Researchers from Arizona State University and the Banner Alzheimer’s Institute, along with their collaborators, have discovered a surprising link between a chronic intestinal infection caused by a common virus and the development of Alzheimer’s disease in a subset of people.
It is believed that most people are exposed to this virus; called cytomegalovirus or HCMV -; during the first decades of life. Cytomegalovirus is one of nine herpes viruses, but is not considered a sexually transmitted disease. The virus is usually passed on through exposure to bodily fluids and only spreads when the virus is active.
According to the new research, in some people the virus may linger in an active state in the gut, where it can travel to the brain via the vagus nerve; a critical information highway connecting the gut and the brain. Once there, the virus can alter the immune system and contribute to other changes associated with Alzheimer’s disease.
If the researchers’ hypotheses are confirmed, they may be able to evaluate whether existing antiviral medications can treat or prevent this form of Alzheimer’s disease. They are currently developing a blood test to identify people who have an active HCMV infection and who may benefit from antiviral medications.
We believe we have identified a biologically unique subtype of Alzheimer’s disease that may affect 25% to 45% of people with this disease. This subtype of Alzheimer’s disease includes the characteristic amyloid plaques and tau tangles – microscopic brain abnormalities used for diagnosis – and shows a distinct biological profile of viruses, antibodies and immune cells in the brain.
Dr. Ben Readhead, co-first author of the study and research associate professor at ASU-Banner Neurodegenerative Disease Research Center in ASU’s Biodesign Institute
The findings were published today in “Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.” Researchers from ASU, Banner Alzheimer’s Institute, Banner Sun Health Research Institute and the Translational Genomics Research Institute (TGen) led the joint effort, including researchers from UMass Chan Medical School, Institute for Systems Biology, Rush University Medical Center, Icahn School of Medicine Mount Sinai and other institutions.
The research team suggests that some people exposed to HCMV develop a chronic intestinal infection. The virus then enters the bloodstream or travels to the brain via the vagus nerve. There it is recognized by the brain’s immune cells called microglia, which turn on the expression of a specific gene called CD83. The virus may contribute to the biological changes involved in the development of Alzheimer’s disease.
The role of the brain’s immune cells
Microglia, or the brain’s immune cells, are activated when they respond to infections. Although initially protective, sustained increases in microglial activity can lead to chronic inflammation and neuronal damage, which has been implicated in the progression of neurodegenerative diseases, including Alzheimer’s disease.
In a study published earlier this year in Nature Communications, researchers found that the postmortem brains of research participants with Alzheimer’s disease were more likely than those without Alzheimer’s disease to specifically harbor CD83(+) microglia. While investigating why this happened, they discovered an antibody in the intestines of these subjects; consistent with the possibility that an infection could contribute to this form of Alzheimer’s.
In the latest study, researchers sought to understand what might drive the production of intestinal antibodies. The team examined spinal fluid from the same individuals, which showed that the antibodies were specific to HCMV. This led to a search for evidence of HCMV infection in the intestinal and brain tissue of these subjects – and they found it.
They also saw HCMV in the vagus nerve of the same subjects, raising the possibility that the virus travels to the brain this way. In collaboration with RUSH University, the researchers were able to reproduce the association between cytomegalovirus infection and CD83(+) microglia in an independent cohort of Alzheimer’s patients.
To further investigate the impact of this virus, the research team then used human brain cell models to demonstrate the virus’s ability to induce molecular changes associated with this specific form of Alzheimer’s disease. Exposure to the virus increased the production of amyloid and phosphorylated tau proteins and contributed to the degeneration and death of neurons.
Is HCMV responsible for Alzheimer’s disease in some people?
HCMV can infect people of all ages. In most healthy people, the infection occurs without symptoms, but can present as a mild flu-like illness. About 80% of people show signs of antibodies by age 80. Nevertheless, the researchers detected HCMV in the intestines only in a subset of individuals, and this infection appears to be a relevant factor in the presence of the virus in the brain. For this reason, the researchers note that simply coming into contact with HCMV, which happens to almost everyone, should not be a cause for concern.
And although researchers proposed more than 100 years ago that harmful viruses or microbes might contribute to Alzheimer’s disease, no single pathogen has been consistently linked to the disease.
The researchers suggest that these two studies illustrate the potential impact that infections can have on brain health and neurodegeneration in general. Still, they add that independent studies are needed to test their findings and resulting hypotheses.
The NOMIS Foundation, Banner Alzheimer’s Foundation, National Institutes of Health and Arizona Alzheimer’s Consortium supported the study. Arizona’s unique biorepositories, specifically the Banner Sun Health Research Institute’s Brain and Body Donation Program, provided tissue samples and devices, including colon, vagus nerve, brain and spinal fluid. The Rush University-led Religious Orders Study and Memory and Aging Study provided additional brain samples and data. This allowed researchers to conduct a more nuanced study, highlighting the systemic rather than purely neurological roots of Alzheimer’s disease.
“It was critical for us to have access to different tissues from the same individuals. This allowed us to merge the study. Arizona is the only place I know of where a study like this could have been done, and we are grateful to Banner Health Brain and Body Donation Program for its support,” said Readhead, who is also the Edson Endowed Professor of Dementia Research at the center.
“We are deeply grateful to our research participants, colleagues and supporters for the opportunity to advance this research in a way that none of us could have done alone,” said Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute and the study’s senior author. “We are excited about the opportunity to have researchers test our findings in ways that will make a difference in the study, subtyping, treatment and prevention of Alzheimer’s disease.”
The findings of the recent study raise an important question: Can antiviral drugs help treat Alzheimer’s patients with chronic HCMV infection?
The researchers are now working on a blood test to identify individuals with this type of chronic intestinal HCMV infection. They hope to use it in combination with the emerging blood tests for Alzheimer’s disease to evaluate whether existing antiviral drugs can be used to treat or prevent this form of Alzheimer’s disease.
Source:
Magazine reference:
Reading head, BP, et al. (2024) Alzheimer’s disease-associated CD83(+) microglia are associated with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagus nerve, and brain. Alzheimer’s and dementia. doi.org/10.1002/alz.14401.