But researchers at Tufts University and the University of Oxford, using a three-dimensional human tissue culture model mimicking the brain, have shown that varicella zoster virus (VZV), which commonly causes chickenpox and shingles, may activate herpes simplex (HSV), another common virus, to set in motion the early stages of Alzheimer’s disease.
Normally HSV-1 – one of the main variants of the virus – lies dormant within the neurons of the brain, but when it is activated it leads to accumulation of tau and amyloid beta proteins, and loss of neuronal function – signature features found in patients with Alzheimer’s.
“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” said Dana Cairns, GBS12, a research associate in the Biomedical Engineering Department. “While we demonstrated a link between VZV and HSV-1 activation, it’s possible that other inflammatory events in the brain could also awaken HSV-1 and lead to Alzheimer’s disease.”
The study is published in the Journal of Alzheimer’s Disease
Viruses Lying in Wait
“We have been working off a lot of established evidence that HSV has been linked to increased risk of Alzheimer’s disease in patients,” said David Kaplan, Stern Family Professor of Engineering and chair of the Department of Biomedical Engineering at Tufts’ School of Engineering. One of the first to hypothesize a connection between herpes virus and Alzheimer’s disease is Ruth Itzhaki of the University of Oxford, who collaborated with the Kaplan lab on this study.
“We know there is a correlation between HSV-1 and Alzheimer’s disease, and some suggested involvement of VZV, but what we didn’t know is the sequence of events that the viruses create to set the disease in motion,” he said. “We think we now have evidence of those events.”
According to the World Health Organization, an estimated 3.7 billion people under the age of 50 have been infected with HSV-1—the virus that causes oral herpes. In most cases it is asymptomatic, lying dormant within nerve cells.
When activated, it can cause inflammation in nerves and skin, causing painful open sores and blisters. Most carriers—and that’s one in two Americans according to the CDC—will have between very mild to no symptoms before the virus becomes dormant.
Varicella zoster virus is also extremely common, with about 95 percent of people having been infected before the age of 20. Many of those cases are expressed as chicken pox. VZV, which is a form of herpes virus, can also remain in the body, finding its way to nerve cells before then becoming dormant.
Later in life, VZV can be reactivated to cause shingles, a disease characterized by blisters and nodules in the skin that form in a band-like pattern and can be very painful, lasting for weeks or even months. One in three people will eventually develop a case of shingles in their lifetime.
The link between HSV-1 and Alzheimer’s disease only occurs when HSV-1 has been reactivated to cause sores, blisters, and other painful inflammatory conditions.
How Sleeping Viruses May Wake
To better understand the cause-and-effect relationship between the viruses and Alzheimer’s disease, the Tufts researchers re-created brain-like environments in small 6 millimeter-wide donut-shaped sponges made of silk protein and collagen.
They populated the sponges with neural stem cells that grow and become functional neurons capable of passing signals to each other in a network, just as they do in the brain. Some of the stem cells also form glial cells, which are typically found in the brain and help keep the neurons alive and functioning.
The researchers found that neurons grown in the brain tissue can be infected with VZV, but that alone did not lead to the formation of the signature Alzheimer’s proteins tau and beta-amyloid—the components of the tangled mess of fibers and plaques that form in Alzheimer’s patients’ brains—and that the neurons continued to function normally.
However, if the neurons already harbored quiescent HSV-1, the exposure to VZV led to a reactivation of HSV, and a dramatic increase in tau and beta-amyloid proteins, and the neuronal signals begin to slow down.
“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” said Cairns.
“It’s still possible that other infections and other pathways of cause and effect could lead to Alzheimer’s disease, and risk factors such as head trauma, obesity, or alcohol consumption suggest they may intersect at the re-emergence of HSV in the brain,” she added.
The researchers observed that the VZV infected samples started to produce a higher level of cytokines—proteins which are often involved in triggering an inflammatory response. Kaplan noted that VZV is known in many clinical cases to cause inflammation in the brain, which could possibly lead to activation of dormant HSV and increased inflammation.
A vaccine for VZV – to prevent chickenpox and shingles – has also been shown to considerably reduce the risk of dementia. It’s possible that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.
The researchers also noted the long-term neurological effects that some COVID patients have experienced from the SARS-CoV-2 virus, particularly among the elderly, and that both VZV and HSV-1 can be reactivated after a COVID infection. Keeping an eye on possible follow-on cognitive effects and neurodegeneration would be advisable in these cases, they said.
…. BUT …
To our knowledge, this is the most comprehensive MR analysis to examine the causal associations of four herpesvirus infections and AD. Our results found a significant association between mononucleosis and AD, as well as an association between mononucleosis and family history of AD. The result is less susceptible to confounding and reverse causality bias than many previous conventional observational studies .
Mendelian randomization rests on three key assumptions . The relevance assumption required that the genetic variants are robustly associated with the exposure of interest. We have selected our IVs from a large GWAS for infections. All SNPs were genome-wide significant (P < 5 × 10−8), which is a very strict threshold. Although the proportion of variance explained by IVs was not very high, the F-statistics were all highly above the threshold of weak instruments of F-statistic < 10 . The other two assumptions are collectively known as independence from pleiotropy. In pleiotropy analyses, we found some SNPs (i.e., rs2596465, rs885950) were associated with “treatment with insulin” from UKB (see Additional file 4). However, recent MR analyses have suggested type-2 diabetes and high plasma glucose are not causally related to the risk of Alzheimer’s disease [30, 31]. According to the existing knowledge, there are no obvious evidences that SNPs in our study influence AD through other pathways, indicating our MR analysis to be valid.
The exposures in our MR analysis were defined by the self-reported history of infection diseases  rather than the serological or polymerase chain reaction (PCR) measures of exact pathogens which were often used in observational studies . That was due to the lack of appropriate GWAS. However, researchers have done several surveys to define each infectious disease phenotype and have taken vaccination into account. And their surveys and phenotype scoring logic were showed in the original study . From some point of view, defining infection by clinical diagnosis may have greater clinical significance for AD prevention and may provide a new perspective for exploring the mechanism of the causal effects.
We found evidence that mononucleosis (mainly caused by EBV)  was associated with a higher risk of AD. And it was validated using a GWAS dataset of the family history of AD, which enhanced the robustness of the causal relationship. As for EBV, a recent article detected EBV-specific T cell receptors in cerebrospinal fluid from patients with AD; however, their data were still not a directly evidence of a causality . A meta-analysis based on two case–control studies demonstrates that the EBV infection (OR [95% CI] = 1.45 [1.00, 2.08]) is associated with a higher risk of AD . A prospective cohort study also reports that the presence of EBV in the peripheral blood might be a risk factor for AD (OR = 1.843) . Nevertheless, observational results are prone to reverse causation and confounding bias. Taking the advantage of overcoming these limitations adherent in observational studies , our MR findings can be used to provide more reliable evidence of causality between EBV and AD.
Although the specific mechanism underlying the association between infection and AD has not been fully understood, studies have proposed several possible mechanisms. Some have suggested that herpesviridae infection could promote the accumulation of amyloid-β plaques in brain . Carbone et al. have suggested that persistent cycles of latency of the EBV might contribute to stress the systemic immune response and induce altered inflammatory processes, resulting in cognitive decline during aging . Also, a recent article has found evidences indicating the effects of adaptive immunity in AD . Our MR finding was from the aspect of mononucleosis other than the latent infection. In light of the fact that over 90% of the world’s adult population is chronically infected with EBV , our results from mononucleosis seem to be more practical, which might imply the underlying effects of immune mechanisms and provide contributions to the current literature .
There was no clear evidence to suggest an effect of chickenpox or shingles on AD. Although primary analysis showed a significant association between shingles and risk of AD, it was not validated in independent data, and the direction of point estimates in primary analysis and in validation analysis was the opposite. The two infection diseases are caused by VZV; however, chickenpox results from primary infection of VZV, while shingles are caused by the reactivation of the latent VZV within a dorsal root ganglion. Thus, the effect of the two infectious diseases on AD may be different. Although observational studies have found that VZV DNA and sera VZV antibodies showed no positive correlations with AD risk [35–37], it is not clear whether the primary infection and reactivation of VZV act differently on AD risk. In particular, recent cohort studies have reported that the use of antiviral agents in herpes zoster patients was associated with lower risks of dementia [38, 39], adding weight to the potential association between VZV infection and dementia. Further investigation is warranted concerning whether VSV reactivation is involved in triggering AD onset or progression.
Our MR results showed no significant association between cold sores, mainly caused by reactivation of herpes simplex virus type 1 (HSV-1), and AD risk. Accumulating evidence suggest HSV-1 alone does not confer an elevated risk of AD [35, 40, 41], but together with the carriage of APOE-ε4 allele increases AD risk [2, 42, 43]. Nevertheless, in an observational study which has determined APOE genotype and other possible confounders previously, they also suggested that both carriage of and reactivated HSV-1 infection increased the risk of developing AD . A likely explanation for those controversial findings is that there could be some unmeasured confounding or other bias [3, 4]. A published MR study has suggested similar results as us that any HSV infection was not related to cognitive function or late-onset AD . However, constrained by the MR approach, the potential link between APOE genotype and HSV-1 cannot be clarified in the present study, which requires further study. On the other hand, although the commonest manifestation of HSV-1 infection are cold-sores, only ~ 40% of people that are seropositive for HSV-1 actually get cold-sores. Therefore, cold sores are only a fairly specific subset of the infectious phenotypes that occur for HSV-1, and the effects of cold sores on AD are not equivalent to that of HSV-1 infection.
REFERENCE LINK : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464096/
More information: Dana M. Cairns et al, Potential Involvement of Varicella Zoster Virus in Alzheimer’s Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1, Journal of Alzheimer’s Disease (2022). DOI: 10.3233/JAD-220287