The human brain is an incredible, complex web of connections. Cells called neurons send signals from region to region, and their communication allows us to do everything from forming thoughts to accessing memories.

But for nearly 6 million Americans, neurodegenerative diseases like dementia, chronic traumatic encephalopathy (CTE), and Alzheimer’s disease prevent neurons from functioning properly. The progressive memory loss that characterizes these diseases is well-known. Yet the mechanisms that cause them—and ways to treat them—are still poorly understood. That’s partly because neurodegenerative diseases have different causes. CTE can be triggered by repeated head trauma, while fronto-temporal dementia is caused by a genetic mutation, and Alzheimer’s can be triggered by environmental, genetic, and behavioral factors. But all of these diseases are characterized by malfunctions in two proteins found in neurons: beta-amyloid and tau.

Now, scientists are starting to understand more about how tau could trigger and spread disease. In a paper published last week in Cell, researchers at the Buck Institute for Research on Aging detailed the “interactome” of tau, showing all the proteins it comes into contact with. That information offers new insights about how dysfunctional tau affects the cell and how it can travel from neuron to neuron, possibly seeding disease throughout the brain.

“These kinds of studies give us insight into the disease process at the molecular level,” says Tara Tracy, an assistant professor at the Buck Institute and lead author on the paper. “That’s the goal with all of these studies, to get more information for things that could be targeted to slow progression.”

For the last several decades, scientists have focused on beta-amyloid, which forms clumps around the outside of cells and blocks communication between them. The theory was that if scientists could find a way to bust those clumps apart—or keep them from appearing in the first place—then the disease could be kept in check.

But after years of development, a number of drugs aimed at beta-amyloid have largely failed to improve patient outcomes. Last year the US Food and Drug Administration granted accelerated approval for Aduhelm, the first such treatment approved since 2003, but it is extremely expensive and has been criticized by doctors who say it’s ineffective at halting the progression of the disease. Many large health systems, including Massachusetts General Hospital, the Cleveland Clinic, and the Department of Veterans’ Affairs, won’t prescribe it.

Concentrating on other proteins involved in neurodegenerative diseases could help scientists find new ways to treat them. “Proteins don’t act in isolation,” says Nicholas Seyfried, an associate professor of biochemistry and neurology at Emory University who studies neurodegeneration. He says the more scientists understand how these malfunctioning proteins affect cells, the more therapeutic options there could be.

What causes tau to transition from a normal protein to a diseased one is sometimes a mystery. For patients with frontotemporal dementia, this is caused by a genetic mutation. But for people with other diseases, the reason tau starts to misbehave is still unknown. In cases of CTE, it may be the consequence of repeated head trauma. In Alzheimer’s disease, environmental factors like air pollution or vascular problems that prevent blood from flowing to the brain may play a role. No matter what the trigger is, eventually the diseased tau proteins will create clumps. Unlike beta-amyloid, these gum up the inside of neurons.

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