Researchers at the University of Central Florida have found that genetic mutations linked to Alzheimer’s disease can disrupt the nerves that control muscle movement outside the brain or spinal cord, potentially signalling trouble well before memory problems become apparent. The work, led by Professor James Hickman of the Nanoscience Technology Center and Research Professor Xiufang “Nadine” Guo, was conducted with scientists at the healthcare technology firm Hesperos and funded by the National Institutes of Health’s National Institute on Aging. The findings are published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
The study suggests that movement difficulties such as changes in walking, balance or coordination could provide earlier warning signs of the disease and that treatments focused solely on the brain may overlook problems elsewhere in the body. “Motor deficits may be an earlier indication [of Alzheimer’s],” Guo says. “If we can detect those changes and intervene earlier, that could help delay the onset of central nervous system symptoms.”
To explore this, the researchers focused on familial Alzheimer’s, a rare inherited form that typically presents earlier in life. Their experiments demonstrated that motor neurons carrying familial Alzheimer’s mutations could disrupt the connections responsible for controlling muscles, even in systems entirely free of brain or spinal cord tissue.
“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.”
The peripheral nervous system comprises nerves outside the brain and spinal cord, transmitting signals between the central nervous system and the body to control movement, sensation and other functions. The new findings point to a possible direct impact of Alzheimer’s mutations on these nerves, rather than movement problems arising solely from brain damage.
Guo adds that preserving motor function could yield benefits beyond physical health. Regular physical activity is associated with better cognitive well-being, so protecting the ability to move may also help support brain health.
Key to the study was the use of an innovative laboratory platform known as “human-on-a-chip” technology, developed and manufactured through Hesperos, a company co-founded by Hickman. These miniature systems bring different human cell types together under controlled conditions to recreate specific biological functions and observe how diseases interfere with them. Unlike conventional experiments on isolated cells, these systems reproduce important tissue interactions and offer an alternative to animal models.
For this project, the team built a miniature model of the neuromuscular junction—the connection where a motor neuron communicates with a muscle cell—without a brain or spinal cord. Healthy muscle cells were combined with motor neurons derived from stem cells carrying familial Alzheimer’s mutations to assess how well the altered nerves could signal muscles.
The results showed that the Alzheimer’s-linked mutations could interfere with normal nerve-to-muscle communication, suggesting that some movement problems in the disease may originate directly in the peripheral nervous system rather than from central nervous system degeneration alone. However, the researchers caution that the experiments do not establish whether these changes occur before memory loss in patients, and further work is needed to determine how closely the laboratory findings mirror disease progression in people with the more common form of Alzheimer’s.
The findings open a potential new line of enquiry for earlier detection, with researchers considering whether tests of walking, coordination, or nerve-to-muscle activity could identify disease-related changes before overt cognitive symptoms emerge. They also raise questions about treatment, as many therapies target processes in the brain, and may not address abnormalities in peripheral nerves and muscles. Understanding these separate effects could help scientists pursue treatments that protect physical function alongside cognitive health.
Beyond Alzheimer’s, the researchers see significant promise in using human-on-a-chip platforms to study a range of diseases and evaluate potential therapies. By closely mimicking human physiology, these systems could aid drug development by revealing tissue-level interactions and effects that are difficult to detect in animal models. For Hickman, the work represents the culmination of three decades of effort to model disease in ways that reflect real human biology. “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.
