7 Aug 2022

Link between Alzheimer’s and viruses questioned

From Sunday Morning, 11:05 am on 7 August 2022

A link between conditions like Alzheimer’s disease and dementia and herpes viruses posited by Oxford University scientists recently is tenuous, says a leading medical academic.

There has been growing evidence to suggest microbial organisms are involved in the onset of Alzheimer's Disease (AD), in particular, herpes simplex virus type 1 (HSV-1), the so-called cold sore virus.

Professor John Fraser, the Dean of Medical & Health Sciences at Auckland University, tells Sunday Morning he remains cautious about the paper's position that there is evidence of a virus reactivation sequence leading to Alzheimer's disease.

Young doctor giving helping hands for elderly woman

Photo: 123RF

In a paper published last week in the Journal of Alzheimer's Disease, Professor Ruth Itzhaki, working at Oxford’s Institute of Population Ageing, jointly with researchers at Tufts, expanded the study of viral roles in Alzheimer's disease to include another type of herpes virus, varicella zoster virus (VZV), which causes chickenpox and shingles.
They investigated whether VZV can play a similar role to HSV-1 - that might implicate VZV directly in disease development. Using both laboratory-grown brain cells and a 3D brain model, the researchers looked at whether VZV infection caused the accumulation of beta amyloid (Aβ) and abnormally phosphorylated tau (P-tau) and other AD-like features, as is the case with HSV-1.

The researchers found VZV infection of lab-grown brain cells does not lead to the formation of Aβ and P-tau, the main components respectively of the characteristic AD plaques and neurofibrillary tangles in the brain. However, they did find VZV infection resulted in both gliosis and up-regulation of inflammatory cytokines. This makes it unlikely that VZV could be a direct cause of AD, but the study suggests instead it has an indirect effect by reactivating dormant HSV-1.

They also found upon VZV infection of cells containing latent HSV-1, reactivation of HSV1 occurred and a dramatic increase in levels of Aβ and P-tau, suggesting severe VZV infection in humans, as in shingles, could reactivate latent HSV-1 in brain, which, in turn, could lead to formation of AD-like damage.

Fraser says it is a theory that has been around for some time.

“It’s a theory that is based on the fact most people carry dormant viruses in their brains and the two viruses in question in this particular publication were the viruses that cause chicken pox and cold sores,” he says.

About 80 percent of New Zealanders are infected by herpes zoster by the age of 20, while it is estimated at least 50 percent of the world’s population has been infected with herpes simplex.

The viruses lie dormant in the nerve cells in the ganglia region of the brain and occasionally these infections will erupt and cause symptoms, Fraser says.

In the case of shingles, the virus moves down the nerve axon on to the skin and then the virus starts to erupt on the nerve endings, causing very painful micro lesions. Some people get shingles later in life after carrying the virus for many years.

Simplex erupts in the same way, although it typical manifests around the mouth with cold sore.

“There’s been a lot of work looking at shingles and the relation of shingle infections with the onset of dementia and Alzheimer’s and there isn’t a really strong correlation there’s been some large-scale studies looking at people who have been vaccinated for shingles or how have had shingles and then followed up to see if they had Alzheimer’s disease," Fraser says. 

He acknowledges both the strength and weaknesses of the Oxford study.

“The beauty of this paper is they’ve been able to grow nerve cells in the lab in these things called organoids… what they’ve done is infected these organoids with herpes simplex and then followed it up with a herpes zoster infection and low-and-behold they see the hallmarks of Alzheimer’s disease and that’s the position of the deposition of proteins, called beta-amyloid and we know with people with Alzheimer’s disease, when we look at their brains after they’ve died, they have these massive plaques in their brains that are formed by these two main proteins.

“So, we are absolutely sure that Alzheimer’s is caused by the deposition of these two proteins and that’s what leads to the disease. We’re pretty sure that this is caused by chronic inflammation that occurs in the brain. The billion dollar question is what causes that inflammation. These authors are arguing that it is caused by herpes viruses and they’ve shown that this can happen in these organoids

The problem with the paper's contention, he says, is these organoids are nothing like the brain itself, and says if you infected these organoids with other other viruses you would get the same effect – an inflammatory response with causes these unique proteins.

The Welsh study published in April this year found individuals vaccinated against shingles were at reduced risk of dementia. Fraser was again wary of the study's limitations, as those given the jab were in their later years, while the development of neuro-inflammation that could lead to dementia may take place years earlier,

However, the shingles jab stops the virus from being reactivated later in life, so it’s well worth taking, Fraser says.

“If there is a link there, there’s no reason why you shouldn’t get vaccinated against shingles.

What causes the inflammatory response is something that is still an open question, Fraser says. But what worries him is the growing prevalence of dementia and Alzheimer's in younger people, suggesting modern environmental triggers.

“We see Alzheimer’s Disease occurring in younger people and it’s almost an acute formation," he says.

"It happens with a very rapid onset. Alzheimer’s is not the disease that it used to be – it’s now occurring in people much younger and it’s occurring much more rapidly. It’s almost certainly so sort of inflammatory process that’s occurring in the brain that causing this formation of these nasty plaques that disrupt your brain functions. Discovering what that inflammatory response is will be the Holy Grail of what causes Alzheimer’s disease. It might be viruses, or it might be something else.

“Although a word of caution is we’re living a lot longer, so we’re seeing more of these age-related diseases. But the real message is the fact that these are occurring in more younger and younger ages says something about the environment that we’re living in.”