Researchers Say They May Have Found ‘Big Bang’ in Alzheimer’s Disease

Institute scientists say they’re zeroing in on when healthy tau proteins start to turn into deadly tangles in the brain. This could lead to new interventions.

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People in midlife may find some gray hair on the outside of their heads while they develop a new fear about what’s inside their skull.

One of the biggest worries is developing dementia.

Now, a leading dementia expert says his team has discovered a “big bang” of Alzheimer’s disease — the exact point at which a healthy protein becomes toxic but hasn’t yet formed deadly tangles in the brain.

A study from the University of Texas Southwestern’s O’Donnell Brain Institute offers a novel insight into the shape-shifting nature of a tau molecule just before it begins sticking to itself to form larger aggregates.

Those sticky formations are a marker found in the brains of people with Alzheimer’s.

The results suggest new strategies to detect the brain-ravaging disease before it takes hold.

It’s also spawned an effort to develop treatments that stabilize tau proteins before they shift their shape.

“We think of this as the Big Bang of tau pathology. This is a way of peering to the very beginning of the disease process,” said Dr. Marc Diamond, director of UT Southwestern Center for Alzheimer’s and Neurodegenerative Diseases.

“This is perhaps the biggest finding we have made to date, though it will likely be some time before any benefits materialize in the clinic. This changes much of how we think about the problem,” he told Science Daily.

Diamond, who holds the distinguished chair in basic brain injury and repair, is founding director of the Center for Alzheimer’s and Neurodegenerative Diseases.

He’s also a professor of neurology and neurotherapeutics with the Peter O’Donnell Jr. Brain Institute.

Diamond collaborated on the study with co-corresponding author Lukasz Joachimiak, PhD, an assistant professor in the Center for Alzheimer’s and Neurodegenerative Diseases and an Effie Marie Cain scholar in medical research.

Diamond is credited with determining that tau acts like a prion — an infectious protein that can self-replicate.

It was previously believed that an isolated tau protein has no distinct shape of its own and is harmful only after it begins to assemble with other tau proteins to form those distinctive tangles.

This recent study, published in the journal eLife, contradicts that assumption.

More research needed

Despite billions of dollars spent on clinical trials through the decades, Alzheimer’s disease remains one of the most baffling diseases in the world, affecting more than 5 million people in the United States.

According to Heather M. Snyder, PhD, senior director of medical and scientific operations at the Alzheimer’s Association, the government’s role in funding research has grown exponentially, from $500 million in 2009 to $2 billion today.

“And we still need more,” she said.

The disease is being analyzed and attacked from all sides.

Earlier this month, researchers at Yale University tested a new method for measuring synaptic loss in people with Alzheimer’s.

“This is an interesting study. What they’ve put together is solid research as well as exciting,” Snyder told Healthline.

Knowing how tau may assemble into tangles is essential to developing treatments.

“There are things that need to happen before we get to a solution,” Snyder said. “Understanding biology is key.”

She also stresses the need for federal funding.

“This work is so valuable and needs to continue. And the Alzheimer’s Association is a leader in that conversation,” she said.

“The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins,” Diamond added. “If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”

Studying tau

Diamond’s lab, at the forefront of many notable findings relating to tau, previously determined that tau acts like a prion — an infectious protein that can spread like a virus through the brain.

The tau protein in the human brain can form many distinct strains, or self-replicating structures. The team has developed methods to reproduce that phenomenon in the laboratory.

Diamond says his newest research indicates that a single pathological form of tau protein may have multiple possible shapes, each associated with a different form of dementia.

He hopes the scientific field can use the new findings to help identify the genesis of the disease.

They have a viral target in diagnosing the condition at an early stage before the symptoms of memory loss and cognitive decline become apparent, he says.

Next on his agenda is for the team to develop a simple clinical test that examines a person’s blood or spinal fluid to detect the first biological signs of the abnormal tau protein.

But just as important, Diamond says, efforts are underway to develop a treatment that would make the diagnosis the basis for useful intervention.

He cites a compelling reason for cautious optimism: Tafamidis, a drug recently approved by the U.S. Food and Drug Administration, stabilizes a different shape-shifting protein called transthyretin that causes deadly protein accumulation in the heart, similar to how tau overwhelms the brain.

The hope is that someday gray hair will become older adults’ biggest worry about their head.

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