Alzheimer’s disease

Possible causes of Alzheimer’s diseases

We currently don’t know the cause of all forms of Alzheimer’s disease. There may be more than one cause. But today we have increasingly strong evidence that many cases are caused by a combination of a genetic mutation and Herpes virus.

Prions

Two proteins central to the pathology of Alzheimer’s disease act as prions—misshapen proteins that spread through tissue like an infection by forcing normal proteins to adopt the same misfolded shape—according to new UC San Francisco research.

Using novel laboratory tests, the researchers were able to detect and measure specific, self-propagating prion forms of the proteins amyloid beta (A-β) and tau in postmortem brain tissue of 75 Alzheimer’s patients. In a striking finding, higher levels of these prions in human brain samples were strongly associated with early-onset forms of the disease and younger age at death.

by University of California, San Francisco

Alzheimer’s disease is a ‘double-prion disorder,’ study shows

Herpes virus

Alzheimer’s: The heretical and hopeful role of infection

David Robson writes

…. The “amyloid beta hypothesis” has inspired countless trials of drugs that aimed to break up these toxic plaques. Yet this research has ended in many disappointments, without producing the desired improvements in patients’ prognosis. This has led some to wonder whether the amyloid beta hypothesis may be missing an important part of the story. “The plaques that Alzheimer observed are the manifestation of the disease, not the cause,” says geriatrics scientist Tamas Fulop at the University of Sherbrooke in Canada.

Scientists studying Alzheimer’s have also struggled to explain why some people develop the disease while others don’t. Genetic studies show that the presence of a gene variant – APOE4 – can vastly increase someone’s chances of building the amyloid plaques and developing the disease.

But the gene variant does not seal someone’s fate as many people carry APOE4 but don’t suffer from serious neurodegeneration. Some environmental factors must be necessary to set off the genetic time bomb, prompting the build-up of the toxic plaques and protein tangles.

Early evidence

Could certain microbes act as a trigger? That’s the central premise of the infection hypothesis.

Itzhaki has led the way with her examinations into the role of the herpes simplex virus (HSV1), which is most famous for causing cold sores on the skin around the mouth. Importantly, the virus is known to lie dormant for years, until times of stress or ill health, when it can become reactivated – leading to a new outbreak of the characteristic blisters.

While it had long been known that the virus could infect the brain – leading to a dangerous swelling called encephalitis that required immediate treatment – this was thought to be a very rare event. In the early 1990s, however, Itzhaki’s examinations of post-mortem tissue revealed that a surprising number of people showed signs of HSV1 in their neural tissue, without having suffered from encephalitis.

Importantly, the virus didn’t seem to be a risk for the people without the APOE4 gene variant, most of whom did not develop dementia. Nor did the presence of APOE4 make much difference to the risk of people without the infection.

Instead, it was the combination of the two that proved to be important. Overall, Itzhaki estimates that the two risk factors make it 12 times more likely that someone will develop Alzheimer’s, compared to people without the gene variant or the latent infection in their brain.

Itzhaki hypothesised that this was due to repeated reactivation of the latent virus – which, during each bout, invades the brain and somehow triggers the production of amyloid beta, until eventually, people start to show the cognitive decline that marks the onset of dementia.

Itzhaki says that her findings were met with a high degree of scepticism by other scientists. “We had the most awful trouble getting it published.” Many assumed that the experiments were somehow contaminated, she says, leading to an illusory result. Yet she had been careful to avoid this possibility, and the apparent link between HSV1 infection and Alzheimer’s disease has now been replicated in many different populations.

One paper, published earlier this year, examined cohorts from Bordeaux, Dijon, Montpellier and rural France. By tracking certain antibodies, they were able to detect who had been infected with the herpes simplex virus.  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.

To date, the most compelling evidence for the infection hypothesis comes from a large study in Taiwan, published in 2018, which looked at the progress of 8,362 people carrying a herpes simplex virus. Crucially, some of the participants were given antiviral drugs to treat the infection. As the infection hypothesis predicted, this reduced the risk of dementia.

Overall, those taking a long course of medication were around 90% less likely to develop dementia over the 10-year study period than the participants who had not received any treatment for their infection.

“It’s a result that is so striking, it’s hard to believe,” says Anthony Komaroff, a professor at Harvard Medical School and a senior physician at Brigham and Women’s Hospital in Boston, who recently reviewed the current state of the research into the infection hypothesis for the Journal of the American Medical Association. Although he remains cautious about lending too much confidence to any single study, he is now convinced that the idea demands more attention. “It’s such a dramatic result that it must be taken seriously,” he says.

Komaroff knows of no theoretical objections to the theory. “I haven’t heard anyone, even world-class Alzheimer’s experts who are dubious about the infection hypothesis, give a good reason why it has to be bunkum,” he adds. We simply need more studies providing direct evidence for the link, he says, to be able to convince the sceptics.

– from Alzheimer’s: The heretical and hopeful role of infection, BBC Future, David Robson, 6th October 2021

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Alzheimer’s disease: mounting evidence that herpes virus is a cause, The Conversation US, Oct 19, 2018

Ruth Itzhaki, Professor Emeritus of Molecular Neurobiology, University of Manchester

More than 30m people worldwide suffer from Alzheimer’s disease – the most common form of dementia. Unfortunately, there is no cure, only drugs to ease the symptoms. However, my latest review, suggests a way to treat the disease. I found the strongest evidence yet that the herpes virus is a cause of Alzheimer’s, suggesting that effective and safe antiviral drugs might be able to treat the disease. We might even be able to vaccinate our children against it.

The virus implicated in Alzheimer’s disease, herpes simplex virus type 1 (HSV1), is better known for causing cold sores. It infects most people in infancy and then remains dormant in the peripheral nervous system (the part of the nervous system that isn’t the brain and the spinal cord). Occasionally, if a person is stressed, the virus becomes activated and, in some people, it causes cold sores.

We discovered in 1991 that in many elderly people HSV1 is also present in the brain. And in 1997 we showed that it confers a strong risk of Alzheimer’s disease when present in the brain of people who have a specific gene known as APOE4.

The virus can become active in the brain, perhaps repeatedly, and this probably causes cumulative damage. The likelihood of developing Alzheimer’s disease is 12 times greater for APOE4 carriers who have HSV1 in the brain than for those with neither factor.

Later, we and others found that HSV1 infection of cell cultures causes beta-amyloid and abnormal tau proteins to accumulate. An accumulation of these proteins in the brain is characteristic of Alzheimer’s disease.

We believe that HSV1 is a major contributory factor for Alzheimer’s disease and that it enters the brains of elderly people as their immune system declines with age. It then establishes a latent (dormant) infection, from which it is reactivated by events such as stress, a reduced immune system and brain inflammation induced by infection by other microbes.

Reactivation leads to direct viral damage in infected cells and to viral-induced inflammation. We suggest that repeated activation causes cumulative damage, leading eventually to Alzheimer’s disease in people with the APOE4 gene.

Presumably, in APOE4 carriers, Alzheimer’s disease develops in the brain because of greater HSV1-induced formation of toxic products, or less repair of damage.

New treatments? The data suggest that antiviral agents might be used for treating Alzheimer’s disease. The main antiviral agents, which are safe, prevent new viruses from forming, thereby limiting viral damage.

In an earlier study, we found that the anti-herpes antiviral drug, acyclovir, blocks HSV1 DNA replication, and reduces levels of beta-amyloid and tau caused by HSV1 infection of cell cultures.

It’s important to note that all studies, including our own, only show an association between the herpes virus and Alzheimer’s – they don’t prove that the virus is an actual cause. Probably the only way to prove that a microbe is a cause of a disease is to show that an occurrence of the disease is greatly reduced either by targeting the microbe with a specific anti-microbial agent or by specific vaccination against the microbe.

Excitingly, successful prevention of Alzheimer’s disease by use of specific anti-herpes agents has now been demonstrated in a large-scale population study in Taiwan. Hopefully, information in other countries, if available, will yield similar results.

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Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease

Ruth F. Itzhaki, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Front. Aging Neurosci., 19 October 2018, https://doi.org/10.3389/fnagi.2018.00324

Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer’s disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD….

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How an outsider in Alzheimer’s research bucked the prevailing theory — and clawed for validation

Sharon Begley, Stat News, 10/29/2018

Robert Moir was damned if he did and damned if he didn’t. The Massachusetts General Hospital neurobiologist had applied for government funding for his Alzheimer’s disease research and received wildly disparate comments from the scientists tapped to assess his proposal’s merits.

It was an “unorthodox hypothesis” that might “fill flagrant knowledge gaps,” wrote one reviewer, but another said the planned work might add little “to what is currently known.” A third complained that although Moir wanted to study whether microbes might be involved in causing Alzheimer’s, no one had proved that was the case.

As if scientists are supposed to study only what’s already known, an exasperated Moir thought when he read the reviews two years ago.

He’d just had a paper published in a leading journal, providing strong data for his idea that beta-amyloid, a hallmark of Alzheimer’s disease, might be a response to microbes in the brain. If true, the finding would open up vastly different possibilities for therapy than the types of compounds virtually everyone else was pursuing.

But the inconsistent evaluations doomed Moir’s chances of winning the $250,000 a year for five years that he was requesting from the National Institutes of Health. While two reviewers rated his application highly, the third gave him scores in the cellar. Funding rejected.

Complaints about being denied NIH funding are as common among biomedical researchers as spilled test tubes after a Saturday night lab kegger. The budgets of NIH institutes that fund Alzheimer’s research at universities and medical centers cover only the top 18 percent or so of applications. There are more worthy studies than money.

Moir’s experience is notable, however, because it shows that, even as one potential Alzheimer’s drug after another has failed for the last 15 years (the last such drug, Namenda, was approved in 2003), researchers with fresh approaches — and sound data to back them up — have struggled to get funded and to get studies published in top journals. Many scientists in the NIH “study sections” that evaluate grant applications, and those who vet submitted papers for journals, have so bought into the prevailing view of what causes Alzheimer’s that they resist alternative explanations, critics say.

“They were the most prominent people in the field, and really good at selling their ideas,” said George Perry of the University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease. “Salesmanship carried the day.”

Dating to the 1980s, the amyloid hypothesis holds that the disease is caused by sticky agglomerations, or plaques, of the peptide beta-amyloid, which destroy synapses and trigger the formation of neuron-killing “tau tangles.” Eliminating plaques was supposed to reverse the disease, or at least keep it from getting inexorably worse. It hasn’t. The reason, more and more scientists suspect, is that “a lot of the old paradigms, from the most cited papers in the field going back decades, are wrong,” said MGH’s Rudolph Tanzi, a leading expert on the genetics of Alzheimer’s.

Even with the failure of amyloid orthodoxy to produce effective drugs, scientists who had other ideas saw their funding requests repeatedly denied and their papers frequently rejected. Moir is one of them.

For years in the 1990s, Moir, too, researched beta-amyloid, especially its penchant for gunking up into plaques and “a whole bunch of things all viewed as abnormal and causing disease,” he said. “The traditional view is that amyloid-beta is a freak, that it has a propensity to form fibrils that are toxic to the brain — that it’s irredeemably bad. In the 1980s, that was a reasonable assumption.”

But something had long bothered him about the “evil amyloid” dogma. The peptide is made by all vertebrates, including frogs and lizards and snakes and fish. In most species, it’s identical to humans’, suggesting that beta-amyloid evolved at least 400 million years ago. “Anything so extensively conserved over that immense span of time must play an important physiological role,” Moir said.

What, he wondered, could that be?

In 1994, Moir changed hemispheres to work as a postdoctoral fellow with Tanzi. They’d hit it off over beers at a science meeting in Amsterdam. Moir liked that Tanzi’s lab was filled with energetic young scientists — and that in cosmopolitan Boston, he could play the hyper-kinetic (and bone-crunching) sport of Australian rules football. Tanzi liked that Moir was the only person in the world who could purify large quantities of the molecule from which the brain makes amyloid.

Moir initially focused on genes that affect the risk of Alzheimer’s — Tanzi’s specialty. But Moir’s intellectual proclivities were clear even then. His mind is constantly noodling scientific puzzles, colleagues say, even during down time. Moir took a vacation in the White Mountains a decade ago with his then-6-year-old son and a family friend, an antimicrobial expert; in between hikes, Moir explained a scientific roadblock he’d hit, and the friend explained a workaround.

Moir’s inclination toward unconventional thinking took flight in 2007. He was (and still is) in the habit of spending a couple of hours Friday afternoons on what he calls “PubMed walkabouts,” casually perusing that database of biomedical papers. One summer day, a Corona in hand, he came across a paper on something called LL37. It was described as an “antimicrobial peptide” that kills viruses, fungi, and bacteria, including — maybe especially — in the brain.

What caught his eye was that LL37’s size and structure and other characteristics were so similar to beta-amyloid, the two might be twins.

Moir hightailed it to Tanzi’s office next door. Serendipitously, Tanzi (also Corona-fueled) had just received new data from his study of genes that increase the risk of Alzheimer’s disease. Many of the genes, he saw, are involved in innate immunity, the body’s first line of defense against germs. If immune genetics affect Alzheimer’s, and if the chief suspect in Alzheimer’s (beta-amyloid) is a virtual twin of an antimicrobial peptide, maybe beta-amyloid is also an antimicrobial, Moir told Tanzi.

If so, then the plaques it forms might be the brain’s last-ditch effort to protect itself from microbes, a sort of Spider-Man silk that binds up pathogens to keep them from damaging the brain. Maybe they save the brain from pathogens in the short term only to themselves prove toxic over the long term.

Tanzi encouraged Moir to pursue that idea. “Rob was trained [by Marshall] to think out of the box,” Tanzi said. “He thinks so far out of the box he hasn’t found the box yet.”

Moir spent the next three years testing whether beta-amyloid can kill pathogens. He started simple, in test tubes and glass dishes. Those are relatively cheap, and Tanzi had enough funding to cover what Moir was doing: growing little microbial gardens in lab dishes and then trying to kill them.

Day after day, Moir and his junior colleagues played horticulturalists. They added staph and strep, the yeast candida, and the bacteria pseudomonas, enterococcus, and listeria to lab dishes filled with the nutrient medium agar. Once the microbes formed a thin layer on top, they squirted beta-amyloid onto it and hoped for an Alexander Fleming discovery-of-penicillin moment.

How an outsider in Alzheimer’s research bucked the prevailing theory — and clawed for validation. Stat News

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