New Approach to Alzheimer's Treatment

In the 1990s, the solution to Alzheimer’s disease seemed clear. New genetic studies all pointed to one culprit—hard clumps of protein, called amyloid, that litter the brains of most people with the disease.

Pharmaceutical companies jumped in to develop drugs that clear amyloid from the brain. Results from animal studies looked promising, and the drugs appeared to improve memory.

Scott Small, MD

Scott Small

But in people, the results have been disheartening. Over the past several years, as results from clinical trials have come in one after the other, researchers have seen that drugs designed to eliminate amyloid have failed to slow the disease. Last year, the FDA approved one amyloid-based drug, but the decision was controversial and many physicians and researchers argue that the drug does not provide any benefit to patients.

Columbia’s Scott Small, MD, has been one of many Alzheimer’s researchers who say it’s time to abandon amyloid-based therapies.

“In the 90s, the idea that amyloid is the trigger of Alzheimer’s was extremely exciting, and there was a sense that we were on the cusp of curing this devastating, horrible disease,” he says. “It was the right idea based on the available evidence, but the evidence has changed.”

That evidence–which Small and other Columbia researchers played pivotal roles in developing over the past 20 years–is pointing to an alternative theory of Alzheimer’s.


Alzheimer’s as a shipping problem

The new theory proposes that Alzheimer’s is essentially an internal shipping problem. To stay healthy, a cell must ship cargo—mostly proteins—from one site in the cell to another.

“The health of neurons, more so than other cells,” says Small, “depends on shipping cargo in and out of one particular site: the endosome."

About 20 years ago, Small found the first signs that traffic jams of cargo in the endosome might be initiating the disease. The study was one of the earliest in-depth studies of the neurons first affected by Alzheimer’s.

A few years later, a genetic study—led by Richard Mayeux, MD, chair of neurology at Columbia's Vagelos College of Physicians and Surgeons, and others—revealed that endosomal genes are linked to Alzheimer’s, providing more support for the theory.

Since then, Small and other researchers around the world have gathered more evidence for the endosomal traffic jam theory, connecting shipping problems in the endosome with amyloid and other signs of Alzheimer’s.

“In Alzheimer’s, the flow of cargo coming out of the endosome is blocked, and we think that causes the other problems we see in the disease: the amyloid, the tau tangles also common in the Alzheimer’s brain, and the neurodegeneration,” says Small.

It’s not that amyloid has nothing to do with Alzheimer’s, he adds, but that its role has been misunderstood. “Amyloid is the smoke, not the fire. Clearing smoke can do some good, but it will not extinguish the fire.”

Testing a new solution

Small’s recent studies provide the most compelling evidence that one part of the endosomal system—called retromer—is broken in Alzheimer’s but can be fixed to alleviate the traffic jams.

It’s evidence that recently helped launch a new company, Retromer Therapeutics, that will try to develop a retromer drug to slow or stop the destructive path Alzheimer’s takes through the brain.

“Sometimes we can’t fix things that we know are broken,” says Small, “but we’ve shown that retromer is druggable. In principle, there are drugs that can fix it.”

distribution inside a neuron of a potential new target for Alzheimers drugs

The Vps26b protein (green) inside neurons has emerged as a potential target for Alzheimer's disease. Targeting the protein could reduce the traffic jams inside neurons that appear to be fueling the disease. Photo: Sabrina Simoes / Columbia University Irving Medical Center.

Joel Klein, CEO of Retromer Therapeutics, heard about the research when Small presented his findings to the external advisory board of Columbia’s Zuckerman Institute. “The work that was going on with Scott and retromer was very exciting to me, and I thought to myself, this is something that can really be transformative,” he says.

Klein did more research, looked at the landscape of current Alzheimer’s theories, and decided to make a bet on retromer and the endosomal theory. “If you read the literature now, this shift from the amyloid to the endosomal hypothesis has been profound,” Klein says. “And that’s really because of 20 years of scientific work started by Scott.”

With funding from venture capitalists, Retromer Therapeutics is now researching a potential drug that could be packaged in a pill and a gene therapy as ways to fix retromer and relieve the traffic jams in the endosome.

But it may take several years, at least, before a therapy is ready to be tested in clinical trials. “Taking scientific theory and converting it into therapeutic reality is an odyssey,” Klein says. “It’s a data-driven and unpredictable process.”

For Small, the company offers new hope that Alzheimer’s will eventually become a treatable condition. “The only way we’ll know we’re right is by testing our drugs in clinical trials in patients, but I wouldn’t be in this line of work if I wasn’t an optimist.”


Scott Small, MD, is the Boris and Rose Katz Professor of Neurology and director of the Alzheimer’s Disease Research Center at Columbia University Vagelos College of Physicians and Surgeons. He is scientific co-founder of Retromer Therapeutics.

Richard Mayeux, MD, is the Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology, chair of the Department of Neurology at Columbia University's Vagelos College of Physicians and Surgeons, and neurologist-in-chief at NewYork-Presbyterian/Columbia University Irving Medical Center. He also directs the Gertrude H. Sergievsky Center, a center devoted to the epidemiologic investigation of neurological diseases, and is co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia.

Top image: A human brain donated to the New York Brain Bank at Columbia University. Photo by Jörg Meyer originally published in Columbia Medicine magazine.