On 23 January, Dr Mary Allnutt and colleagues published a paper in Neuron, showing no differences in herpesvirus detection in brain samples from people with Alzheimer’s disease (AD) and their unaffected peers.
Several studies have previously linked herpesviruses such as HHV-6A, HHV-6B and HSV-1 with the development of AD. HHV-6 (which causes the common childhood infection, roseola) and HSV-1 are known to infect cells of the central nervous system, and are linked to conditions such as multiple sclerosis, encephalitis and epilepsy. In animal models of AD, scientists have shown that amyloid plaque formation can be stimulated by the presence of HHV-6 or HSV-1. Using genetic sequencing techniques to analyse post mortem brain samples for the presence of herpesvirus, two recent publications have shown an increase in viral DNA in the brains from people with AD compared to unaffected controls. However, the genetic sequencing techniques and statistical analyses used in these papers have been criticised by some scientists in the AD field.
To clarify and extend the results of these and other studies investigating the link between herpesvirus and AD, Dr Allnutt and colleagues set out to re-analyse the large genetic datasets used in the previous studies. Using RNA-sequencing data from the Mount Sinai Brain Bank (MSBB) and Religious Orders Study/Memory and Aging Project (ROSMAP) studies, they were able to screen post mortem brain samples from over 900 individuals, looking for HHV-6 sequences. To perform this large-scale bioinformatics analysis they used PathSeq, a new screening tool that was developed by the Broad Institute to detect the presence of over 100 different types of virus. Unlike previous studies, PathSeq did not detect any significant association between the presence of HHV-6 and AD. For example, of the 177 people in the MSBB cohort with definite or probable AD, only 4 showed any evidence of HHV-6 infection in brain samples – and only at very low levels.
The research team then moved on to directly test post mortem brain samples for the presence of herpesvirus DNA, using a highly-sensitive analysis technique called digital droplet PCR (ddPCR). This technique can provide a measurement of viral load in samples, expressed as the number of virions per million cells analysed. Here, the researchers extended their analyses to include samples from MSBB and a further brain bank (the JHBRC), assessing a total of 708 post mortem brain samples, 510 of which came from people with AD. When they evaluated the HHV-6 viral load across the two brain banks, they observed no significant differences between people with AD and healthy controls. In other words, people with AD do not have substantially higher levels of HHV-6 in their brains when compared to unaffected individuals.
Together, these results appear to contradict the results of previous studies showing an association between herpesvirus and AD. However, Dr Allnutt and colleagues cautioned that while their study found no link between HHV-6 and AD, it does not necessarily rule out an association. An acknowledged limitation of studies based on genetic sequencing analyses is that they are dependent on complex mathematical algorithms, applied using high-performance computers. Small modifications in these algorithms and the way they are applied can lead to substantial differences in the results. Consequently, the researchers are now looking at even larger cohorts and brain banks, to extend the study and validate its results.
Link to article: https://www.sciencedirect.com/science/article/pii/S0896627319310979
