  2. Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

    • Kaoru Yamada
  3. Department of Neurobiology, School of Medicine, Stanford University, Stanford, California 94305, USA

    • Shane Antony Liddelow
    •  & Ben A. Barres
  4. Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Parkville, Victoria 3010, Australia

    • Shane Antony Liddelow
  5. Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Scott T. Smith
    • , Caroline Baufeld
    •  & Oleg Butovsky
  6. Appel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA

    • Lingzhi Zhao
    •  & Wenjie Luo
  7. Memory and Aging Center, Department of Neurology, University of California, San Francisco, California 94143 USA.

    • Richard M. Tsai
    • , Salvatore Spina
    • , Lea T. Grinberg
    • , Julio C. Rojas
    • , Bruce L. Miller
    • , Adam L. Boxer
    •  & William W. Seeley
  8. Department of Pathology, University of California, San Francisco, California 94143, USA

    • Lea T. Grinberg
    •  & William W. Seeley
  9. Department of Ophthalmology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA

    • Grace Robinson
  10. Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center’s Geriatric Research, Education and Clinical Center, Durham, North Carolina 27705, USA

    • Patrick M. Sullivan
  11. AstraZeneca R&D, Wilmington, Delaware 19850, USA

    • Michael W. Wood
  12. Division of Biostatistics, Washington University in St Louis, St Louis, Missouri 63110, USA

    • Lena McCue
    •  & Chengjie Xiong
  13. Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue B8134, St. Louis, Missouri 63110, USA

    • Jorge L. Del-Aguila
    •  & Carlos Cruchaga
  14. Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA

    • Carlos Cruchaga
  15. Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Oleg Butovsky
  16. Voyager Therapeutics, Cambridge, Massachusetts 02139, USA

    • Steven M. Paul


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D.M.H., S.M.P., and Y.S. conceived the study. Y.S., K.Y., and D.M.H. designed the study. Y.S. performed most of the experiments and analysed the data, assisted by K.Y., K.W., G.G., L.Z, M.W.W., J.R., G.R., M.B.F., and H.J.; S.T.S., C.B., and O.B. performed the Nanostring microglial gene expression assay; S.A.L. and B.A.B. performed the astrocytic gene expression assay; W.L. performed the microglia LPS stimulation assay; R.M.T., S.S., L.T.G., B.L.M., W.W.S., J.C.R., and A.L.B. performed data analysis for human primary tauopathies; J.D.A., L.M., C.S., C.X., J.C.M., A.F., and C.C. performed data analysis in human patients with Alzheimer disease; P.M.S. provided the ApoE KI mice. Y.S. and D.M.H. wrote the manuscript. All authors discussed the results and commented on the manuscript. A portion of the human Alzheimer disease data used in preparation of this article was obtained from the ADNI database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found in the Supplementary Information.

Competing interests

D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. He consults for Genentech, AbbVie, Eli Lilly, Proclara, GlaxoSmithKline, and Denali. Washington University receives research grants to the laboratory of D.M.H. from C2N Diagnostics, Eli Lilly, AbbVie, and Denali.

Corresponding author

Correspondence to David M. Holtzman.

Reviewer Information Nature thanks C. Haass, E. Roberson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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