What's the science?

Alzheimer’s disease has previously been associated with various bacteria and viruses — in particular herpes simplex virus. However, the mechanism by which viruses may contribute to Alzheimer’s disease is not clear. This week in Neuron, Readhead and colleagues used a neuropathological network model (at the gene, transcription, protein, and histopathology levels) to understand the contribution of viruses to Alzheimer’s.

How did they do it?

The authors obtained data from brains (after death) of healthy individuals, those with ‘pre-clinical’ Alzheimer’s (i.e. early, visible pathology but no cognitive impairment at time of death), and those with later stage Alzheimer’s disease. They first used computational modelling (they created probabilistic causal networks) to understand the differences in gene expression networks between healthy individuals and those with pre-clinical Alzheimer’s disease. They focused analyses on the entorhinal cortex and hippocampus (two regions affected by the disease). From the pre-clinical and control groups, they found genes they referred to as ‘network drivers’ that regulated a large portion of the gene expression in the network.

They then evaluated viral activity (viral RNA and DNA sequences) in patients with clinical Alzheimer’s (four independent cohorts) versus healthy controls. They first performed RNA sequencing in tissue from the superior temporal gyrus, anterior prefrontal cortex, inferior frontal gyrus, and parahippocampal gyrus obtained from one of the four cohorts, and looked for the presence of genes associated with viruses known to infect the human transcriptome. They also performed whole-exome sequencing to assess viral DNA in the same regions. The relationship between Alzheimer’s traits (Clinical Dementia Rating, Amyloid Plaque Density) and elevated viral RNA and DNA levels was also examined.

What did they find?

When the authors assessed pre-clinical Alzheimer’s versus healthy control gene networks, they found that promoters (i.e. the region of the gene that turns on transcription) for gene network drivers lost or gained in pre-clinical Alzheimer’s were enriched for C2H2 zinc factor transcription factor binding motifs. The “lost in pre-clinical Alzheimer’s disease” drivers had more G-quadruplex motifs within their genes. There was also a negative relationship between the density of G-quadruplex (co-regulatory with C2H2 transcription factor) and the expression of these genes in the entorhinal cortex in the pre-clinical Alzheimer’s and Alzheimer’s disease samples. These types of changes have been previously associated with viral biology/viral infection, suggesting that viral activity is associated with Alzheimer’s. As a second line of evidence, they found overlap between identified gene network drivers and gene targets of human microRNAs that had been previously associated with innate immunity and DNA viral activity.