Herpesvirus may cause Alzheimer’s and also lead to its progression, study finds

In a recent study conducted and published in Neuron, the researchers found evidence that links the activity of specific viral species with molecular, genetic, clinical, and neuropathological aspects of AD. Interpretation of these findings in light of the disturbances in G4 and C2H2-TF regulation in the preclinical AD samples that prompted the researchers’ evaluation of viral activity is supportive of an important role for viral activity, especially Roseoloviruses HHV-6A and HHV-7, in the development and progression of AD.

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. The researchers, in the study, 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. Increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) was observed from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. The researchers also 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.

The researchers, however, noted that the findings reported in the study are not sufficient to definitively demonstrate that viral activity causally contributes to the onset or progression of AD, which would be most naturally established in a prospective, intervention-based study. The team further highlighted that they do report on multiple streams of indirect evidence, however, that enabled them to partially address this with the available data, including: (1) causal inference testing that supports a role for HHV-6A in contributing to neuronal loss in AD, (2) AD GWAS risk loci enrichments in virus-host network eQTLs, (3) emergence of molecules such as miR-155 from preclinical AD networks and virus-host networks, and (4) relative specificity of HHV-6A and HHV-7 for AD, compared with other neurodegenerative diseases. Follow-up studies that evaluate the onset and progression of AD phenotypes in virally infected AD model systems would be one approach to better delineate the causal and mechanistic relationships that link pathogen activity with the evolution of AD-associated behavioral, molecular, and neuropathological changes.

The full study can be read at https://www.cell.com/neuron/fulltext/S0896-6273(18)30421-5

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