Summary: New research suggests that the balance and walking issues associated with Alzheimer’s disease may not be “top-down” problems caused by brain decay, but rather “bottom-up” failures in the peripheral nervous system.
The study utilized “human-on-a-chip” technology to prove that genetic mutations for familial Alzheimer’s can damage the connection between nerves and muscles directly, independent of the brain or spinal cord.
Key Findings
- Beyond the Brain: This is the first time researchers have demonstrated that peripheral nervous system deficits arise directly from Alzheimer’s mutations.
- Why Medications Fail: Hickman notes that drugs targeting the brain’s “plaques and tangles” may fail to address movement issues if those problems are rooted in the nerves of the limbs.
- The “Human-on-a-Chip” Advantage: Traditional animal models often fail to replicate human Alzheimer’s progression. This lab-grown system uses actual human stem cells to recreate biological functions more accurately.
- The Reflex Connection: The failure at the NMJ is the same circuit tested when a doctor taps your knee with a mallet. In Alzheimer’s patients, this “reflex” hardware may be breaking down at a cellular level.
Source: University of Central Florida
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.
The study was recenty 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.
Key Questions Answered:
A: Not exactly. It’s still a neurological disease, but this research shows it affects the entire nervous system, not just the brain. The “wiring” that connects your spine to your legs might be failing just as early as the “hard drive” in your head.
A: The researchers suggest that maintaining motor function may support overall brain health. If we can intervene at the nerve-muscle level early on, we might be able to delay the onset of the more severe cognitive symptoms.
A: It’s a miniature system that uses live human cells grown on a microchip to mimic organ functions. It allows scientists to test how “diseased” nerves talk to “healthy” muscles without needing a human volunteer or an animal subject.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Margot Winick
Source: University of Central Florida
Contact: Margot Winick – University of Central Florida
Image: The image is credited to Neuroscience News
Original Research: Open access.
“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, James Hickman. Alzheimer’s & Dementia
DOI:10.1002/alz.71281
Abstract
Evaluating the peripheral nervous system pathology of Alzheimer’s disease utilizing a functional human NMJ microphysiological system
INTRODUCTION
Alzheimer’s Disease (AD) is a central nervous system (CNS) neurodegenerative disease leading to dementia, but can also show symptoms of motor deficits. It is not clear whether the peripheral motor deficits in AD are derived from upstream centers or intrinsic to the neuromuscular circuit. This study developed a model to evaluate the neuromuscular pathology of familial AD (fAD) in a functional neuromuscular junction (NMJ) system.
METHODS
The fAD iPSC motoneurons (MNs), together with healthy iPSC skeletal myoblasts (SKM), were adapted into a dual chamber NMJ system. The formation and function of the NMJs formed were evaluated utilizing clinically translatable readouts.
RESULTS
Functional analysis indicated that NMJs formed with fAD MNs showed severe (PSEN1 A246E) to moderate (APP K595N/M596L) deficiencies in NMJ function.
DISCUSSION
These findings confirmed that fAD mutations lead to NMJ deficiencies, supporting that motor deficits can be induced independently from cognitive deficits.
