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Deconstructing and targeting the genomic architecture of human neurodegeneration

Nature Neuroscience volume 21, pages 1310–1317 (2018)Cite this article

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Abstract

The field of neurodegenerative disease research has seen tremendous advances over the last two decades as new technologies and analytic methods have enabled well-powered human genomic studies. Driven first by genetic studies and more recently by transcriptomic and epigenomic studies of proper size, we have uncovered a large repertoire of loci, genes, and molecular features that are implicated in discrete, syndromically defined neurodegenerative conditions, such as Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Parkinson’s disease. As we begin to understand the impact of these genomic features in each disease, we also appreciate that many aging individuals accumulate each of these pathologies without fulfilling criteria for syndromic diagnoses, that other pathologies are common in individuals with a given diagnosis, and that there may be shared protective factors against central nervous system injury. Thus, we now need to bring these disparate observations together into a person-centered approach that considers all neurodegenerative and protective processes simultaneously to modulate the trajectory of cognitive and functional decline that comes with brain aging.

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Fig. 1: Overlap among the results of GWAS for AD, FTD, MS, and PD.
Fig. 2: Allelic and phenotypic heterogeneity in the UNC5C locus.
Fig. 3: An initial network map of the aging brain provides a framework for integrating additional factors influencing the function of older individuals.
Fig. 4: Functional and pathologic heterogeneity of brains in the older population.

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Acknowledgements

We thank C. White and D. Felsky for their help in preparing Figs. 1 and 4.

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Authors and Affiliations

  1. Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA

    Philip L. De Jager

  2. Cell Circuits Program, Broad Institute, Cambridge, MA, USA

    Philip L. De Jager & Hyun-Sik Yang

  3. Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    Hyun-Sik Yang

  4. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    David A Bennett

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De Jager, P.L., Yang, HS. & Bennett, D.A. Deconstructing and targeting the genomic architecture of human neurodegeneration. Nat Neurosci 21, 1310–1317 (2018). https://doi.org/10.1038/s41593-018-0240-z

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