Does Alzheimer's Start Outside The Brain? The Silent Signs That Appear in The Body

What if the first signs of Alzheimer's weren't in the brain, but in your muscles? A new study reveals surprising clues that could change everything we know about the disease.

Alzheimer's disease is generally known as a condition that affects memory and reasoning. However, recent evidence suggests that its first signs may appear much earlier, and outside the brain. This study starts precisely from this idea: what if Alzheimer's is also a disease of the body, especially of the muscles and nerves?

Clinical research has already been indicating important clues. People with Alzheimer's in the early stages often experience loss of strength, walk more slowly, and have changes in communication between nerves and muscles. In some cases, these changes appear years before cognitive symptoms. This has led scientists to suspect that the neuromuscular system may be involved from the beginning of the disease.

To investigate this hypothesis more precisely, the researchers used advanced technology based on human stem cells. They collected cells from patients with a genetic form of Alzheimer's disease and "reprogrammed" them in the laboratory to transform them into motor neurons, cells responsible for sending signals from the brain to the muscles.

In parallel, they used healthy cells to generate muscle tissue. This allowed them to create a controlled model, similar to the human body, but entirely in the laboratory.

These cells were then connected in a special two-chamber system, designed to simulate the neuromuscular junction, the point of communication between neurons and muscles. This system functions as a kind of "functional miniature" of the human body, allowing them to observe how nerve signals activate the muscles. Extremely sensitive sensors measured the strength, efficiency, and quality of this communication.

The results showed something striking: the connections between neurons and muscles formed from cells of Alzheimer's patients presented clear flaws. In some cases, these flaws were severe, indicating that the muscles were receiving signals inefficiently. This suggests that the disease can directly compromise muscle function, and not just as a consequence of brain damage.

The researchers also tested medications already used in the treatment of Alzheimer's, such as memantine and galantamine, to see if they could improve this communication between nerves and muscles.

However, the results indicated that these treatments did not have a significant effect in this aspect, reinforcing the idea that the motor symptoms of the disease may require specific therapeutic approaches.

These findings change how we understand Alzheimer's. Instead of a disease restricted to the brain, it can be seen as a systemic condition that affects multiple body systems. This opens new possibilities for early diagnosis, for example, through the analysis of muscle strength or gait, and also for the development of more comprehensive treatments.

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Evaluating the peripheral nervous system pathology of Alzheimer’s disease  utilizing a functional human NMJ microphysiological system

Akhmetzada Kargazhanov, Romy Aiken, Kenneth Hawkins, Rafael Lopez, Ahmad Nawaz, Gaurav Srivastava, Chase Miller, Will Bogen, Christopher Long, David Morgan, Xiufang Guo, and James Hickman

Alzheimer’s & Dementia. Volume22, Issue 4, April 2026, e71281

DOI: 10.1002/alz.71281

Abstract: 

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. 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. Functional analysis indicated that NMJs formed with fAD MNs showed severe (PSEN1 A246E) to moderate (APP K595N/M596L) deficiencies in NMJ function. These findings confirmed that fAD mutations lead to NMJ deficiencies, supporting that motor deficits can be induced independently from cognitive deficits.