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For Alzheimer’s Sufferers, Brain Inflammation Ignites A Neuron-Killing “Forest Fire”

by Karen Weintraub: And it could also be the kindling sparking Parkinson’s and other neurodegenerative maladies…

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For decades researchers have focused their attacks against Alzheimer’s on two proteins, amyloid beta and tau. Their buildup in the brain often serves as a defining indicator of the disease. Get rid of the amyloid and tau, and patients should do better, the thinking goes.

But drug trial after drug trial has failed to improve patients’ memory, agitation and anxiety. One trial of a drug that removes amyloid even seemed to make some patients worse. The failures suggest researchers were missing something. A series of observations and recently published research findings have hinted at a somewhat different path for progression of Alzheimer’s, offering new ways to attack a disease that robs memories and devastates the lives of 5.7 million Americans and their families.

One clue hinting at the need to look further afield was a close inspection of the 1918 worldwide flu pandemic, which left survivors with a higher chance of later developing Alzheimer’s or Parkinson’s. A second inkling came from the discovery that the amyloid of Alzheimer’s and the alpha-synuclein protein that characterizes Parkinson’s are antimicrobials, which help the immune system fight off invaders. The third piece of evidence was the finding in recent years, as more genes involved in Alzheimer’s have been identified, that traces nearly all of them to the immune system. Finally, neuroscientists have paid attention to cells that had been seen as ancillary—“helper” or “nursemaid” cells. They have come to recognize these brain cells, called microglia and astrocytes, play a central role in brain function—and one intimately related to the immune system.

All of these hints are pointing toward the conclusion that both Alzheimer’s and Parkinson’s may be the results of neuroinflammation—in which the brain’s immune system has gotten out of whack. “The accumulating evidence that inflammation is a driver of this disease is enormous,” says Paul Morgan, a professor of immunology and a member of the Systems Immunity Research Institute at Cardiff University in Wales. “It makes very good biological sense.”

The exact process remains unclear. In some cases the spark that starts the disease process might be some kind of insult—perhaps a passing virus, gut microbe or long-dormant infection. Or maybe in some people, simply getting older—adding some pounds or suffering too much stress could trigger inflammation that starts a cascade of harmful events.

This theory also would explain one of the biggest mysteries about Alzheimer’s: why some people can have brains clogged with amyloid plaques and tau tangles and still think and behave perfectly normally. “What made those people resilient was lack of neuroinflammation,” says Rudolph Tanzi, a professor of neurology at Harvard Medical School and one of the leaders behind this new view of Alzheimer’s. Their immune systems kept functioning normally, so although the spark was lit, the forest fire never took off, he says. In Tanzi’s fire analogy, the infection or insult sparks the amyloid match, triggering a brush fire. As amyloid and tau accumulate, they start interfering with the brain’s activities and killing neurons, leading to a raging inflammatory state that impairs memory and other cognitive capacities. The implication, he says, is that it is not enough to just treat the amyloid plaques, as most previous drug trials have done. “If you try to just treat plaques in those people, it’s like trying to put out forest fire by blowing out a match.”

LIGHTING THE FIRE

One study published earlier this year found gum disease might be the match that triggers this neuroinflammatory conflagration—but Tanzi is not yet convinced. The study was too small to be conclusive, he says. Plus, he has tried to find a link himself and found nothing. Other research has suggested the herpes virus could start this downward spiral, and he is currently investigating whether air pollution might as well. He used to think amyloid took years to develop, but he co-authored a companion paper to the herpes one last year, showing amyloid plaques can literally appear overnight.

It is not clear whether the microbes—say for herpes or gum disease—enter the brain or whether inflammation elsewhere in the body triggers the pathology, says Jessica Teeling, a professor of experimental neuroimmunology at the University of Southampton in England. If microbes can have an impact without entering the brain or spinal cord—staying in what’s called the peripheral nervous system—it may be possible to treat Alzheimer’s without having to cross the blood–brain barrier, Teeling says.

Genetics clearly play a role in Alzheimer’s, too. Rare cases of Alzheimer’s occurring at a relatively young age result from inheriting a single dominant gene. Another variant of a gene that transports fats in brain cells, APOE4, increases risk for more typical, later-onset disease. Over the last five years or so large studies of tens of thousands of people have looked across the human genome for other genetic risk factors. About 30 genes have jumped out, according to Alison Goate, a professor of neurogenetics and director of the Loeb Center for Alzheimer’s Disease at Icahn School of Medicine at Mount Sinai in New York City. Goate, who has been involved in some of those studies, says those genes are all involved in how the body responds to tissue debris—clearing out the gunk left behind after infections, cell death and similar insults. So, perhaps people with high genetic risk cannot cope as well with the debris that builds up in the brain after an infection or other insult, leading to a quicker spiral into Alzheimer’s. “Whatever the trigger is, the tissue-level response to that trigger is genetically regulated and seems to be at the heart of genetic risk for Alzheimer’s disease,” she says. When microglia—immune cells in the brain—are activated in response to tissue damage, these genes and APOE get activated. “How microglia respond to this tissue damage—that is at the heart of the genetic regulation of risk for Alzheimer’s,” she says.

But APOE4 and other genes are part of the genome for life, so why do Alzheimer’s and Parkinson’s mainly strike older people? says Joel Dudley, a professor of genetics and genomics, also at Mount Sinai. He thinks the answer is likely to be inflammation, not from a single cause for everyone but from different immune triggers in different individuals.

Newer technologies that allow researchers to examine a person’s aggregate immune activity should help provide some of those answers, he says. Cardiff’s Morgan is developing a panel of inflammatory markers found in the blood to predict the onset of Alzheimer’s before much damage is done in the brain, a possible diagnostic that could point to the need for anti-inflammatory therapy

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