Summary: New research indicates that balance and walking problems seen in Alzheimer’s disease may originate in the peripheral nervous system rather than solely from brain degeneration. Using a lab-grown “human-on-a-chip” neuromuscular model, researchers show that genetic mutations linked to familial Alzheimer’s can directly damage the nerve-to-muscle connection, independent of the brain and spinal cord.
Key Findings
- Beyond the Brain: For the first time, scientists have demonstrated that peripheral nervous system dysfunction can arise directly from familial Alzheimer’s mutations.
- Implications for Treatments: Drugs aimed only at brain pathology—such as plaque and tangle reduction—may not resolve movement problems if those issues are rooted in peripheral nerves.
- Human-on-a-Chip Advantage: Lab-grown human cell systems better reproduce human biology than many animal models, allowing functional study of neuromuscular interactions affected by Alzheimer’s mutations.
- Reflex and Function: The neuromuscular junction (NMJ) that was impaired in the model underlies simple reflexes—like the knee-jerk test—and its breakdown could explain early motor signs in some patients.
Source: University of Central Florida
Overview
Researchers at the University of Central Florida (UCF) report evidence that some movement-related symptoms of Alzheimer’s disease may begin outside the brain. Led by Professor James Hickman and Research Professor Xiufang “Nadine” Guo, and supported by the National Institute on Aging, the team used human stem-cell based microphysiological systems to test how familial Alzheimer’s (fAD) mutations affect motor neurons and the neuromuscular junction.
Their study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, highlights a potential shift in how clinicians and drug developers think about early signs and treatments for Alzheimer’s. If motor deficits originate in peripheral circuits, earlier detection and targeted peripheral therapies could help delay or lessen central nervous system symptoms.
Connecting Movement and Alzheimer’s
Familial Alzheimer’s is an inherited, early-onset form of the disease that typically appears between ages 40 and 65. Clinicians have long noted that some patients develop changes in gait, balance, and motor coordination years before memory or cognitive decline becomes obvious. These observations raised the question: are early motor problems caused by upstream brain pathology, or do they stem from intrinsic defects in the peripheral motor system?
To answer this, the research team created a simplified, functional neuromuscular circuit in vitro that excluded the brain and spinal cord. By pairing healthy human muscle cells with motor neurons derived from induced pluripotent stem cells (iPSCs) carrying fAD mutations, they assessed whether the motor neurons alone could disrupt neuromuscular function.
Results showed that motor neurons with fAD mutations produced clear deficits at the neuromuscular junction, impairing the ability of nerves to reliably trigger muscle contractions and reducing endurance before fatigue—functional changes similar to those measured in clinical evaluations of movement disorders.
Why the Neuromuscular Junction Matters
The neuromuscular junction is the critical synapse where a nerve signal causes a muscle to contract. Damage to this connection leads to weakness, loss of coordination, and reduced endurance in everyday activities. In this study, NMJs formed with fAD motor neurons exhibited moderate to severe functional impairment depending on the mutation, supporting the idea that peripheral dysfunction can occur independently from cognitive decline.
As Professor Hickman explains, simple clinical tests—like tapping the knee to check the reflex—probe this same circuit. If that circuitry is compromised at a cellular level, it could explain why some patients show motor symptoms early in the disease course.
Human-on-a-Chip Models and Future Research
The study employed a neuromuscular junction-on-a-chip developed in collaboration with Hesperos, a company co-founded by Hickman. These microphysiological systems recreate interactions between human cells, enabling direct measurement of biological function that often does not appear in animal models. Because they use human-derived cells and clinically translatable readouts, these systems may improve drug discovery and allow testing of therapies that target peripheral components of Alzheimer’s disease.
The authors suggest that preserving motor function through early intervention or rehabilitative approaches could also support cognitive well-being, since physical activity contributes to overall brain health.
Key Questions Answered:
A: No. Alzheimer’s remains a neurological disease, but this research shows it can affect the entire nervous system, including peripheral motor circuits that connect the spine to muscles. Peripheral dysfunction can contribute to early motor symptoms alongside central nervous system changes.
A: Maintaining motor function may support brain health. The findings suggest that interventions targeting nerve-muscle connections—such as physical therapy—could potentially delay or reduce the progression of cognitive symptoms if applied early, though clinical trials would be needed to confirm this.
A: It is a miniature laboratory system that uses living human cells arranged on microengineered platforms to mimic organ or tissue functions. These systems allow researchers to study diseased human tissues and test how altered cells interact without relying on animal models.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by editorial staff to clarify implications for diagnosis and therapy.
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 neurodegenerative disorder primarily affecting the central nervous system and leading to dementia, but it can also present with motor deficits. It has been unclear whether peripheral motor symptoms arise from upstream degeneration in the brain and spinal cord or from intrinsic dysfunction of the neuromuscular circuit. This study developed a functional NMJ model to evaluate neuromuscular pathology in familial Alzheimer’s (fAD).
METHODS
fAD iPSC-derived motor neurons were co-cultured with healthy iPSC-derived skeletal myoblasts in a dual-chamber NMJ microphysiological system. Formation and function of the resulting neuromuscular junctions were evaluated using clinically translatable measures of neuromuscular performance.
RESULTS
Functional tests showed that NMJs formed with fAD motor neurons exhibited deficiencies in neuromuscular transmission, ranging from moderate to severe depending on the specific mutation (for example, PSEN1 A246E showed severe deficits; APP K595N/M596L showed moderate deficits).
DISCUSSION
These results support the conclusion that familial Alzheimer’s mutations can induce neuromuscular junction dysfunction independently of central nervous system degeneration, offering a potential explanation for early motor symptoms in some patients and highlighting the need to consider peripheral targets when developing diagnostic tools and treatments.