UCF Study Suggests Some Alzheimer’s Symptoms May Begin Outside the Brain

UCF researchers have uncovered evidence that some movement-related symptoms of Alzheimer's disease may originate outside the brain, which could change how the disease is diagnosed and treated in the future.

The study was sponsored by the National Institutes of Health's National Institute on Aging and was led by UCF Nanoscience Technology Center Professor James Hickman and Research Professor Xiufang "Nadine" Guo. In collaboration with researchers at healthcare tech company Hesperos, the team used lab-grown, human-cell systems designed to model how the body functions to examined how genetic mutations associated with familial Alzheimer's affects movement. Today, the study was published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

"Motor deficits may be an earlier indication [of Alzheimer's]," she says. "If we can detect those changes and intervene earlier, that could help delay the onset of central nervous system symptoms."

How Movement and Alzheimer's Are Connected

Familial Alzheimer's is a rare form of the disease that is hereditary and appears earlier (from 40 to 65 years of age) in people affected than those with the typical condition.

While Alzheimer's disease is widely associated with memory loss and dementia, clinicians have long observed that some patients show changes in balance, gait (manner of walking) or movement years before cognitive symptoms appear. These early motor changes raise questions about whether parts of the disease begin outside the brain.

Through a tech-powered approach, the team found that the diseased motor neurons - even without involvement from the brain - disrupted the neuromuscular junction, which is central to daily movement.

"This is the first time it's been demonstrated that deficits in the peripheral nervous system can arise directly from these mutations," Hickman says. "It means drugs that target the brain may not fix problems in the rest of the body."

Maintaining motor function may also support overall brain health, as physical activity is known to play a role in cognitive well-being, Guo notes.

How Researchers Build Human Disease Models in the Lab

To explore how these mutations affect movement, the researchers turned to a cutting-edge approach called "human-on-a-chip" technology, which is manufactured through Hesperos, a company co-founded by Hickman. These miniature lab systems recreate the way human cells interact and function in the body, allowing scientists to study disease in a more realistic way than traditional lab or animal models.

The team built a neuromuscular junction-on-a-chip - a small system that mimics the connection between motor neurons and muscle cells. What makes this system powerful is what's left out: the brain and spinal cord. By isolating motor neurons and muscle cells, the researchers could determine whether movement problems could arise without the central nervous system being involved.

To test this, the researchers paired healthy muscle cells with motor neurons that were created from stem cells and carried familial Alzheimer's disease mutations. The findings suggest that Alzheimer's-related movement issues may begin in the network of nerves outside the brain and spinal cord rather than being caused solely by brain degeneration.

Why the Nerve-to-Muscle Connection Matters

The neuromuscular junction is the point where a nerve cell signals a muscle to contract, making movement possible. If that connection is damaged, the body may lose strength, coordination or endurance.

In the study, the researchers measured several aspects of neuromuscular function, including how reliably nerve signals triggered muscle contraction and how long muscles could remain contracted before fatiguing. These measurements mirror the kinds of tests doctors use to evaluate movement disorders.

"You can't move unless the motor circuit works," Hickman says. "When a doctor taps your knee to check your reflex, they're testing that exact connection."

The Future of 'Human-on-a-Chip' Technology

The researchers believe their approach will become increasingly important as drug developers look for more accurate ways to study human disease.

Because the models use human cells and measure real biological function, they can reveal effects that may not appear in animal studies.

For Hickman, the work reflects 30 years of research to better understand disease and help people.

"These systems let us study disease in a way that's closer to what actually happens in the human body, and that's what we need to develop better treatments," he says.

Research reported in this article was supported by the National Institutes of Health's National Institute on Aging under award number R01AG077651 and R44AG071386. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

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