A small group of scientists, including some in Philadelphia, have been bucking the research establishment for years by arguing that microbes might trigger the deadly form of dementia in older people. They contend that their ideas deserve more respect — and money — now that years of attempts to attack Alzheimer’s disease by focusing research and medications on its hallmark signs in the brain — clumps of amyloid called plaques and misshapen tangles of tau — have so far failed to produce a good treatment.
“It does not appear that therapeutics based on tau and amyloid are going to work,” said Brian Balin, a neuropathologist who directs the Center for Chronic Disorders of Aging at Philadelphia College of Osteopathic Medicine, and has been studying the role of the Chlamydia pneumoniae bacteria in Alzheimer’s since 1998. “Is this really the problem? It’s more of an end result, many of us think.”
Balin organized the first scientific meeting on the pathogen hypothesis theory of Alzheimer’s in Philadelphia in October 2014. There were eight speakers. The follow-up meeting, which posited that Alzheimer’s is a “chronic inflammatory disorder,” was held this October in Switzerland and drew 24 speakers. Balin was also among more than 30 scientists who signed an editorial in the Journal of Alzheimer’s Disease in 2016 calling for more research into the connection between infection and Alzheimer’s. It is not clear, they said, whether plaques and tangles are causes or consequences of disease. There was evidence that the process may start with various viruses and bacteria. Some microbes, they said, may remain latent in the body for years.
Asked if the group’s ideas are getting more respect, Balin replied with a laugh, “I don’t know if it’s better accepted. We don’t have people railing against it.”
New work is indeed bolstering the idea that microbes could play a role in starting the cascade of brain changes that lead to cognitive decline. A recent Mount Sinai and Arizona State University study, for example, found that the brains of people with Alzheimer’s disease contained more of two types of herpes viruses — HHV-6 and HHV-7 — than the brains of people without dementia. Harvard University researchers have found evidence, in lab studies and mice, that amyloid clumps are part of the body’s innate, or most primitive, immune system.
In earlier studies, Balin found chlamydia disproportionately in brains of Alzheimer’s patients. Other studies implicate the herpes virus that causes cold sores. (Sexually transmitted forms of chlamydia and herpes are not suspects.) Judith Miklossy, director of the Prevention Alzheimer International Foundation and International Alzheimer Research Center in Switzerland, says the pathology in brains of people with late-stage syphilis is virtually indistinguishable from that in Alzheimer’s. She has also found Borellia burgdorferi, which causes Lyme disease, in the brains of Alzheimer’s patients and was able to induce Alzheimer’s pathology with it in cell culture. Infection with HIV, the virus that causes AIDS, is known to increase the risk for dementia, even when it’s suppressed by medications.
Other experts caution that the science is not yet strong enough to prove germs are the cause or, more likely, one of the causes of dementia. And because several of the germs found more frequently in the brains of people with Alzheimer’s are ubiquitous, scientists suspect that if they are involved, they are likely part of a complex interplay of genes, age, inflammation, environmental exposures, head trauma, and metabolic factors.
“It is clear that there are more and more data being accumulated that point to a connection of some kind between viral sequences and Alzheimer’s in the brain,” said Richard Hodes, director of the National Institute on Aging. He added, however, that a correlation between the presence of microbes in the brain and Alzheimer’s pathology does not prove one causes the other.
Eliezer Masliah, director of the NIA’s division of neuroscience, said the agency is funding research into potential treatments from “multiple directions.” It has targeted funding for how the body’s microbiome affects the nervous system and why people with HIV are at higher risk for dementia. Hodes said the NIA will consider whether to make research on germs and Alzheimer’s a higher priority during the next round of funding.
Private funders intrigued by the infectious-disease hypothesis have already stepped in. In 2017, Leslie Norins, a doctor who became a medical publisher, offered a $1 million prize to anyone who can identify an Alzheimer’s germ. He’s also supporting the Infectious Diseases Society of America with two $50,000 grants to study infection and Alzheimer’s. The Cure Alzheimer’s Fund is supporting the work of Rudolph Tanzi and Robert Moir, neuroscientists at Harvard and Massachusetts General Hospital, who are studying amyloid’s immune properties and how microbes in the gut may affect the brain. “We want that revolutionary mindset,” said Meg Smith, the fund’s senior vice president for research management.
James Truchard, co-founder and chairman of National Instruments, created the Oskar Fischer Project — Fischer was a Jewish academic in Prague who described Alzheimer’s disease in the same year as Alois Alzheimer, but who died in a concentration camp — to support research he finds promising. Truchard’s goal is to “cross boundaries.” Much of the “tens of millions” he’s given to researchers was for studies on how metabolism affects dementia, but he also gave $759,000 to Garth Ehrlich at Drexel University to catalog and analyze pathogens found in brains.
John Trojanowski, co-director of the University of Pennsylvania’s Center for Neurodegenerative Disease Research, thinks it is too early to count amyloid and tau out as drug targets. There’s a “whole convergence of evidence arguing that these are important in Alzheimer’s disease,” he said. Early trials of anti-beta-amyloid medications came before imaging techniques allowed researchers to measure Alzheimer’s tau and beta-amyloid pathology in living people. Scientists later learned that up to a quarter of trial participants did not actually have beta-amyloid deposition. Current approaches are better targeted and are aimed at people who are in earlier stages of the disease, when there is less brain damage. Fewer drugs that target tau, which correlates better with the degree of dementia than amyloid, have been tested.
Studies are also revealing that dementia is a messier, more complicated phenomenon than previously thought. Elderly people with cognitive decline that looks clinically like Alzheimer’s often have a combination of vascular damage in the brain plus “misfolded” proteins associated with more than one type of dementia, Trojanowski said. Work at Penn has shown that the form of tau found in Alzheimer’s and errant proteins found in other forms of dementia can themselves spread from cell to cell, an infection-like process that may also present targets for medications. (Trojanowski emphasized that Alzheimer’s itself is not infectious.) All this means that combating dementia may require more than one medication. “What we need is combination therapy,” he said.
Harvard’s Tanzi and Moir have found that beta amyloid is produced as a response to infection and can protect against it. Plaques can actually entrap microbes. The researchers say that infection proponents and those most interested in amyloid and tau don’t have to be in warring camps.
“Infection is the prequel to the amyloid hypothesis, not a replacement,” said Tanzi, who is also known for identifying three genes involved in early-onset Alzheimer’s.
Tanzi and Moir think plaques may form in response to multiple brain invaders, including particles of air pollution. If too many plaques form and the brain fails to dispose of them properly, that sets a path that leads to the buildup of tangles, triggers inflammation, and causes cells to die, they said. Moir suspects that gut toxins and possibly immune-system dysfunction could also set off the plaques. The pair think that the neuroinflammation, the most damaging part of the disease, takes on a life of its own once the process gets started. That may explain why attacking amyloid hasn’t been enough. “It’s like thinking you can put out a forest fire by putting out the match,” Tanzi said.
They are investigating the brain microbiome now to see if any particular microbes, or balance of microbes, is associated with dementia. “Everybody has their favorite,” Tanzi said. “We’re agnostic.” Moir said so far herpes simplex 1 and human herpesvirus 6 stand out as suspected “bad players.” They’ve already found more than 200 bacteria that can make it past the blood-brain barrier in older people — that barrier weakens with age — and haven’t even started on viruses yet. The brains of younger people, Moir said, contained more bacteria associated with low inflammation.
Balin’s work on Alzheimer’s and infection started with finding C. pneumoniae in 90 percent of brains with Alzheimer’s pathology and only 5 percent of brains without it. He thinks the bacteria, which can “act like a virus” in cells, is a good suspect because it enters the body through the nose and, from there, can access the parts of the brain where Alzheimer’s typically starts. The loss of sense of smell is one of the first symptoms of Alzheimer’s disease. For his most recent work, Balin exposed mice to chlamydia and they developed clumps of amyloid beta, a plaque building block. His team has not yet found tau tangles or cognitive changes.
Ehrlich’s interest in Alzheimer’s stems from a conference he attended six years ago about the systemic effects of bacteria involved in periodontal disease, including their presence in the brain. He had long studied how bacteria can form colonies called biofilms, causing chronic inflammation in places like the middle ear while avoiding detection. He helped develop special DNA-based tests that could find the bugs and had identified one culprit in artificial joint loosening as a periodontal organism, Treponema denticola, that, like syphilis and Lyme disease bacteria, is a spirochete. Spirochetes, he said, are partial to skin, joints and the central nervous system and can form biofilms.
He suspects that multiple germs could trigger brain inflammation. He has not yet published results of his brain testing. He’ll start with bacteria, then move to fungi. Viruses, which are harder to test for, will come later.
W. Sue T. Griffin, who studies the molecular biology of Alzheimer’s at the University of Arkansas for Medical Sciences, has been studying for years how various stressors — epilepsy, HIV, aging, traumatic brain injury — can set off a series of immune responses in the brain that lead to the production of extra beta amyloid. She still questions how many microbes can actually make it into the brain, but is intrigued by the pathogen theory. “If the germs are there,” she said, “I know exactly what’s going to happen. Those immune responses will set off a self-repeating cycle of more and more plaques and nerve cell stress and loss.”
Tampering with immune response could be risky. Tanzi is developing a therapy that would lower production of beta amyloid but not eliminate it. “It’s a balancing act,” he said.
Researchers said it may be important to figure out how to strengthen the blood-brain barrier. Perhaps people with genes known to increase the risk for late-onset Alzheimer’s, like APOE4, will someday get more aggressive treatment for germs now considered relatively benign. There’s some evidence that antiviral medications can reduce risk, another avenue that needs more evidence.
For now, though, researchers said the best approach is to engage in behaviors that might reduce inflammation and keep your immune system healthy. You guessed it: Eat healthy, including lots of fiber. Avoid type 2 diabetes. Exercise.