Drugs Can’t Stop Alzheimer’s. A New Model of the Disease Explains Why.

A new model of Alzheimer’s disease – proposed by scientists at Columbia University Irving Medical Center and Weill Cornell Medicine – may explain why clinical trials of potential Alzheimer’s drugs have a high failure rate.

We spoke with co-author Scott Small, MD,  the Boris and Rose Katz Professor of Neurology and director of the Alzheimer’s Disease Research Center in the Taub Institute at CUIMC, about the theory, published in a new article in Trends in Neuroscience.

Explain your new model for Alzheimer’s disease.

A system of train stations is a good analogy. Neurons are made up of different compartments, which are sometimes called stations. Proteins are continuously shuttled from one compartment to the other, and this process is called "protein trafficking."

The health of neurons, more so than other cells, depends on protein trafficking in and out of one particular station: the endosome. In the world of a neuron, the endosome is Grand Central Station. Our model proposes that traffic jams in and out of the endosome are a primary defect within neurons that leads to Alzheimer’s disease.

What evidence is there for the new model?

Multiple pieces of evidence need to fit like a jigsaw puzzle in order to develop causal models for complex disorders like Alzheimer’s disease. Our model is based on three main sets of studies: (1) genetic studies that have identified new Alzheimer’s-causing genes that lead to traffic jams; (2) studies that have identified trafficking defects in the part of the brain that is most vulnerable to Alzheimer’s; and (3) cellular studies that show endosomal traffic jams make neurons sick and ultimately kill them.

What does your model say about amyloid protein deposits, long thought of as a primary cause of Alzheimer’s?

The new model does not negate the importance of amyloid. Rather, we propose that the amyloid within neurons is a culprit because it causes traffic jams. This differs from the original "amyloid hypothesis," which argues that amyloid deposits outside neurons are the primary driver of disease.

Does your model shed any light on previously failed clinical trials?

We believe so. Most drugs tested in clinical trials are directed against amyloid that accumulates outside of neurons. Our model predicts that this site of amyloid accumulation is just the "smoke" and not the "fire." In this situation, simply clearing the smoke will not put out the fire, or, in other words, many such drugs will not relieve the traffic jams.

How can your model inform future therapeutic approaches?

Our model makes two strong predictions. The first is that therapeutic approaches that target amyloid inside neurons might work. However, studies suggest that traffic jams can occur independent of amyloid. So our model predicts that therapeutic approaches designed to unjam trafficking within neurons carry the highest therapeutic promise.