Scientists Have Finally Discovered How Alzheimer’s Disease Spreads in the Brain

A common brain protein may allow Alzheimer’s disease to spread in an unexpected way, ferrying toxic tau protein from damaged neurons to healthy ones. Researchers believe that by blocking these harmful proteins before they reach new cells, it may one day be possible to slow the disease’s relentless progression.

Alzheimer’s disease is characterized by the accumulation of a toxic protein called tau, which damages and eventually kills brain cells. The illness worsens as this harmful protein moves into new regions of the brain, leading to memory loss and cognitive decline.

Now, researchers have identified an unexpected player in this process. In a study in mice, they found that a brain protein called Arc, which normally helps neurons communicate, also appears to help toxic tau spread from diseased brain cells to healthy ones.

The finding points to a new strategy that might slow Alzheimer’s. Rather than trying to eliminate tau protein entirely, future treatments might instead stop it from reaching healthy brain cells in the first place.

“I’m excited that we’ve identified a new way to potentially arrest the development of Alzheimer’s disease,” said Dr. Jason Shepherd, a professor of neurobiology at University of Utah Health and the senior author of the study.

The findings were published in the journal Cell.[1]

How Arc Helps Toxic Tau Move

To investigate how Alzheimer’s spreads, the researchers compared mouse models with and without the Arc protein. Their experiments showed that Arc is essential for moving toxic tau between neurons.

Under normal conditions, Arc plays an important role in brain function. The protein wraps itself inside tiny membrane bound sacs called extracellular vesicles (EVs), which are passed from one neuron to another, carrying important cellular signals.

The researchers discovered that toxic tau can hijack this natural communication system. By attaching itself to Arc inside these tiny vesicles, tau is able to transfer from an unhealthy neuron to a healthy one, where it can continue to propagate the disease.

Tau Turns Healthy Brain Cells Toxic

Every neuron contains tau protein, but in Alzheimer’s disease, tau begins to clump into large, sticky tangles that interfere with the cell’s internal transport system before eventually killing the neuron.

Dr. Mitali Tyagi, a postdoctoral research associate at Washington University in St. Louis and the first author of the study, conducted the research as a graduate student in Shepherd’s lab at U of U Health. She likened these tangles to “glue monsters.”

“They stick together and block transport inside the neuron,” Tyagi explained. “But they can break apart into smaller glue monster pieces, called tau seeds, which can then transfer to new neurons. Once that tau seed encounters healthy tau, it can corrupt it. So, in a healthy neuron, the pathological process starts all over again.”

In a mouse model of Alzheimer’s, the team found extracellular vesicles containing both Arc and “sticky” tau in brain tissue. These vesicles were able to enter healthy cells and trigger the formation of new tau tangles.

When Arc was removed, the picture changed dramatically. The extracellular vesicles from mice lacking Arc contained very little tau, and the disease no longer spread effectively to neighboring brain cells.

“When we removed Arc, we saw that tau transfer was severely, severely reduced,” Tyagi said. “It almost disappeared.”

Arc Has Both Harmful and Beneficial Roles

While blocking Arc might sound like an obvious therapeutic strategy, the researchers found that the protein also plays an important protective role in the early stages of the disease.

By helping neurons pump out excess toxic tau, Arc appears to allow damaged cells to survive longer. In mice without Arc, toxic tau remained trapped inside neurons, causing those already sick cells to die more quickly.

When Arc is absent, tau gets stuck inside the neuron and builds up to toxic levels. When Arc is present, tau can be released in extracellular vesicles. Tyagi noted that while this helps reduce tau accumulation inside the original neuron, the released tau can be taken up by nearby healthy neurons, thereby promoting the spread of pathology.

These findings suggest that the most effective treatment might not be to stop diseased cells from releasing tau. Instead, it may be better to block these toxic extracellular vesicles from entering healthy neurons.

A Potential New Target for Alzheimer’s Treatment

The researchers also found extracellular vesicles containing both Arc and tau in human brain tissue, suggesting that the same mechanism may operate in humans. However, they emphasize that much more research is needed before any potential therapy can be tested in patients.

“Most of what we’ve done is in mice, not in humans,” Shepherd said. “We have some clues that what happens in these mice may also happen in humans, but we don’t know yet. We are far from saying we’re developing a cure for any disease. But it could open up new avenues to get there.”

One promising possibility is to intercept tau containing extracellular vesicles after they leave diseased neurons but before they reach healthy ones. While this approach would not reverse existing brain damage, it could potentially slow or prevent further spread of Alzheimer’s.

“If we could target those specific EVs, that would be a very useful therapeutic strategy,” Tyagi said. “For people with early onset Alzheimer’s or dementia, if we could stop the spread, then we could prevent further damage and cognitive decline.”

[1]Mitali Tyagi, Eric de Hoog, Matthew Grega, et al. Arc mediates intercellular tau transmission via extracellular vesicles. Cell. Volume 189, Issue 15.

https://www.cell.com/cell/fulltext/S0092-8674(26)00695-1