Alzheimer’s may have early warning signs outside the brain

Alzheimer’s may have early warning signs outside the brain

- Date:

- November 9, 2026

- Source:

- University of Central Florida

- Summary:

- A surprising discovery suggests that some early signs of Alzheimer’s disease may begin outside the brain. Using miniature laboratory systems made from human cells, scientists found that genetic mutations associated with inherited Alzheimer’s can disrupt nerve-to-muscle connections without any involvement from the brain or spinal cord. This could help explain why some patients experience changes in balance, walking, and coordination long before memory problems develop.

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Alzheimer's disease is best known for its effects on memory and thinking, but new research suggests that some symptoms may develop in a surprising place: outside the brain.

Scientists at the University of Central Florida (UCF) have discovered that genetic mutations associated with Alzheimer's can interfere with the nerves that control muscle movement, even without involvement from the brain or spinal cord. The findings could help explain why some people with Alzheimer's experience changes in walking, balance, or coordination long before noticeable memory problems emerge.

The discovery raises the possibility that movement difficulties could provide earlier warning signs of the disease and that treatments focused exclusively on the brain may overlook important problems elsewhere in the body.

The research was led by James Hickman, a professor at UCF's Nanoscience Technology Center, and Research Professor Xiufang "Nadine" Guo, working alongside scientists at the healthcare technology company Hesperos. Funded by the National Institutes of Health's National Institute on Aging, the study used laboratory systems built from human cells to investigate how inherited Alzheimer's mutations affect movement. The findings were published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

"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."

Why Alzheimer's Symptoms May Appear Before Memory Loss

Alzheimer's is generally associated with progressive memory loss, confusion, and declining cognitive abilities. However, doctors have also observed that some patients develop physical symptoms, including changes in balance, coordination, and gait (manner of walking), years before clear cognitive difficulties become apparent.

These observations have raised an important question: Are such movement problems simply a consequence of damage occurring in the brain, or could Alzheimer's also interfere directly with nerves elsewhere in the body?

To investigate, the UCF team focused on familial Alzheimer's, a rare inherited form of the disease that typically develops earlier in life (from 40 to 65 years of age) than the more common form.

Their experiments revealed that motor neurons carrying mutations linked to familial Alzheimer's could disrupt the connections responsible for controlling muscles, even when the brain and spinal cord were completely absent from the experimental system.

Motor neurons are specialized nerve cells that transmit signals to muscles, telling them when to contract and produce movement. The new findings suggest that Alzheimer's mutations can interfere with this process directly, rather than affecting movement only through damage to 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."

The peripheral nervous system includes the nerves located outside the brain and spinal cord. These nerves carry signals between the central nervous system and the rest of the body, helping control movement, sensation, and other essential functions.

Guo also points out that preserving the ability to move could have benefits beyond physical health. Regular physical activity is associated with better cognitive well-being, so protecting motor function may also help support brain health.

How a Miniature Human Cell System Revealed the Discovery

To examine the relationship between Alzheimer's mutations and muscle movement, the scientists used 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 types of human cells together under controlled conditions. They allow researchers to recreate specific biological functions and observe how diseases interfere with them.

Unlike conventional laboratory experiments that examine isolated cells, these systems can reproduce important interactions between different tissues. They also provide an alternative to animal models, which do not always accurately reflect how human diseases behave.

For this study, the team created a miniature model of the neuromuscular junction, the connection where a motor neuron communicates with a muscle cell.

The model was deliberately designed without a brain or spinal cord. This was a crucial part of the experiment because it allowed the researchers to investigate whether Alzheimer's-related changes could cause movement problems independently of the central nervous system.

The scientists combined healthy muscle cells with motor neurons derived from stem cells that carried genetic mutations associated with familial Alzheimer's disease. Stem cells are cells that can develop into specialized types of cells, making them valuable tools for studying human diseases in the laboratory.

The researchers then examined how effectively the altered nerve cells communicated with otherwise healthy muscle tissue.

The results showed that the Alzheimer's-associated mutations could interfere with normal nerve-to-muscle function. This suggests that at least some movement difficulties linked to the disease may arise directly in the peripheral nervous system rather than being caused entirely by degeneration in the brain.

Why Damaged Nerve Connections Can Affect Walking and Balance

Every voluntary movement depends on successful communication between the nervous system and the muscles.

At the neuromuscular junction, an electrical signal traveling along a motor neuron triggers chemical communication that causes a muscle to contract. This process makes everyday activities possible, from walking and maintaining posture to lifting objects and performing precise movements.

When the connection becomes impaired, muscles may respond less effectively to nerve signals. Depending on the severity and location of the problem, this can contribute to weakness, reduced coordination, and difficulty sustaining physical activity.

To evaluate these effects, the research team measured how consistently nerve signals produced muscle contractions and how long the muscles could continue contracting before becoming fatigued.

These measurements provided a direct assessment of how well the nerve and muscle cells worked together. They also resemble aspects of the functional testing physicians use when examining patients with 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."

By demonstrating impaired nerve-to-muscle communication in a system containing no brain or spinal cord, the study provides evidence that mutations linked to familial Alzheimer's can produce effects beyond the central nervous system.

However, the experiments do not establish that these changes necessarily occur before memory loss in patients. Further research will be needed to determine how closely the laboratory findings reflect the progression of Alzheimer's in people, particularly those with the more common forms of the disease.

Could This Discovery Lead to Earlier Alzheimer's Detection?

The findings suggest a potentially important new direction for Alzheimer's research: looking beyond memory and other cognitive symptoms when investigating the disease.

If future studies confirm that changes in motor function are detectable early in certain patients, tests of walking, coordination, or nerve-to-muscle activity might eventually help identify disease-related changes before more obvious neurological symptoms develop.

The results also raise questions about treatment. Many Alzheimer's therapies are designed to address processes occurring in the brain, but medications that target the central nervous system may not necessarily correct abnormalities affecting peripheral nerves and muscles.

Understanding these separate effects could help researchers investigate treatments that protect physical function alongside cognitive health.

Human-on-a-Chip Technology Could Transform Disease Research

Beyond the implications for Alzheimer's, the researchers see considerable potential in using human-on-a-chip systems to investigate other diseases and evaluate possible treatments.

Because these platforms contain human cells and reproduce measurable biological activities, they can help scientists observe disease-related changes in conditions that more closely resemble human physiology than some conventional experimental models.

This approach may be particularly useful in drug development, where researchers need to understand not only how a potential treatment affects individual cells but also how it influences interactions between different tissues.

Such systems can also uncover biological effects that may be difficult to detect in animal experiments, potentially helping researchers identify promising therapies and recognize limitations earlier in development.

For Hickman, the progress represents the culmination of three decades of work devoted to understanding disease through more realistic laboratory models.

"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.

Story Source:

Materials provided by University of Central Florida. Original written by Emily Dougherty. Note: Content may be edited for style and length.

Journal Reference:

- Akhmetzada Kargazhanov, Romy Aiken, Kenneth Hawkins, Rafael Lopez, Ahmad Nawaz, Gaurav Srivastava, Chase Miller, Will Bogen, Christopher Long, David Morgan, Xiufang Guo, James Hickman. Evaluating the peripheral nervous system pathology of Alzheimer\'s disease utilizing a functional human NMJ microphysiological system. Alzheimer\'s, 2026; 22 (4) DOI: 10.1002/alz.71281

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