Can germs cause Alzheimer’s disease?
"It does not appear that therapeutics based on tau and amyloid are going to work," said
Balin organized the first scientific meeting on the pathogen hypothesis theory of Alzheimer's in
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
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.)
Is there a link? That’s still a big maybe
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
Private funders intrigued by the infectious-disease hypothesis have already stepped in. In 2017,
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.
Can a single strategy be enough?
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.
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.
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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.
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