Last month, Professor Julie Williams of Cardiff University, who leads the Genetic and Environmental Risk in Alzheimer’s Disease Consortium, made an intriguing statement. Dr. Williams said, “If you just look at the genetic risk factors that are emerging for Alzheimer’s, you would think it was an auto-inflammatory disease.”
We have long known that inflammation is present in the brains of Alzheimer’s patients. And the mainstream research community is warming to the idea that inflammation is an important target to halt or reverse Alzheimer’s progression. But we still don’t know exactly what role “neuroinflammation” plays in the disease. Is it a malicious driver of Alzheimer’s? Or perhaps it is an inconsequential byproduct of the brain cell damage and death common in the disease. It could also be a beneficial response that is activated to repair or clear away damage. Like most things in biology, the answer is complicated, but more and more research suggests that inflammation plays a very active and early role in the development of Alzheimer’s.
Inflammation and the Brain’s Immune System
To understand neuroinflammation, we first need to understand microglia. These are the second most common cells in our brains, after neurons, and act in part as the immune system for our central nervous system. Microglia constantly patrol the brain, looking for signs of infection or inflammation caused by toxic proteins such as beta-amyloid and anything else than may damage our neurons.
As microglia clear sources of damage from the brain, they also release pro-inflammatory molecules called cytokines that activate other microglia. Normally, this cytokine release is short-lived. Groups of microglia activate to deal with the problem, and then go back to their “resting” state for patrolling. But in Alzheimer’s, research suggests microglia become overactive, increasing their production of cytokines and simultaneously clearing less. In this case, microglia could begin to cause the neuroinflammation they are designed to alleviate and their ability to clear away damage wanes, creating a vicious cycle. The result is more and more damaged neurons, which can lead to the onset of Alzheimer’s disease.
Drug Development Approaches
Previous research found that people taking non-steroidal anti-inflammatory drugs (NSAIDs) in mid-life had a lower risk of developing Alzheimer’s disease. But some early clinical trials testing NSAIDs as a potential treatment for Alzheimer’s patients failed. Because of this, most researchers abandoned neuroinflammation as a target for Alzheimer’s drugs.
The Alzheimer’s Drug Discovery Foundation (ADDF) did not. In 2001, we made our first investment in a program targeting neuroinflammation by D. Martin Watterson at Northwestern University. Since then, we have funded several dozen more drug programs around the world. Dr. Watterson’s research has produced three separate drugs—MW150, MW151, and MW189—that are expected to reach human clinical trials within the next year. They each block different aspects of microglial overactivation to protect neurons. In Italy, researchers at Axxam are in preclinical stages of development on a drug that blocks the release of a specific cytokine from microglia, so they can clear away damage without also causing it. And in Boston, Philip Haydon of Gliacure is preparing for a phase 2 clinical trial of a drug designed to lower cytokine production and enhance the clearance function of microglia.
And despite the failure of earlier NSAID trials, we haven’t abandoned the possibility that an existing anti-inflammatory medication may work for Alzheimer’s. Inflammation is involved in many different diseases—rheumatoid arthritis, pain, multiple sclerosis—and there are many approved drugs to treat it. We are currently supporting a clinical trial of etanercept, a rheumatoid arthritis drug, by Clive Holmes at the University of Southampton. And the ADDF is very interested in pursuing more investments in repurposed anti-inflammatory drugs.
The Future
Currently, 16% of our active portfolio of drug discovery and development programs is dedicated to neuroinflammation, and we expect this to grow. There is still a lot to be learned about the role of inflammation in Alzheimer’s and how to treat it. Because of these unanswered questions, neuroinflammation remains an underfunded, high-risk target for Alzheimer’s drugs. But with new discoveries emerging on promising drug targets, it is also ripe for high reward.
The ADDF’s scientific team is proactively working to get emerging targets into the drug pipeline while continuing to invest in the progress of more advanced drug programs. Our goal is to de-risk neuroinflammation programs so more funders and researchers will join us. The ADDF was an early champion of this strategy and remains at its forefront, advancing the most promising neuroinflammation drugs for Alzheimer’s disease.
Diana Shineman, PhD is the former Senior Director, Scientific Affairs at the ADDF.