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

Neuron 2018 07 21;99(1):64-82.e7. Epub 2018 Jun 21.

Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287-5001, USA. Electronic address:

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.

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http://dx.doi.org/10.1016/j.neuron.2018.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551233PMC
July 2018
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