Connection between herpes virus and Alzheimer’s refuted

By Dr. Ananya Mandal, MDDec 19 2019

A new study has shown that unlike previous claims, there is no association between getting herpes infections and developing Alzheimer’s disease. The study from the researchers at the Baylor College of Medicine was titled, “Are HHV-6A and HHV-7 really more abundant in Alzheimer’s disease?” and was published in the journal Neuron.

3d rendered illustration of Herpes Virus. RAJ CREATIONZS / Shutterstock

The team explained that Alzheimer’s disease affects 50 million individuals across the globe and it is a progressive condition that leads to a steady decline in memory functions and cognitive functions until verbal skills and performing day to day activities become difficult. There are medications to treat the condition but most of them are effective in slowing the progression of the disease and do not address the underlying pathology or provide cure. One of the lead authors of the study, Dr. Zhandong Liu, associate professor of pediatrics at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, in a statement said, “Like all types of dementia, Alzheimer's disease is characterized by massive death of brain cells, the neurons. Identifying the reason why neurons begin and continue to die in the brains of Alzheimer's disease patients is an active area of research.”

The researchers explained that over the last year there have been reports that human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) infections are associated with Alzheimer’s disease. A 2018 study on post mortem brain samples of normal and nearly 1000 persons with Alzheimer’s disease showed that the levels of HHV-6A and HHV-7 were higher among the latter. The ages of both groups of patients were similar. The brains of persons with Alzheimer’s were also compared with brains of those with other neurodegenerative conditions and the results were unaltered. There was a higher level of genetic material linked to the human herpes virus in the brains of those who had died of Alzheimer’s disease. Within the next few months there have been several studies that have shown causal links between herpes infection and Alzheimer’s disease.

The study in question by Redhead et al was titled, “Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus,” and was published in Neuron in July 2018. The authors had written, “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.” To consolidate their results, the team of researchers had also replicated their study in “two additional, independent and geographically dispersed cohorts,” or populations. They had concluded, “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.”

For this study Dr. Hyun-Hwan Jeong, a postdoctoral fellow working with Dr. Liu looked at the data gathered for the 2018 study. They used tougher statistical tests and filtered out any possible bias. They used four common statistical tools to prove that there was no association between the high levels of genetic material associated with Herpes virus and Alzheimer’s disease. Dr. Liu’s team was first alerted to the possible difference in the 2018 study by the fact that differences in the data was not visibly significantly different (for example levels of herpes virus genes in normal and Alzheimer’s brains), but the “p value” – a mark of statistical significance, was found to be highly significant, indicating a significant difference in the values.

They wrote, “Prompted by these observations, we re-analyzed the data, which we were able to do because the authors provided their raw data and source code with the paper.” The team re-analyzed the data and found that on applying simple logistic regression principles of statistics, they could not prove the high levels of herpes DNA or RNA to be associated with Alzheimer’s disease.  Logistic regression is a special type of analysis that can predict the outcome of the data as one of the two states as previously defined.
Liu said, “As high-throughput 'omics' technologies, which include those for genomics, proteomics, metabolomics and others, become affordable and easily available, there is a rising trend toward 'big data' in basic biomedical research. In these situations, given the massive amounts of data that have to be mined and extracted in a short time, researchers may be tempted to rely solely on p-values to interpret results and arrive at conclusions.” Jeong explained, “Our study highlights one of the potential pitfalls of over-reliance on p-values. While p-values are a very valuable statistical parameter, they cannot be used as a stand-alone measure of statistical correlation - data sets from high-throughput procedures still need to be carefully plotted to visualize the spread of the data. Data sets also have to be used in conjunction with accurately calculated p-values to make gene-disease associations that are statistically correct and biologically meaningful.”

Liu said in conclusion, “Our goal in pursuing and publishing this study was to generate tools and guidelines for big data analysis, so the scientific community can identify treatment strategies that will likely benefit patients.”
The study was supported by the Huffington Foundation.