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
A similar inflammatory process is probably also at play in Parkinson’s disease, says Ole Isacson, a professor of Neurology at Harvard Medical School. Isacson points to another early clue about the role of inflammation in Parkinson’s: people who regularly took anti-inflammatory drugs like ibuprofen developed the disease one to two years later than average. Whereas other researchers focused exclusively on genetics, Isacson found the evidence suggested the environment had a substantial impact on who got Parkinson’s.
In 2008–09, Isacson worked with a postdoctoral student on an experiment trying to figure out which comes first in the disease process: inflammation or the death of dopamine-producing neurons, which make the brain chemical involved in transmitting signals among nerve cells. The student first triggered inflammation in the brains of some rodents with molecules from gram-negative bacteria and then damaged the neurons that produce dopamine. In another group of rodents, he damaged the neurons first and then introduced inflammation. When inflammation came first, the cells died en masse, just as they do in Parkinson’s disease. Blocking inflammation prevented their demise, they reported in The Journal of Neuroscience.
Other neurodegenerative diseases also have immune connections. In multiple sclerosis, which usually strikes young people, the body’s immune system attacks the insulation around nerve cells, slowing the transmission of signals in the body and brain.
The spinal fluid of people with MS include antibodies and high levels of white blood cells, indicating the immune system is revved up — although it is not clear whether that immune system activation is the cause or result of MS, says Mitchell Wallin, who directs the Veterans Affairs Multiple Sclerosis Centers of Excellence. People with antibodies to the Epstein–Barr virus in their systems, especially if they caught the virus in late adolescence or early adulthood run a higher risk of developing MS — supporting the idea that an infection plays a role in MS.
Thanks to newer medications and improvements in fighting infections, people with MS are now living longer. This increased longevity puts them at risk for neurological diseases of aging, including Alzheimer’s and Parkinson’s, Wallin says. Lack of data has left it unclear whether people with MS are at the same, higher or lower risk for these diseases than the general population. “How common it is, we’re just starting to explore right now,” Wallin says.
It will be years before the concept of a neuroinflammatory can be fully tested, but there are already some relevant drugs in development. One start-up, California-based INmune Bio, recently received a $1-million grant from the Alzheimer’s Association to advance XPro1595, a drug that targets neuroinflammation. The company is beginning its first clinical trial this spring, treating 18 patients with mild to moderate-stage Alzheimer’s who also show signs of inflammation. The company plans to test blood, breath by-products and cerebral spinal fluid as well as conduct brain scans to look for changes in inflammatory markers. That first trial will just explore if XPro1595 can safely bring down inflammation and change behaviors such as depression and sleep disorders. Company CEO and co-founder Raymond Tesi says he expects to see those indicators improve, even in a short, three-month trial.
The best way to avoid Alzheimer’s is to prevent it from ever starting, which might require keeping brain inflammation to a minimum, particularly in later life. Preventative measures are already well known: eat healthy foods, sleep well, exercise regularly, minimize stress and avoid smoking and heavy drinking.
You can’t do anything about your genetics but living a healthy lifestyle will help control your inheritance, says Tanzi, who, along with Deepak Chopra, wrote a book on the topic, The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life. “It’s important to get that set point as high as possible.”