Commentary: Alzheimer’s Research Pipeline Is Poised to Conquer Alzheimer’s with Combination Drug Treatments

by Howard Fillit, M.D.


The recent approval of Aduhelm, a drug that removes amyloid plaques from the brains of people with Alzheimer’s, is a reason for cautious celebration. Not just because it is the first new treatment approved in 17 years, but because it is the first piece of a complex puzzle that researchers are hot on the trail of solving.

Protein abnormalities in the brain, like tau tangles and the amyloid plaques that Aduhelm attacks, are what usually come to mind when most people think about Alzheimer’s disease. But more than 20 years ago, the Alzheimer’s Drug Discovery Foundation (ADDF) began urging scientists to broaden their research to include the many biological processes that falter with aging and contribute to the disease.

For example, as people age, they are more likely to have chronic inflammation, including inflammation in the brain, which is associated with poorer cognitive function. Other aging malfunctions in the brain trigger inefficient use of internal and external energy sources, vascular problems, changes in how certain genes work, and loss of synapses, the pathways that carry signals across our brains.

Compared to 20 or even just 10 years ago, scientists today have a much stronger understanding of how each of these pathways — and indeed the overall biology of aging — contribute to Alzheimer’s disease. Alzheimer’s is not caused by one single factor, but by a complex set of these mechanisms that interact with one another and lead to deterioration and death of brain cells. This is what causes the loss of memory and cognitive abilities that Alzheimer’s patients and their families fear.

Today’s Alzheimer’s research pipeline is built on this deeper understanding of the biology of the disease. As a result, today’s pipeline is more robust and diverse than ever before. There are more than 120 potential Alzheimer’s drugs currently in clinical trials, and most work on targets other than the abnormal buildup of amyloid and tau.

Here are just a few examples of research that the ADDF is supporting in these areas.

Researchers at the University College London have identified an overactive protein in the brains of Alzheimer’s patients that damages the blood brain barrier (BBB). The blood brain barrier controls what gets into and out of the brain, including glucose, which provides the essential energy the brain needs to stay healthy. These researchers are working on ways to inhibit the overactive protein to help the BBB maintain its normal function.

A drug being tested at Johns Hopkins University in Baltimore also aims to maintain balance in the brain, but in this case, focusing on nerve cell signaling. Nerve cells, or neurons, are information messengers that carry essential signals within the brain and between the brain and the rest of the nervous system. Disruptions in the normal balance of nerve cell signaling contribute to cognitive deficits and memory impairment.

At Wake Forest School of Medicine in North Carolina, researchers are looking at ways to rid the aging brain of “zombie cells.” These cells activate internal programs to sidestep the natural death cycle that all cells go through. These cells survive, but like zombies, they have no useful function. Instead, zombie cells release toxins that damage nearby healthy cells, causing harmful inflammation.

These are just three of the pathways for which prospective drugs are in various stages of development that go beyond the once traditional targets of amyloid and tau proteins. Today, we have more than two dozen trials in phase 3 development, which is usually the last phase of testing before the FDA considers whether a drug can be approved for routine use in this country.

Dozens more potential drugs are in phase 2 of development. This is when a drug’s effectiveness is usually first tested in small number of patients. And while phase 1 drugs, the “safety” phase, have a longer way to go before they make their way to patients, the fact that we have about two dozen drugs in phase 1 means our pipeline will continue to deliver for years to come.

As a physician and researcher who has been working with Alzheimer’s patients and their families for more than 40 years, I am more optimistic than ever about our drug pipeline. The research pipeline is primed to give us drugs that target a range of pathways that contribute to the development and progression of Alzheimer’s disease.

In time, physicians will have the tools they need so they can combine medications, much as we do today for cancer, to address individual patient needs rather than having a “one-size-fits-all” approach to Alzheimer’s disease. We have entered a modern era and are moving closer to the real prize: personalized medicine for Alzheimer’s that will treat the full range of patients, including new ways to treat the disease, as well as better methods to prevent or delay its onset for those at risk.

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Howard Fillit, M.D. is the Founding Executive Director and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation (ADDF).






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