Common Gut Infection Tied to Alzheimer’s Disease

Researchers are gaining new insight into the relationship between the human cytomegalovirus (HCMV), a common herpes virus found in the gut, and the immune response associated with CD83 antibody in some individuals with Alzheimer’s disease (AD).

Using tissue samples from deceased donors with AD, the study showed CD83-positive (CD83+) microglia in the superior frontal gyrus (SFG) are significantly associated with elevated immunoglobulin gamma 4 (IgG4) and HCMV in the transverse colon (TC), increased anti-HCMV IgG4 in the cerebrospinal fluid (CSF), and both HCMV and IgG4 in the SFG and vagus nerve.

“Our results indicate a complex, cross-tissue interaction between HCMV and the host adaptive immune response associated with CD83+ microglia in persons with AD,” the investigators including Benjamin P. Readhead, MBBS, research associate professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, Arizona, noted.

The results suggest antiviral therapy in patients with biomarker evidence of HCMV, IgG4, or CD83+ microglia might ward off dementia.

“We’re preparing to conduct a clinical trial to evaluate whether careful use of existing antivirals might be clinically helpful in preventing or slowing progression of CD83+ associated Alzheimer’s disease,” Readhead told Medscape Medical News.

The study was published on December 19, 2024, in Alzheimer’s & Dementia.

Vagus Nerve a Potential Pathway?

CMV is a common virus. In the United States, nearly 1 in 3 children are already infected with CMV by age 5 years. Over half the adults have been infected with CMV by age 40 years, the Centers for Disease Control and Prevention reported.

It is typically passed through bodily fluids and spread only when the virus is active. It’s not considered a sexually transmitted disease.

Compared with other IgG subclasses, IgG4 is believed to be a less inflammatory, and therefore less damaging, immune response. But this response may be less effective at clearing infectionsand allow invasion of HCMV into the brain.

Experts speculate HCMV may travel via the vagus nerve from the colon to the brain where it triggers the onset of AD.

The researchers previously found a CD83+ microglial subtype in the SFG of 47% of brain donors with AD vs 25% of unaffected control individuals. They reported this subtype is associated with increased IgG4 in the TC.

The current analysis extends investigations of the potential etiology and clinicopathologic relevance of CD83+ microglia in the context of AD.

Researchers conducted experiments using donated tissue samples from deceased patients with AD and control individuals. Sources for these samples included the Banner cohort, for whom classifications for the presence of CD83+ microglia were available, as were tissue samples from the SFG, TC, and vagus nerve, and theReligious Orders Study and Rush Memory and Aging Project (ROSMAP), in which participants without known dementia are evaluated annually.

From the Banner cohort, researchers completed immunohistochemistry (IHC) studies on 34 SFG samples (21 AD and 13 control individuals) and included 25 TC samples (13 AD and 12 control individuals) and eight vagal nerve samples (six AD and two control individuals) in the study. From the ROSMAP cohort, they completed IHC studies on 27 prefrontal cortex samples from individuals with AD.

They carefully selected these samples to ensure matching for critical factors such as postmortem interval, age, and sex, as well as other relevant covariates, said the authors.

The study verified that CD83+ microglia are associated with IgG4 and HCMV in the TC and showed a significant association between CD83+ microglia and IgG4 immunoreactivity in the TC.

Investigators confirmed HCMV positivity in all nine CD83+ TC samples evaluated and in one CD83− TC sample, indicating a strong positive association between HCMV within the TC and CD83+ microglia within the SFG.

HCMV IgG seroprevalence is common, varies by age and comorbidity, and is present in 79% of 85-year-olds, the investigators noted. “Despite this, we note that HCMV presence in the TC was not ubiquitous and was significantly associated with CD83+ microglia and HCMV in the SFG,” they wrote.

This observation, they added, “may help reconcile how a common pathogen might contribute to a disease that most individuals do not develop.”

The experiments also uncovered increased anti-HCMV IgG4 in the CSF and evidence of HCMV and IgG4 in the vagus nerve.

“Overall, the histochemical staining patterns observed in TC, SFG, and vagus nerve of CD83+ subjects are consistent with active HCMV infection,” the investigators wrote. “Taken together, these results indicate a multiorgan presence of IgG4 and HCMV in subjects with CD83+ microglia within the SFG,” they added.

Accelerated AD Pathology

The team showed HCMV infection accelerates production of two pathologic features of AD — amyloid beta (Aβ) and tau — and causes neuronal death. “We observed high, positive correlations between the abundance of HCMV, and both Aβ42 and pTau-212,” they wrote.

As HCMV histochemistry is consistent with an active HCMV infection, the findings “may indicate an opportunity for the administration of antiviral therapy in subjects with AD and biomarker evidence of HCMV, IgG4, or CD83+ microglia,” they added.

In addition to planning a clinical trial of existing antivirals, the research team is developing a blood test that can help identify patients with an active HCMV infection who might benefit from such an intervention, said Readhead.

But he emphasized that the research is still in its infancy. “Our study is best understood as a series of interesting scientific findings that warrant further exploration, replication, and validation in additional study populations.”

Although it’s too early for the study to impact practice, “we’re motivated to understand whether these findings have implications for clinical care,” he added.

Tipping the Balance

A number of experts have weighed in on the research via the Science Media Center, an independent forum featuring the voices and views on science news from experts in the field.

Andrew Doig, PhD, professor, Division of Neuroscience, The University of Manchester, Manchester, England, said the new work supports the hypothesis that HCMV might be a trigger that tips the balance from a healthy brain to one with dementia. “If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.”

Doig noted newly approved drugs for AD are expensive, provide only a small benefit, and have significant risks, such as causing brain hemorrhages. “Antiviral drugs are an attractive alternative that are well worth exploring.”

Richard Oakley, PhD, associate director of research and innovation, Alzheimer’s Society, cautionedthe study only established a connection and didn’t directly show the virus leads to AD. “Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.”

The significance of the new findings is “far from clear,” commented William McEwan, PhD, group leader at the UK Dementia Research Institute at Cambridge, England. “The study does not address how common this infection is in people without Alzheimer’s and therefore cannot by itself suggest that HCMV infection, or the associated immune response, is a driver of disease.”

The experts agreed follow-up research is needed to confirm these new findings and understand what they mean.

The study received support from the National Institute on Aging, National Institutes of Health, Global Lyme Alliance, National Institute of Neurological Disorders and Stroke, Arizona Alzheimer’s Consortium, The Benter Foundation, and NOMIS Stiftung.

Readhead is a co-inventor on a patent application for an IgG4-based peripheral biomarker for the detection of CD83+ microglia.

Doig is a founder, director, and consultant for PharmaKure Ltd., which works on AD drugs and diagnostics, although not on viruses. He has cowritten a review on Viral Involvement in Alzheimer’s Disease.

McEwan reported receiving research funding from Takeda Pharmaceuticals and is a founder and consultant to Trimtech Therapeutics.