Researchers report that certain movement-related symptoms of Alzheimer’s disease may originate in the peripheral nervous system rather than the brain.
Researchers at the University of Central Florida say some early movement problems linked to Alzheimer’s may begin outside the brain, raising new questions about where the disease starts and how soon it might be detected. If confirmed in further studies, the finding could help explain why subtle changes in walking, balance, or muscle control sometimes appear before memory loss becomes obvious.
The study was led by UCF Nanoscience Technology Center Professor James Hickman and Research Professor Xiufang “Nadine” Guo. Working with scientists from healthcare technology company Hesperos, the team used lab-grown human cell systems that mimic how the body functions to examine how genetic mutations tied to familial Alzheimer’s affect movement.
The findings were recently 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 inherited form of the disease that develops earlier (from 40 to 65 years of age) than the more common type.
Although Alzheimer’s is best known for memory loss and dementia, doctors have long reported that some patients experience changes in balance, gait (manner of walking), or movement years before cognitive symptoms appear. These early signs suggest that aspects of the disease may start outside the brain.
Using an advanced laboratory approach, the researchers showed that affected motor neurons can disrupt the neuromuscular junction, a key connection required for movement, even without input from the brain.
“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.”
Guo adds that preserving motor function may also benefit brain health, since physical activity is linked to cognitive well-being.
How Researchers Build Human Disease Models in the Lab
To study how these mutations influence movement, the team used “human-on-a-chip” technology developed by Hesperos, a company co-founded by Hickman. These small systems replicate how human cells interact in the body, offering a more realistic way to study disease than traditional lab or animal models.
The researchers created a neuromuscular junction-on-a-chip, a system that recreates the link between motor neurons and muscle cells. Notably, it excludes the brain and spinal cord. By focusing only on motor neurons and muscle cells, the team could test whether movement problems can arise without involvement from the central nervous system.
They combined healthy muscle cells with motor neurons derived from stem cells carrying familial Alzheimer’s mutations. The results indicate that movement-related problems may begin in peripheral nerve networks rather than being caused solely by brain degeneration.
Why the Nerve-to-Muscle Connection Matters
The neuromuscular junction is where a nerve signals a muscle to contract, enabling movement. Damage to this connection can reduce strength, coordination, and endurance.
In the study, the team evaluated how effectively nerve signals triggered muscle contractions and how long muscles could sustain activity before fatigue. These measures are similar to tests used in clinical evaluations of 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 say this approach could play a growing role in drug development as scientists seek more accurate ways to study human disease.
Because these systems use human cells and measure real biological activity, they can reveal effects that might not appear in animal studies.
For Hickman, the project builds on three decades of research focused on improving disease understanding and treatment.
“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.
Reference: “Evaluating the peripheral nervous system pathology of Alzheimer’s disease utilizing a functional human NMJ microphysiological system” by Akhmetzada Kargazhanov, Romy Aiken, Kenneth Hawkins, Rafael Lopez, Ahmad Nawaz, Gaurav Srivastava, Chase Miller, Will Bogen, Christopher Long, David Morgan, Xiufang Guo and James Hickman, 16 April 2026, Alzheimer’s & Dementia.
DOI: 10.1002/alz.71281
The study was funded by the National Institutes of Health.
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