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 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.”