Could inflammation be the key to finding a drug to treat Alzheimer’s disease?Chelsea Stahl / NBC News; Getty Images
The past decade of Alzheimer’s disease research has been fraught with disappointment.
Years of focus on one hallmark of the disease ultimately resulted in no progress toward treatment or prevention.
But next week, when top scientists gather in Los Angeles at the Alzheimer’s Association International Conference, an annual meeting, many will present research on a different target: inflammation.
“The big breakthrough is that neuroinflammation is the target. It’s killing the bulk of the nerve cells that leads to dementia,” said Rudolph Tanzi, a professor of neurology at Harvard University and the director of neurology at Massachusetts General Hospital.
Moving beyond plaques
Early research into Alzheimer’s disease pointed toward a conspicuous target: clumps of protein in the brain called amyloid plaques. When scientists studied the brains of people with Alzheimer’s disease who died, they noticed the brain tissue was full of these plaques, which are still considered a hallmark of the disease.
But although research has shown time and time again that amyloid plaques may play a role in Alzheimer’s, it’s not the singular key to a cure.
Indeed, on Thursday, pharmaceutical companies Amgen and Novartis announced their trial of a drug meant to help block the production of amyloid plaques had failed. In fact, patients who received the drug got worse. The Alzheimer’s Association called the outcome “disappointing.
But according to Tanzi, going after the plaques after they’ve formed means you’re too late. That’s because amyloid develops very early in the Alzheimer’s disease process — even 20 years before the first symptoms appear. Attacking amyloid in patients who already have dementia is like trying to stop a forest fire by blowing out a match, he said. It’s inflammation that’s allowing the fire to rage out of control.
“If you want to hit the plaques, you have to do so early on with early detection,” Tanzi said. “I believe that will be the future for preventing Alzheimer’s disease. But for now, how do we help the 5 million patients in this country? You have to put out the forest fire.”
Putting out the inflammation fire
Tanzi is working with a Boston-based company called AZTherapies to find drugs already in existence that can tackle that neuroinflammation. Tanzi serves as director of the company’s scientific advisory board, and has financial ties to the company.
Part of AZTherapies’ research involves a drug used to treat asthma, called Cromolyn, which targets inflammation in the lungs. The company altered the medication so that it reaches the brain, and is testing it in combination with ibuprofen.
“This is one of the first trials to take a relatively safe drug … reformulate it, and then ask if we turn off neuroinflammation, can we put out the forest fire and, just like a forest, allow it to grow back?” Tanzi said.
AZTherapies has enrolled almost 600 patients for that trial, and expects results within the next year or two. Still, it’s far too early to suggest people take anti-inflammatory medications to help stave off dementia. Drugs on the market now either don’t reach the brain, or come with other risks associated with long-term use, like increased risk for heart attack, stroke and stomach ulcers.
AZTherapies is not the only company moving away from amyloid research and into areas that target inflammation.
Neurotrope will present research at next week’s Alzheimer’s Association conference about its drug, bryostatin-1.
Originally tested as a cancer drug, bryostatin-1 works by activating a protein involved with the “wiring”of the brain.
“It induces the regeneration of wiring and synaptic networks that are lost. It prevents neuronal death. And also it is very significantly anti-inflammatory,” Dr. Daniel Alkon, Neurotrope’s president, said.
Alkon told NBC News that in early studies of Alzheimer’s patients, those taking bryostatin-1 showed cognitive improvement that was sustained for at least a month after treatment.
“To us, this is consistent with new networks being formed,” Alkon said. “We think the ways we have been using anti-inflammatories as part of an overall pro-survival approach to the brain networks could be a breakthrough for the field.”
That inflammation plays a role in Alzheimer’s is not a new idea — scientists have been studying its role for some time. In 2013, researchers at the Mayo Clinic published a study that looked at post-mortem brains. All of the brains had evidence of amyloid plaques and another Alzheimer’s hallmark, tau tangles.
But only half of the patients had dementia when they were alive. The others were cognitively normal.
“The only thing that differentiated them was an inflammatory response. There were more inflammatory cells in the brain … in the people who had clinical dementia versus those who were clinically normal, again suggesting that inflammation is a key mediator here,” Dr. Ronald Petersen, a neurologist at the Mayo Clinic, said.
The hunt for an effective treatment for Alzheimer’s disease will remain critical as the number of patients — estimated as 5.8 million in the U.S. alone — is projected to swell to 14 million by 2050, according to the Alzheimer’s Association. It is the sixth leading cause of death in the U.S.
Memory loss associated with Alzheimer’s can be mild in the early stages of the disease. But over time, patients develop more serious confusion and memory loss, as well as mood and behavior changes, disorientation and difficulty speaking, swallowing and walking.
There is no cure for Alzheimer’s disease. Available treatments can only improve quality of life and temporarily slow a person’s decline.
I feel like we’re finally seeing a light at the end of the tunnel.
Maria Carrillo, chief science officer at the Alzheimer’s Association, is not ready to call the last decade of research on amyloid a waste. On the contrary, she said it’s helped scientists understand that it’s not only amyloid and tau that matter.
“Today’s science tells us there might be as many as four or five other proteins that are going wrong, contributing to the cell death we experience in Alzheimer’s dementia,” Carrillo said.
“It’s important that we understand what those are and how to tackle all of them with pharmaceuticals. That’s where we need to go, a combination approach that may also include lifestyle changes, just like other diseases do,” she said.
Tanzi agrees. He suggests an approach he calls SHIELD, an acronym for lifestyle factors that appear to help reduce the risk of developing Alzheimer’s. They include:
- developing good sleep habits
- getting a handle on stress
- interacting with friends
- exercising daily
- learning new skills
- eating a healthy diet
“It’s never too early to start thinking about how to protect your brain,” he said. He is hopeful those lifestyle changes, plus research into neuroinflammation, will make a marked impact on Alzheimer’s disease.
“I feel like we’re finally seeing a light at the end of the tunnel,” said Tanzi. “We’ve made mistakes, but those mistakes have taught us where we need to get to next.”