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Neurogenetic contributions to amyloid beta and tau spreading in the human cortex

Nature Medicine volume 24, pages 1910–1918 (2018)Cite this article

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Abstract

Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer’s disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as ‘axon related’ and the Aβ profile as ‘dendrite related’. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain.

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Fig. 1: Propagation routes from prominent areas of tau and amyloid deposits.
Fig. 2: Hubs of pathology propagation of tau and amyloid.
Fig. 3: Tau and amyloid propagation-based staging.
Fig. 4: Brain colocalization of in vivo propagation patterns and Allen gene expression data.
Fig. 5: Interactome and Gene Ontology analyses of imaging genetic profiles.
Fig. 6: Propagation-based staging of tau and Aβ and APOE genotype in individuals.

Data availability

All neuroimaging and clinical data that support the findings of this study are available from https://nmr.mgh.harvard.edu/lab/harvard-aging-brain-study/public-data-releases. HABS data curation is overseen by Aaron P. Schultz (aschultz@nmr.mgh.harvard.edu) at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

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Acknowledgements

We thank the investigators and staff of the Harvard Aging Brain Study, Massachusetts Alzheimer’s Disease Research Center, the individual research participants, and their families and caregivers. We also thank the PET Core of the MGH, the Harvard Center for Brain Science Neuroimaging Core and the Athinoula A. Martinos Center for biomedical imaging support. This research was supported by grants from the National Institutes of Health (NIH) (K23-EB019023 to J.S.; T32EB013180 to L.O.-T.; R01HL137230 and P41-EB022544 to G.E.-F.; R01-AG027435-S1 to R.A.S. and K.A.J.; P50-AG00513421 and R01AG046396 to K.A.J. and R.A.S.; P01-AG036694 to R.A.S. and K.A.J.; and RF1AG052653 to Q.L.); Massachusetts ADRC; Alzheimer’s Association (NIRG-11-205690 to J.S.; IIRG-06-32444 to R.A.S. and K.A.J.; and ZEN-10-174210 to K.A.J.); and the Alzheimer Forschung Initiative e.V. (to M.J.G.). The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

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Authors and Affiliations

  1. Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jorge Sepulcre, Laura Ortiz-Terán, Ibai Diez, Heidi I. L. Jacobs, Bernard J. Hanseeuw, Quanzheng Li, Georges El-Fakhri & Keith A. Johnson

  2. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Jorge Sepulcre, Bernard J. Hanseeuw & Reisa A. Sperling

  3. German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany

    Michel J. Grothe

  4. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Federico d’Oleire Uquillas, Hyun-Sik Yang, Reisa A. Sperling & Keith A. Johnson

  5. Neurotechnology Laboratory, Tecnalia Health Department, Derio, Spain

    Ibai Diez

  6. Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Hyun-Sik Yang, Reisa A. Sperling & Keith A. Johnson

  7. Department of Neurology, Saint-Luc University Hospital, Institute of Neuroscience, University of Louvain, Brussels, Belgium

    Bernard J. Hanseeuw

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  1. Jorge Sepulcre
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Contributions

J.S. contributed to the design, analysis and interpretation of the data and preparation of the manuscript. M.J.G. contributed to the design, analysis and interpretation of the data and preparation of the manuscript. F.d.U. contributed to the analysis of the data and preparation of the manuscript. L.O.-T. contributed to the analysis of the data and preparation of the manuscript. I.D. contributed to the analysis and interpretation of the data and preparation of the manuscript. H.-S.Y. contributed to the analysis of the data and preparation of the manuscript. H.I.L.J. contributed to the interpretation of the data and preparation of the manuscript. B.H. contributed to the interpretation of the data and preparation of the manuscript. Q.L. contributed to the interpretation of the data and preparation of the manuscript. G.E.-F. contributed to the interpretation of the data and preparation of the manuscript. R.A.S. contributed to the design and interpretation of the data and preparation of the manuscript. K.A.J. contributed to the design and interpretation of the data and preparation of the manuscript.

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Correspondence to Jorge Sepulcre.

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Sepulcre, J., Grothe, M.J., d’Oleire Uquillas, F. et al. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat Med 24, 1910–1918 (2018). https://doi.org/10.1038/s41591-018-0206-4

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