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. 2020 Mar 18;105(6):1027-1035.e2.
doi: 10.1016/j.neuron.2019.12.031. Epub 2020 Jan 23.

Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls across Multiple Cohorts

Mary Alice Allnutt  1 , Kory Johnson  2 , David A Bennett  3 , Sarah M Connor  4 , Juan C Troncoso  5 , Olga Pletnikova  5 , Marilyn S Albert  6 , Susan M Resnick  7 , Sonja W Scholz  8 , Philip L De Jager  4 , Steven Jacobson  9
Affiliations

Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls across Multiple Cohorts

Mary Alice Allnutt et al. Neuron. .

Abstract

The interplay between viral infection and Alzheimer's disease (AD) has long been an area of interest, but proving causality has been elusive. Several recent studies have renewed the debate concerning the role of herpesviruses, and human herpesvirus 6 (HHV-6) in particular, in AD. We screened for HHV-6 detection across three independent AD brain repositories using (1) RNA sequencing (RNA-seq) datasets and (2) DNA samples extracted from AD and non-AD control brains. The RNA-seq data were screened for pathogens against taxon references from over 25,000 microbes, including 118 human viruses, whereas DNA samples were probed for PCR reactivity to HHV-6A and HHV-6B. HHV-6 demonstrated little specificity to AD brains over controls by either method, whereas other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), were detected at comparable levels. These direct methods of viral detection do not suggest an association between HHV-6 and AD.

Keywords: Alzheimer’s disease; herpesvirus; human herpesvirus 6.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Detection of HHV-6 in MSBB and ROSMAP RNAseq datasets.
(A) HHV-6A and -6B PathSeq scores are displayed in order of increasing disease severity score (calculated as neuritic plaque density*Clinical Dementia Rating score). (B) HHV-6 was detected in 9 specimens from 4 individuals in the MSBB cohort, with varying PathSeq scores. (C) HHV-6A was detected in 2 individuals in the ROSMAP cohort, both with extremely low PathSeq scores, while no HHV-6B was detected. (D) Brains with HHV-6 in one or more brain regions are classified by CERAD neuropathology, with HHV-6 detected in individuals with definite and probable AD in addition to 1 non-AD control brain. Key: BM10= Brodmann area 10, anterior prefrontal cortex; BM22= Brodmann area 22, superior temporal gyrus; BM36=Brodmann area 36, parahippocampal gyrus; BM44= Brodmann area 44, inferior frontal gyrus. DLPFC=dorsolateral prefrontal cortex
Figure 2.
Figure 2.. CNS-related virus detection across both MSBB and ROSMAP.
All CNS-related viruses detected by PathSeq analysis were distributed across AD classifications in both (A) MSBB and (B) ROSMAP. All CNS-related viruses detected in brains from the definite, probable, and possible AD neuropathology categories are compared to non-AD controls for both cohorts. See also Supplemental Figure S1. CMV= cytomegalovirus, EBV= Epstein-Barr virus, HIV= human immunodeficiency virus, JCV= John Cunningham virus
Figure 3.
Figure 3.. HHV-6 detection via ddPCR across disease statuses.
The HHV-6B viral load, in copies per 106 cells, is compared between AD and non-AD samples in both the ROSMAP and JHBRC cohorts. Viral load did not differ significantly across groups (One-way ANOVA p=0.41). The frequency of detection of HHV-6A and HHV-6B did not differ between AD and non-AD samples (χ2 p=0.81), with frequencies all remaining well below 10% in each disease cohort. Data are represented as mean ± SD.
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