Scientists have long puzzled over the root causes of Alzheimer's disease, a devastating and typically fatal condition that currently denies more than five million Americans their cognition and memory. But in a provocative editorial soon to be published in the Journal of Alzheimer's Disease, a cadre of scientists argue that the complex disease may have a surprisingly simple trigger: tiny brain-infecting microbes. This controversial view, which is not new, has long been dismissed as outlandish, but a growing body of work suggests it may be worth considering and further studying. If researchers can prove the theory and iron out the many argued-over details — both formidable tasks, as brain infections are difficult to study — Alzheimer's could become a preventable illness.
The editorial, signed by 31 scientists around the world, argues that in certain vulnerable individuals — such as those with the APOE ε4 gene variant, a known Alzheimer's risk factor — common microbial infections can infect the aging brain and cause debilitating damage. These microbes may include herpes simplex virus 1 (HSV-1), the ubiquitous virus that causes cold sores as well as Chlamydophila pneumoniae and Borrelia burgdorferi, the bacteria that cause pneumonia and Lyme disease, respectively.
The controversial idea butts heads with the long-standing theory that amyloid-beta proteins and tau tangles, both of which build up inside the brains of those with Alzheimer's, are the main drivers of disease-induced cell death. Instead, supporters of the pathogen hypothesis, as it is called, posit that either pathogens induce brain cells to produce the amyloid proteins and tau tangles or that nerve cells that have been damaged by infection produce them as part of an immune response. "We think the amyloid story does come into play, but it's secondary to the initial inflammation," says editorial co-author Brian Balin, who directs the Center for Chronic Disorders of Aging at the Philadelphia College of Osteopathic Medicine.
Critics of the pathogen theory point out that much of the supportive human research does not establish cause and effect. In a study published in The Lancet in 1997, a team led by Ruth Itzhaki, one of the editorial's co-authors and a molecular neurobiologist at the University of Manchester in England, reported that people whose brains were infected with HSV-1 and who also had the APOE ε4 gene variant were 12 times more likely to develop Alzheimer's than those with either the gene variant or the infection alone. One hypothesis is that the APOE ε4 variant makes it easier for HSV-1 to infect brain cells — but, critics say, it could also be that the gene variant and the infection are associated with Alzheimer's in ways that are not causal.
Scientists have tried to nail down the mechanics of the relationship using animals. Researchers in Spain have found, for instance, that mice whose brains have been infected with HSV-1 produce nearly 14 times as much viral DNA when they have the APOE ε4 variant compared with when they do not. And after infecting the brains of mice with HSV-1, Itzhaki's group showed that their brains accumulated amyloid plaques. But these studies are criticized, too — after all, what happens in a mouse's brain may not happen in a human's.
The burden of proof is formidable for this theory, in part because it is impossible to detect infections like HSV-1 in the brains of living people — they can only be seen postmortem. "'Proof of causation is a major, critical and very complex issue," says David Relman, an infectious disease specialist at Stanford University. Itzhaki agrees, noting that one cannot just inject people with the virus and wait to see if they develop Alzheimer's. (That said, Australian microbiologist Barry Marshall finally convinced skeptics that Heliobactor pylori bacteria cause gastric ulcers by infecting himself.) Itzhaki says that one potential solution would be to conduct a pilot clinical trial that evaluates whether HSV-1-infected individuals with mild Alzheimer's and the APOE ε4 variant improve if they are treated with antiviral drugs. They have already shown in the lab that these drugs inhibit amyloid plaque production in HSV-1 infected cells. But she has applied for funding for a human study multiple times and has so far has been unsuccessful.
Rudolph Tanzi, a neurologist at Harvard University who directs the Genetics and Aging Research Unit at Massachusetts General Hospital, agrees that microbes likely play a role in Alzheimer's — but his work suggests that the brain's response to the infection is more dangerous than the infection itself. "We do need to take the role of microbes in the brain seriously, but it's going to be a lot more involved than simply saying 'infection causes Alzheimer's disease,'" he notes. (He was not involved in the editorial.) In a 2010 study Tanzi and his colleagues reported that the amyloid protein strongly inhibits microbial growth in the brain, which suggests that it accumulates as a protective response to infection. "Over the last five years, following up from that 2010 paper, we've showed that in every Alzheimer's model tested — from cells to flies to dirt worms to mice — beta amyloid potently protects from infection," he explains. The presence of even just a few microbes in the brain, he says, triggers its accumulation.
Infections induce potent immune responses, too, and they likely worsen the problem. Normally, brain immune cells called microglia clear amyloid proteins from the brain. But when these cells get fired up in response to infection, they stop, causing the proteins to build up even faster. As Tanzi's team showed in a 2014 Nature paper, the amyloid proteins that fill up the brain then spark the creation of tau tangles, which cause more brain cell death. "And now, you have the full-blown disease," he says. (Scientific American is part of Springer Nature.)
As for which pathogens might be triggers, HSV-1 is a contender, Tanzi says, but it is too soon to know for sure. "I think we have to take a couple of steps back and say, 'What types of bacteria, viruses and fungus accumulate in the brain as we age?' and study this systematically in an unbiased, agnostic way," he says. He is leading a consortium funded by the nonprofit Cure Alzheimer's Fund to map the microbiome of the human brain; once potentially important microbes are identified, it might be possible to develop neuroimaging techniques to track them in the brains of living individuals, he says.
Other Alzheimer's scientists still are not convinced, however. David Holtzman, chair of the department of neurology at Washington University School of Medicine in St. Louis and associate director of its Knight Alzheimer's Disease Research Center, told Scientific American that although more research on the idea is warranted, "there is not clear or conclusive evidence of whether or how different infections influence risk for Alzheimer’s disease." Tanzi says that when he presents his findings and ideas at scientific meetings, reactions are indeed mixed. One comment Itzhaki often hears is that HSV-1 cannot cause Alzheimer's if it is also found, as it is, in the brains of elderly healthy people. But she points out that other pathogens, including tuberculosis, only cause symptoms in subset of vulnerable individuals, too.
If microbes do turn out to be a potential trigger for Alzheimer's — and to most in the field, this is still a big "if" — the implications would be huge: It might be possible to vaccinate against the debilitating disease simply by inoculating against offending infections. At the very least, doctors might be able to treat infections with antimicrobial drugs before they harm the brain. But building enough evidence to prove the theory could take decades. Among other challenges, researchers working in the area complain of funding woes. "Over the 50-plus years that I've been doing the work, our group has had extreme difficulties nearly all the time — we've been working on a shoestring," Itzhaki says.
But given that hundreds of clinical trials for Alzheimer's drugs have failed based on the prevailing dogma, those working on the various versions of the pathogen theory believe it is worth pushing forward. More than anything, they hope their editorial will encourage skeptics to at least consider the possibility that microbes could play a role in Alzheimer's disease and support their desire to study it more. "We're saying 'wait a minute, folks — we have a body of evidence here from decades of work that we have to stop ignoring,'" Balin says.
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