December 19, 2024

expert reaction to study looking at the role of gut infection in Alzheimer’s disease

A study published in Alzheimer’s & Dementia looks at the link between gut infection and risk of Alzheimer’s disease. 

Prof Andrew Doig, Professor of Biochemistry, University of Manchester, said:

“Substantial evidence has linked microbial infection to an increased risk of Alzheimer’s Disease (AD), with Herpes Simplex Virus (HSV) the prime candidate to date.  Another virus that could be involved with the onset of AD is the human cytomegalovirus (HCMV), another member of the herpes virus family.

“It was found that brain cells from patients with AD were more likely to have an antibody called CD83.  As cells produce antibodies like CD83 in response to infections, the paper’s authors wondered whether an infection was present in the AD patients.  Cells from various tissues were therefore analysed to explore what this infection might be.

“AD patients with CD83 were found to be producing an antibody called IgG4 which is also part of the immune system.  IgG4 antibodies are specific to one particular microbe.  Here, the IgG4 antibodies were interacting with proteins found in a virus called human cytomegalovirus (HCMV).  The virus was found in the colon and the vagus nerve, which connects the gut to the brain, as well as in the brain.  It is therefore possible that HCMV travels from the colon to the brain, via the vagus nerve, where it triggers the onset of AD.  In support of this idea, HCMV levels were shown to correlate with the amounts of two proteins known to be present in AD brains, called Ab42 and pTau-212, particularly in dead cells, though the effects were not large.  How exactly HCMV might induce Ab42 and pTau-212 was not clear.

“Most of us never get Alzheimer’s Disease.  Its onset is likely to require a combination of factors that can tip the balance from a healthy brain to one with dementia.  These triggers could include genetics, oxidative stress, cardiovascular problems, diabetes, head injury, deposits in blood vessels, inflammation, metals, and infection by bacteria or viruses.  The work here adds support to the hypothesis that HCMV might be one of these triggers.  If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.  In our lifetimes, nearly all of us acquire HCMV, though it may not be present everywhere in our bodies, such as in our colons.

“Though new drugs for AD have been appearing in the last few years, they are expensive, give only a small benefit and have significant risks, such as causing brain haemorrhages.  Antiviral drugs are an attractive alternative that are well worth exploring.  While antivirals for HSV are currently being trialled in humans, drugs against HCMV might also be of benefit.  We do need to carry out more work before we are ready to carry out such trials, however, such as trying to pin down exactly how the presence of the virus leads to AD, finding out more on the effects of HCMV in the brain, and seeing whether the link between HCMV and AD stands up in a wider range of people.”

Dr Sheona Scales, Director of Research, Alzheimer’s Research UK, said:

“Alzheimer’s disease is incredibly complex, and research is ongoing to understand its causes.  This study adds to our growing understanding of the important role our immune system plays in the development of Alzheimer’s.

“This small study found a virus that causes a persistent gut infection may change the immune system, possibly driving the disease processes behind Alzheimer’s.  While it’s too early to say for sure what this means, it could help explain some of the earliest changes that lead to Alzheimer’s in a subset of people.

“Importantly, this research opens new possibilities for future treatments and ways to diagnose the disease.  If scientists can better understand differences in the immune system in people with Alzheimer’s, they could explore new therapies that target these processes, including the possibility of using antiviral medicines.

“This is a promising step forward, but it’s early days.  More work is needed to confirm these findings and understand what they mean.  At Alzheimer’s Research UK, we’re committed to supporting the science to understand how diseases like Alzheimer’s develop, which is crucial if we are to find a cure.”

Dr Richard Oakley, Associate Director of Research and Innovation, Alzheimer’s Society, said:

“Around one million people are living with dementia in the UK.  There is an increasing amount of research into possible links between Alzheimer’s disease and immune responses in the brain.

“This research has found a link between bad immune cells in the brain and a type of herpes virus found in the gut called human cytomegalovirus (HCMV).  It only established a connection however, and did not directly show that the virus leads to Alzheimer’s disease in people.  Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.

“More research is needed to learn more about the involvement of viruses and indeed, links with other diseases and conditions.  Alzheimer’s Society is funding research into the causes of dementia, including looking at how immune cells in the brain may be involved in the process of diseases that are linked with dementia.

“Dementia is the UK’s biggest killer.  Research will beat dementia, but we need to make it a reality sooner.  Greater investment will enable scientists to better understand these links and to new avenues for treatments for the diseases that cause dementia.”

Prof Will McEwan, Group Leader at the UK Dementia Research Institute at the University of Cambridge, said: 

“There has been a long-standing suspicion that viral infections may increase the risk of Alzheimer’s disease.  It has, however, been very hard to conclusively establish this link.  This is partly due to the long gap between infection and the disease, which may be measured in decades, and the fact that many of the viruses proposed to cause this damage, and Alzheimer’s itself, are relatively common – a rare virus causing a rare disease would be much easier to conclusively link together.  This has meant many studies have relied on studying signatures of past infection in diseased patients versus their non-diseased counterparts.  Even without overt infection, Alzheimer’s diseased brains share some striking similarities with virally-infected tissue, suggesting that a damaging immune response may contribute to the disease.  If viral infection can trigger or enhance this state, it is plausible that infection could help pour fuel on this fire.

“This study by Readhead et al finds another such phenomenon, suggesting that a common virus, hCMV, is relatively common with a subset of Alzheimer’s patients.  Looking inside deceased patients’ brains and one of the nerves that connects directly to the brain, the vagus, they found evidence of infection.  They also found evidence of an unusual and specific form of immunity.  This involved a subtype of antibodies called IgG4, which are usually associated with a less inflammatory, and therefore less damaging, immune response.  A further signature was CD83 positive microglia.  The association between the two forms of immunity seems to be a very strong.  The IgG4 signature is unexpected given that more aggressive IgG1 or IgG3 would more normally expected to be associated with damage.  There are many possible explanations why this may be – for example the IgG4 response may be less good at clearing the infection than IgG1 or 3 and allow the invasion of hCMV to the brain.

“The study seems well performed and finds a novel immune response.  However, while this is a very interesting finding, the significance is far from clear.  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.  Nonetheless, the finding of infection in the brain is novel and highly deserving of follow-up research, and adds yet another piece of evidence to the body of literature.”

‘Alzheimer’s disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain’ by Benjamin P. Readhead et al. was published in Alzheimer’s & Dementia at 12:00 midday UK time on Thursday 19 December 2024.

DOI: 10.1002/alz.14401

Declared interests

Prof Will McEwan: “I have received research funding from Takeda Pharmaceuticals.  I am a founder and consultant to Trimtech Therapeutics.”