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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2018-07, Vol.99 (1), p.64-82.e7
• Main Authors: Readhead, Ben, Haure-Mirande, Jean-Vianney, Funk, Cory C., Richards, Matthew A., Shannon, Paul, Haroutunian, Vahram, Sano, Mary, Liang, Winnie S., Beckmann, Noam D., Price, Nathan D., Reiman, Eric M., Schadt, Eric E., Ehrlich, Michelle E., Gandy, Sam, Dudley, Joel T.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - virology; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - genetics; Animals; Aspartic Acid Endopeptidases - genetics; Brain - metabolism; Brain - pathology; Brain - virology; Brain research; Case-Control Studies; Clusterin - genetics; Cohort Studies; Data collection; Encephalitis, Viral - genetics; Encephalitis, Viral - metabolism; Encephalitis, Viral - pathology; Encephalitis, Viral - virology; Gene expression; Gene Expression Profiling; Gene Regulatory Networks; Genomics; Herpes viruses; Herpesviridae; Herpesvirus 6, Human; Herpesvirus 7, Human; HHV-6A; HHV-6B; HHV-7; human herpesvirus; Humans; integrative genomics; Mice; Mice, Knockout; Mice, Transgenic; Microbiota; MicroRNAs - genetics; Monomeric Clathrin Assembly Proteins - genetics; multiscale networks; network biology; Neurodegeneration; Neuromodulation; Neuropathology; Nuclear Proteins - genetics; Presenilin-1 - genetics; Protein turnover; Proteins; Proteomics; Roseolovirus; Roseolovirus Infections - genetics; Roseolovirus Infections - metabolism; Roseolovirus Infections - pathology; Roseolovirus Infections - virology; systems biology; Tumor Suppressor Proteins - genetics; Viral Load; Viruses; β-Site APP-cleaving enzyme 1
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.05.023

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. •Common viral species frequently detected in normal, aging brain•Increased HHV-6A and HHV-7 in brains of subjects with Alzheimer’s disease (AD)•Findings were replicated in two additional, independent cohorts•Multiscale networks reveal viral regulation of AD risk, and APP processing genes 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.