Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus

Benjamin Readhead, Jean Vianney Haure-Mirande, Cory C. Funk, Matthew A. Richards, Paul Shannon, Vahram Haroutunian, Mary Sano, Winnie S. Liang, Noam D. Beckmann, Nathan D. Price, Eric M. Reiman, Eric E. Schadt, Michelle E. Ehrlich, Sam Gandy, Joel T. Dudley

Research output: Contribution to journalArticle

178 Scopus citations

Abstract

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD. Readhead et al. construct multiscale networks of the late-onset Alzheimer's disease (AD)-associated virome and observe pathogenic regulation of molecular, clinical, and neuropathological networks by several common viruses, particularly human herpesvirus 6A and human herpesvirus 7.

Original languageEnglish (US)
Pages (from-to)64-82.e7
JournalNeuron
Volume99
Issue number1
DOIs
StatePublished - Jul 11 2018

Keywords

  • Alzheimer's disease
  • HHV-6A
  • HHV-6B
  • HHV-7
  • Roseolovirus
  • human herpesvirus
  • integrative genomics
  • multiscale networks
  • network biology
  • systems biology

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Readhead, B., Haure-Mirande, J. V., Funk, C. C., Richards, M. A., Shannon, P., Haroutunian, V., Sano, M., Liang, W. S., Beckmann, N. D., Price, N. D., Reiman, E. M., Schadt, E. E., Ehrlich, M. E., Gandy, S., & Dudley, J. T. (2018). Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron, 99(1), 64-82.e7. https://doi.org/10.1016/j.neuron.2018.05.023