Scientists find evidence some Alzheimer’s symptoms may begin outside the brain

A recent study has found that the physical movement difficulties often associated with Alzheimer’s disease can originate outside the brain. By creating a microscopic model of human nerves and muscles, researchers demonstrated that these motor problems occur independently of cognitive decline, which suggests new targets for medical treatments. The research was published in the journal Alzheimer’s & Dementia.

Alzheimer’s disease is usually associated with memory loss and severe cognitive decline. Doctors routinely observe that patients also experience movement issues like a slower walking pace, diminished grip strength, and poor balance well before any mental symptoms appear.

Historically, medical research has treated these physical symptoms as secondary effects stemming directly from brain degeneration. It remained unproven if the illness was also independently attacking the body’s peripheral nerves, which make up the vast network connecting the spinal cord to the rest of the body.

To investigate the root of these movement problems, researchers looked closely at the neuromuscular junction. This is the exact biological point where a nerve cell sends a chemical signal to a muscle cell, commanding it to contract and create physical movement.

The study was led by University of Central Florida professors James Hickman and Xiufang Guo, with Akhmetzada Kargazhanov serving as the lead author. The academic team collaborated with scientists at Hesperos, a biotechnology company co-founded by Hickman, to build a specialized laboratory model.

The researchers focused their efforts on familial Alzheimer’s disease. This is a rare, hereditary version of the condition that typically appears when a patient is between 40 and 65 years old. It is distinct from the more common sporadic form of the illness, which generally affects older populations and lacks a single genetic cause.

To conduct the experiment without using live human subjects, the researchers utilized human induced pluripotent stem cells. These are adult cells, usually taken from skin or blood, that have been chemically reprogrammed to act like embryonic stem cells. This reprogramming allows scientists to coax the cells into developing into almost any tissue type in the human body.

The scientists used this cellular technology to grow human motor neurons, which are the specialized nerve cells responsible for controlling our voluntary movements. They genetically modified these nerves to carry one of two specific genetic mutations associated with familial Alzheimer’s disease.

The researchers then paired these mutated nerve cells with healthy human muscle cells in a microscopic laboratory device known as a human-on-a-chip. This miniature system was split into two separate chambers, effectively mimicking a functional neuromuscular junction while completely removing the brain and spinal cord from the equation.

By keeping the central nervous system out of the model, the researchers could isolate the exact source of any physical failures. If the movement system stopped working correctly in this isolated environment, it would prove that the disease attacks the peripheral nerves on its own.

Testing drugs on animal models like mice can be problematic because human and animal biology differ in ways that affect how a condition progresses. The microscopic human cell models bypass this biological gap, allowing researchers to gather data that more accurately reflects the human body.

During the main experiment, the team ran electrical currents through the nerve chamber to stimulate the cells, prompting them to send movement signals to the connected muscle chamber. They used high-speed cameras and computer software to track how well the muscles responded to these commands.

The researchers measured multiple specific parameters to gauge the health of the cells. They looked at fidelity, which measures how reliably the muscle actually contracts when the nerve sends a signal. They also tested the fatigue index, recording how long the muscle could maintain a tight contraction under rapid electrical stimulation.

The results indicated that the nerve cells carrying the Alzheimer’s mutations struggled to communicate with the healthy muscle cells. The neurons carrying a genetic mutation known as PSEN1 displayed severe deficiencies across all testing days.

These specific cells failed to reliably trigger muscle contractions and showed a higher rate of muscle fatigue. The biological connections between the nerves and muscles were also less stable over time compared to healthy control cells.

The neurons carrying a different flaw, called the APP mutation, showed moderate deficiencies. While they performed better than the PSEN1 cells, they still experienced a drop in their ability to trigger reliable muscle contractions during the middle of the testing period.

Because the muscle cells used in the experiment were completely healthy, the breakdown in communication was definitively caused by the diseased motor neurons. The team had successfully demonstrated that peripheral nerve damage happens independently of brain degeneration.

Inside the cells, researchers also looked at microscopic structures called endosomes, which act like tiny transport pods or recycling centers. The scientists noticed that the transport pods in the mutated nerve cells were abnormally enlarged. Because these pods help recycle the chemicals needed to send movement signals, their malfunction offers a biological clue as to why the nerve communication was failing.

The researchers also wanted to see if common Alzheimer’s medications could fix this peripheral nerve dysfunction. They treated the diseased cells with memantine and galantamine, two drugs routinely prescribed to help manage the cognitive symptoms of the illness in its early stages.

Memantine works by blocking a specific chemical receptor to prevent nerve cell damage, while galantamine stops the breakdown of chemical messengers to prolong their effects. Adding these medications to the microscopic model yielded no statistically significant improvement in the function of the nerve and muscle connections.

The medications failed to restore reliable communication between the nerves and muscles. This lack of recovery suggests that treatments designed exclusively to heal the brain do not automatically repair damage in the rest of the body.

Hickman noted the importance of this specific realization. “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.”

While the model provided clear insights, the study does have a few distinct limitations. The microscopic system used in the experiment only contained motor neurons and skeletal muscle cells, making it a very basic representation of human biology.

In a living human body, other cell types, such as protective astrocytes and Schwann cells, interact with nerves and muscles to support their daily function. Introducing these supporting cells into the laboratory model could alter the results, either making the symptoms worse or compensating for the diseased nerves.

Future research will likely expand on this model by testing muscle cells that carry Alzheimer’s mutations, rather than just the nerve cells. Researchers could also use the miniature devices to model sensory neurons, which would help map out how the disease affects the body’s pathways for feeling touch and pain.

Because current medications did not heal the peripheral nerves in this study, the miniature human-on-a-chip could become a testing ground for new pharmaceutical compounds. Developing combination therapies that target both cognitive decline and physical deterioration could eventually improve the overall quality of life for patients.

The study, “Evaluating the peripheral nervous system pathology of Alzheimer’s disease utilizing a functional human NMJ microphysiological system,” was authored 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.