In part one, we laid out the mystery of one of the world’s most debilitating diseases—and the long, futile struggle to identify its cause. We now look at a new and persuasive Alzheimer’s hypothesis: it’s caused by a virus—a common herpes virus, at that.
Editor’s note: When there isn’t a big headline making news, we often pick a Big Story on a topic that we think will be interesting to you. We’d be just as happy to take requests from you. Do write to us at talktous@splainer.in. We’d also love to hear what you think of our leads on these kinds of less-newsy stories on fabric fraud, Enid Blyton, longest study on happiness etc. Interesting? Or more like ‘bore mat kar, yaar’?
Researched by: Rachel John & Priyanka Gulati
The battle against AD: A quick recap
Here’s the ground we covered in part one:
- Alzheimer’s is one of the most common diseases in the world—which affects one in ten people over the age of 65. It's a monstrous disease that literally erodes our brain—ending inevitably in death.
- Yet, since its discovery in 1906, we have not been able to identify its cause—or arrest its progress.
- For the past thirty years, the medical establishment and pharma industry have thrown all their weight behind the ‘amyloid hypothesis’—which claims that AD is caused by aberrant proteins in the brain.
- Yet drug trials targeting amyloids have failed—or offered very modest results.
- The genetic theory of Alzheimer’s—linking it to the mutation APOE4—has also offered only partial answers.
Frustrated with the lack of progress, a number of influential neurologists have turned to what was once a widely mocked theory—and identified a new villain: herpes simplex virus 1.
Herpes, like the STD?
You’re thinking of genital herpes. The Herpes simplex virus comes in two varieties. HSV type 1 is spread through mouth-to-mouth contact. It mostly causes painful infections around the mouth—and is called oral herpes. The disease is typically spread through kissing or sharing things like toothbrushes and eating utensils. Genital herpes—or HSV type 2—requires sexual contact. Both forms of herpes are a lifelong infection—and the sores can recur over the years.
Staggering numbers: Oral herpes is also way more common than its genital version. As of 2016, an estimated 3.7 billion people had an HSV1 infection—which is around 67% of the world’s population under the age of 50.
And this oral herpes causes Alzheimer’s?
Alzheimer’s is far too complex to make that kind of a sweeping claim. But there is increasing evidence that the virus plays a key role in triggering the disease.
When it all started: Scientists have been looking at viruses as one of the leading causes of AD since the late 1970s. US neuropathologist Melvyn Ball first named the cold sore virus or HSV1 as a potential culprit in 1984. However, the first published study establishing a connection was co-authored by Ruth Itzhaki and Richard Sutton in 1986. Itzhaki became a leading (and lonely) advocate of the viral infection theory—but she and her colleagues were ignored by medical journals and refused research grants.
Why oral herpes: One big reason: It was one of the few viruses that could infect the brain. On very rare occasions, HSV1 causes a dangerous swelling called encephalitis. Herpes simplex encephalitis (HSE) also attacks the same parts of the brain as Alzheimer’s. And it can stay dormant in the body for decades. HSV1 is also more pervasive—found in 80-90% of the population back in the 80s. According to Itzhaki, “These features meet two main characteristics of Alzheimer’s disease: that it is all too common, and that it almost always waits until old age to strike its victims.”
A key breakthrough: In 1991, Itzhaki found herpes DNA in the brain tissue of people who had never developed encephalitis. Why this mattered: until then, scientists knew that the virus could stay dormant in the body—but they never suspected it could lurk undetected in the brain. It was the first known microbe that could do so without triggering any disease.
I still don’t get how this leads to Alzheimer’s…
Because the herpes virus stays dormant in our body—but can be reactivated many times over a lifetime. This is why a person repeatedly gets cold sores. According to Itzhaki, the virus travels to the brain in many people—probably in their middle age. And that’s when things start to go wrong:
Once there, they stay dormant for many years before being reactivated in old age, either because the ageing immune system can no longer keep them in check, or something else – a traumatic episode, a head injury or perhaps another infection – spurs them to life. Once awakened – so the theory goes – they begin to wreak havoc.
About those plaques: As we explained in part one, the two main indicators of AD are the buildup of two proteins. Amyloid plaques destroy communication between neurons. Tau tangles, OTOH, kill neurons from within. Over time, a person’s brain begins to shrink—until they die. But how does HSV1 cause either?
The amyloid-HSV1 link: Fifteen years ago, neurologist Rudolph Tanzi discovered that the amyloid protein also has antimicrobial properties:
When an infection attacks your brain, your first response is these little sticky peptides that bind to the microbe, glutinate it into a ball and trap it. We found that amyloid is one of the major peptides in the brain that goes after microbes. I believe the plaques we see in Alzheimer’s brains actually evolved as a way to protect the brain.
Imagine that this amyloid kicks into high gear each time that HSV1 virus is reactivated in our brain. Now imagine that those ‘reactivations’ happen over and over again. But as our bodies start to age, we aren’t able to clear out that sticky amyloid—which then starts to build up and turns into plaques. That’s when we start to exhibit symptoms of Alzheimer’s.
About that genetic factor: It is clear that a mutation—the APOE4 gene—plays an important role in determining who develops AD. But studies also show that merely possessing the gene doesn’t cause the disease. Scientists now think that people who develop Alzheimer’s are victims of a double whammy—HSV1 plus APOE4.
The virus causes the buildup of amyloid—and the gene makes a person far less able to clear it out of their brain. The two work in tandem to increase the risk of Alzheimer’s:
The researchers found that the infection roughly tripled the risk of developing Alzheimer's in APOE4 carriers over a seven-year follow-up period – but had no effect in people who were not carrying the gene. "The herpes virus was only able to have a deleterious effect if there was APOE4," says Catherine Helmer at the University of Bordeaux in France, who conducted the research.
Big data point to note: According to Itzhaki, around 18% of people between the ages 30 and 40 across the world have both these risk factors.
What evidence do we have for any of this?
The most compelling evidence was collected in Taiwan—where 99.9% of citizens are enrolled in the national health insurance database—offering detailed, long-term data. In 2017-2018, three key studies were published on senile dementia—caused primarily by AD. One of them revealed that those carrying HSV1 were 2.5 times more likely to develop dementia. More interestingly, another study showed that participants who took a long course of antiviral medication were around 90% less likely to develop dementia. According to experts, the data is "such a dramatic result that it must be taken seriously."
These studies also confirm Itzhaki’s own research on the location of the viral DNA inside the brain:
Viral DNA is located very specifically within plaques in postmortem brain tissue from Alzheimer's sufferers. The main proteins of both plaques and tangles accumulate also in HSV1-infected cell cultures — and antiviral drugs can prevent this.
Point to note: HSV1 isn’t the only badly behaved virus in the mix. Other studies have highlighted the role of the varicella zoster virus (VZV)—which causes chicken pox. This virus too hangs out in our body after an infection—and most often causes shingles in middle age: “Our results suggest one pathway to Alzheimer’s disease: a VZV infection which creates inflammatory triggers that awaken HSV1 in the brain.”
Others link AD to bacteria that causes a form of gum disease—though drug trials trying to establish a link have failed. And most recently, research has established a link between long Covid and the onset of Alzheimer’s.
But, but, but: Not everyone is sold on this virus hypothesis. The biggest criticism is also the most obvious:
Merely finding herpes virus, however, falls well short of demonstrating that it or other microbes cause Alzheimer’s. That idea has been kicking around since at least the 1950s but has never overcome a key objection: degenerating brains might just be more inviting to pathogens than healthy brains. In that case, the pathogens would be opportunistic, not causal, sneaking across the blood-brain barrier and taking up residence only after Alzheimer’s has developed.
In other words, we may be putting the proverbial cart before the horse.
The definitive proof: Right now, none of the research establishes a causal link. Even the Taiwan studies are based on observational data. To convince the medical establishment, a controlled trial of an antiviral drug must achieve what until now has been near-impossible: alter the course of the disease. Columbia University neurologist Davangere Devanand hopes to do just that with his clinical trial—which looks at whether a herpes drug called valacyclovir could slow the progression of Alzheimer’s in the early stages of the disease. The results will be out in 2024.
The bottomline: We did this two-part series because we find it astonishing that we still understand so little about a disease that will touch most of our lives. At a time when scientists can map vast swathes of the genome, our most critical organ—the human brain—still remains a mystery to us.
Reading list
The Guardian and BBC News offer an excellent deep dive into the viral infection theory. Ruth Itzhaki in The Conversation writes about her long struggle to prove her HSV1 hypothesis. This Stat News column offers a takedown of the amyloid hypothesis—and also the virus theory. Bloomberg News via Mint looks at what long Covid can teach us about Alzheimer’s. Undark has a very good feature on the Epstein-Barr virus—which has now been linked to another debilitating disease: multiple sclerosis.
