Herpes Virus Infection May Contribute to Alzheimer’s Disease

A virus with a nearly 100% infection rate could increase the risk of developing Alzheimer’s disease.

The idea that Alzheimer’s disease may be caused in part by microbial infections has been around for decades and recently started to gain increased support with the scientific community. Hundreds of studies have observed an increased incidence of many types of infections in Alzheimer’s disease patients. However, most of these studies could not establish a direct causative link, and they provided little insight into the mechanisms of this interaction.

Recently, a study published in the journal Neuron provided some of the strongest evidence yet for the infectious theory of Alzheimer’s. Researches from the Icahn School of Medicine at Mount Sinai collected portmortem brain samples from people with preclinical Alzheimer’s disease, as well as healthy controls, and used an advanced laser-capture technology to analyze the gene expression in their neurons. They then constructed computational models to predict which patterns of gene expression were associated with Alzheimer’s disease. They noticed that many of these genes that had different expression in the Alzheimer’s brains played a role in immune system’s response to viral infection.

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This figure from the paper illustrates how researchers employed computational models to connect viral infection rates with the signatures of Alzheimer’s disease.

To further investigate this viral connection, the researchers analyzed the levels of viral RNA in each of the brain samples. They found that the Alzheimer’s brains had significantly more RNA from two types of human herpes viruses (HHV): type 6A and type 7. (Note that HHV is not to be confused with human simplex virus [HSV], which is a sexually transmitted infection.) This suggests that people with Alzheimer’s disease have higher rates of HHV infection in their brains.

Furthermore, they found that the viral infections could perturb many genes that are linked to the development of Alzheimer’s disease, including BACE1, which helps create the sticky plaques that are characteristic of the Alzheimer’s brain. HHV-6A also decreases expression of a microRNA gene called miR-155. When they created mice that lacked expression of miR-155, these mice developed Alzheimer’s plaques in their brains, suggesting that this gene could be an important link between herpes infection and Alzheimer’s.

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This figure from the paper shows the complex network of genes that may link herpes virus infection with the development of Alzheimer’s disease.

This study is different from previous ones in several ways. It includes a large sample size from throughout the United States, which provides higher statistical rigor to the conclusions. It also suggests a possible mechanisms by which viral infections could contribute to the development of Alzheimer’s disease via disruption of neuronal gene expression. The results support the intriguing possibility that the toxic amyloid-beta protein, which has long been thought to be the primary cause of Alzheimer’s disease, could actually be a beneficial response to viral infection, a theory that I described in a previous article. While this study is not yet conclusive proof that herpes infection can directly lead to Alzheimer’s disease, it opens that door for many interesting new avenues for research that should be investigated further.

A connection between herpes and Alzheimer’s disease is both troubling and encouraging. HHV types 6 and 7 are extremely common, with nearly 100% of individuals infected by age 3. Most of us are likely infected as infants through the saliva of our parents or other relatives. After the initial infection, the virus becomes latent and remains circulating in the bloodstream for life. For most of us, HHV-6 and HHV-7 infections are completely asymptomatic. However, as we grow older, our immune systems weaken, allowing these viruses to travel from the bloodstream to the brain. Some reports suggest that the resulting neuroinflammation could contribute to common age-related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.

Yet these results also offer hope. If microbial infections such as HHV are the initial cause of Alzheimer’s disease, this suggests that we could treat the disease using immunosuppressant or antiviral drugs. Should future studies confirm this to be true, this could be a huge boon for the development of effective Alzheimer’s therapies.

 

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4 thoughts on “Herpes Virus Infection May Contribute to Alzheimer’s Disease

  1. Anonymous

    Maya, glad you’re able to summarize these long and complicated articles into something more understandable to the general public. I know this takes a lot of time and effort. Keep up the curiosity and desire to learn so you can figure out this complicated disease!

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  2. Jack Rivers-Auty (@mere_conjecture)

    Hi Maya,

    Great blog. I’m a little skeptical of this one. Everyone has the virus, the difference between AD and control patients outlined in the paper was virus load. It seems to me that it is unlikely that viral load is causing AD. After-all, what would be causing the differences in viral load?

    I would propose that changes due to AD generate conditions that allow the virus to multiply.

    We know that with other herpes viruses stress increases viral load and leads to skin lesions.
    http://jvi.asm.org/content/91/13/e00582-17.full

    My other concern with the paper is the disappearance and reappearance of the correlations.
    For example there was no difference in HHV6a between PSP and AD dementias, suggesting the correlation is non-specific to Alzheimer’s disease. There was no correlation in viral load (either HHV6a or HHV7) with AD in the MAP cohort. HHV7 load also didn’t correlated with AD in the ROS cohort. These inconsistent correlations make me concerned.

    My money is still on the amyloid hypothesis with the requirement of long term amyloidopathy. And possibly amyloidopathy generating a cascade of amyloid independent pathophysiological responses (neuroinflammation and tauopathy).

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    1. AlzScience Post author

      Hi Dr. Rivers-Auty, thanks for your comment! You raised several interesting points. While you propose that AD-related changes are responsible for the increased viral load, I would argue that the opposite correlation (viral load causing AD) has possible merit as well. For instance, one possibility is that a weakened BBB may enhance the ability of viruses to infiltrate the brain. This BBB weakening may not be caused by AD itself but by other genetic or environmental factors that coincide with the aging process. The virus in turn may trigger the early pathology of AD by activating the innate immune system and triggering amyloid aggregation. I don’t think here’s enough evidence yet to say which of our two interpretations is more likely to be correct, and it’s also possible that both may be true, acting in a kind of vicious cycle.

      I agree that the inconsistent correlations raise some possible concerns about the paper’s conclusions, especially when a study like this one with a fairly large sample size seems highly-powered enough to detect such correlations. However, there are many other reports which have observed higher incidence of infections (including several forms of herpes) in AD. Some examples are discussed in these reviews:
      https://www.ncbi.nlm.nih.gov/pubmed/26967229
      https://www.ncbi.nlm.nih.gov/pubmed/29504537

      Best,
      Maya

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  3. Alice Gosztyla

    Fascinating, and overall hopeful for future generations. I actually just saw a short article about this in the Columbus Dispatch! It seems that we keep getting a little closer to solving this puzzling disease.

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