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

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.

Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

“…However, data supporting a role for herpesviridae , or other infections, is widely held as equivocal. Nonetheless, our identification of a plausible pathway for direct viral mediation of β-amyloid deposition and recent transcriptomic data confirming increased abundance of herpes viruses in AD brain (Readhead et al, 2018) add to mounting evidence that viral and other microbial infections may, indeed, play an important role in the etiology and pathogenesis of this devastating neurodegenerative disease.…”

A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex–associated Alzheimer's disease

“…The findings show that genetic background is important for the development of HSV1‐associated AD. This corresponds with AD as a multifactorial disease, caused by genetic susceptibility in combination with environmental factors [1,2,7,16,30]. One plausible explanation could be that AD development with amyloid deposition is fueled by persistent and low‐grade infection in the CNS over long periods of time.…”

“…HSV1 DNA has been detected in the brains of patients with AD patients and colocalized with amyloid plaques in particular [12–15]. More recently, transcriptomic studies also showed an increased abundance of HSV1 in the brains of patients with AD [16]. In epidemiological studies, both carriage of and reactivated HSV1 infection doubled the risk of developing AD [9,10,17].…”

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…In a mouse model, recurrent activation of brain herpes simplex virus 1 (HSV1) infection led to amyloid‐beta accumulation and other AD pathology (tau phosphorylation, neuroinflammation) (De Chiara et al, ), indicating that viral infection can trigger Aβ accumulation and AD pathology. In an AD‐omics study, HHV‐6A and HHV‐7 were identified as prominently associated with human AD across three independent cohorts (Readhead et al, ). Reports like these support the theory that pathogens trigger AD (Haas & Lathe, ; Itzhaki, ; Sochocka, Zwolińska, & Leszek, ), as well as the role of amyloid‐beta as a protection mechanism against viral infection (Li, Liu, Zheng, & Huang, ).…”