What Early-Life Brain Activity May Reveal About Alzheimer’s Risk

“One of the hardest things about Alzheimer’s is the deeply human hope that you’re going to be the lucky ones,” said Keith Hengen, PhD, a BrightFocus Alzheimer’s Disease Research grant recipient. Dr. Hengen lost his father, Steven Hengen, to early-onset Alzheimer’s in 2016, an experience that stays with him today.

He spent their last years together advocating for new treatments and experimental drugs to save him. “I was convinced that each newly published molecule was the one that would break through,” he said. “I made passionate, statistically-sound arguments to his neurology team that all he needed was access to a given drug, or a ticket into an ongoing trial.”

The loss of his father propelled him to chase after Alzheimer’s disease in a way no one has done before.

Dr. Hengen is challenging our scientific understanding of Alzheimer’s and pioneering a novel approach to identifying Alzheimer’s risk in early life. He believes that directly observing activity in the brain will provide a more straightforward window into the disease.

The research will not only broaden our understanding of neurodegeneration but also have a potential real-world impact. If his research team can identify early signs of Alzheimer’s based on brain activity, it could help people like his father seek treatment early, when these measures are more effective.

“I want to stop that whole experience,” he said. “What really matters is that we’re willing to think of as many entry-points as possible [to protect brain health].”

Rethinking Alzheimer’s Disease

For decades, scientists have studied the molecular imprints Alzheimer’s leaves on the brain. But recently, researchers are debating whether hallmark molecular changes are the root cause of Alzheimer’s, or just a symptom of a bigger problem.

“If Alzheimer’s were as simple as the presence of amyloid beta (the misfolded protein whose presence imposes a diagnosis of Alzheimer’s), there would be legions of cognitively normal folks with a meaningless diagnosis,” Dr. Hengen explained. “At its heart, this is a question of cause and effect.”

Scientists already know that Alzheimer’s causes some changes to brain activity. Those changes include three major problems: overall abnormal brain output, dysfunction in individual cells or regions, and large-scale disruptions in “set points” across brain networks. Dr. Hengen likens these disruptions to a thermostat set to the wrong temperature.

He is interested in one facet of those disrupted networks: criticality, a feature of brain activity sometimes called “the edge of chaos.” Criticality is the point where brain tissue is electrically excitable enough to send all the neural signals our minds rely on, but not so excitable that the brain starts devolving into jumbled, seizure-like activity.

“The further you are from criticality, the worse your brain works,” he said.

Could Criticality Predict Alzheimer’s?

Now, Dr. Hengen’s lab at Washington University in St. Louis is investigating the importance of criticality in Alzheimer’s disease development. The team has already discovered that changes in criticality are linked to Alzheimer’s in mice. By recording thousands of neurons in mouse brains for months at a time, they found that disruptions to criticality predicted which mice would eventually die of the disease. Altered criticality was also linked to problems sleeping—a feature often seen in people with Alzheimer’s, too. Because of this connection, he theorizes that sleep is key for restoring criticality.

As Dr. Hengen learns more from these animal models, he plans to begin exploring criticality in people. His lab will measure brain activity in people with early warning signs that put them at high risk of developing Alzheimer’s. He predicts that these people may exhibit different levels of criticality than those at lower risk of developing the disease.

If the lab finds that changes in criticality are also associated with the onset of Alzheimer’s, the results could provide the foundation for new early diagnostics.

“Our study seeks to provide a relatively simple measurement of brain activity in early life that can reliably indicate future neurodegeneration,” Dr. Hengen said. “This is exciting because it immediately opens the door to earlier, more effective diagnosis.”

Why Early Diagnosis and New Approaches Matter

Early diagnosis is an important goal for Alzheimer’s research because most treatments work best when administered earlier. Early diagnosis also allows people to make lifestyle changes that promote healthy brain aging.

Dr. Hengen’s project is one of many funded by BrightFocus Foundation’s Alzheimer’s Disease Research program exploring new, more accessible methods for early detection and diagnosis of Alzheimer’s disease. This line of investigation is part of a 360-degree approach to explore scientific paths toward causes, treatments, and, ultimately, a cure for Alzheimer’s disease.

Understanding the role of criticality in Alzheimer’s disease will not only provide more diagnostic tools but also provide deeper insight into how Alzheimer’s affects the brain.

“The singular pursuit of molecular therapies without understanding the dynamics isn’t likely to suddenly start working,” he explains. “Our best bet, in my view, is a combined approach. If we understood the mathematical principles that define a healthy brain, we would also have a really beautiful definition of the disease.”

When Dr. Hengen describes his philosophy on Alzheimer’s research, he pictures a car in the wrong gear. “If you drove across the country in second gear, you’d build up metal filings in your oil,” he says. Those metal filings will be easy to see, and they’ll be bad for the engine. But the metal filings are only a sign of a deeper problem — just like how the molecular deposits in the brain of people with Alzheimer’s may only be the symptom of more widespread issues in the brain.

“You need to understand the system,” Dr. Hengen said. “I think we know enough now to take this approach in the brain.”

Dr. Hengen credits the donors of BrightFocus Alzheimer’s Disease Research program for making his work possible. Without their support, Dr. Hengen’s “interest in Alzheimer’s disease would be nothing more than that.” Explore ways to support our work and help advance tomorrow’s research breakthroughs.