Amyotrophic lateral sclerosis changes the skin in ways that most people, and even some clinicians, do not expect from a disease usually defined by motor neuron loss. Research over the past several decades has documented a range of skin abnormalities in people with ALS, from altered texture and elasticity to microscopic changes in collagen, nerve fibers, and even the same misfolded proteins found in the brain. These changes are not just curiosities. They are reshaping how researchers think about ALS as a systemic disease, and skin biopsy is gaining traction as a potential tool for earlier diagnosis.
How ALS Changes the Way Skin Looks and Feels
One of the most distinctive features of ALS skin is a change in texture and elasticity. Clinicians have long noted that the skin of people with ALS feels unusually supple, sometimes compared to the feel of tanned leather. When the skin is stretched, it snaps back more slowly than normal. Researchers have called this the “delayed return phenomenon,” and it tends to appear more than two and a half years after symptoms begin.1PubMed. Skin changes in amyotrophic lateral sclerosis The change is subtle enough that it can go unnoticed during routine care, but it is consistent enough across patients that it has been formally described in the literature.
Under the microscope, the skin shows swelling in the dermis and collagen fibers of uneven diameter. Small blood vessels in the skin develop duplicated basement membranes and deposits of beta-amyloid protein. These microscopic changes appear across a range of disability levels, from people who are still relatively mobile to those who are severely impaired, but they are absent in age-matched and sex-matched controls.2The Lancet. Skin involvement in amyotrophic lateral sclerosis That last point matters: the skin changes are not just a product of immobility or aging. They appear specific to ALS itself.
Sweating Abnormalities
Sweating problems are among the earliest autonomic signs in ALS, and they follow a distinctive pattern. In the early stages of the disease, people with ALS tend to sweat more than normal, particularly on the palms. As the disease progresses, sweating decreases across all measured areas. Over a six-month period in one study, sweat production dropped by roughly 40%.3PubMed Central. Progressive sudomotor dysfunction in amyotrophic lateral sclerosis This early-to-late shift, from excess sweating to reduced sweating, points to a progressive breakdown in the sympathetic nervous system’s control over the sweat glands.
Excessive sweating can sometimes be one of the very first symptoms a person notices before the classic muscle weakness and wasting begin. A case involving a young woman with a FUS gene mutation documented hyperhidrosis of the palms and feet as the presenting symptom, confirmed by a positive skin iodine-starch test, alongside prolonged sympathetic skin response latency.4PubMed. Hyperhidrosis as the initial symptom in FUS mutation-associated amyotrophic lateral sclerosis Broader evidence confirms that subclinical dysfunction of sweating regulation exists even in early cases of ALS, alongside other autonomic disturbances affecting the cardiovascular, gastrointestinal, and salivary systems.5Current Opinion in Neurology. Autonomic impairment in amyotrophic lateral sclerosis
For the person living with ALS, this can mean dealing with uncomfortably damp hands or feet early on, followed by dry, poorly regulated skin later. The dryness in later stages may increase vulnerability to skin breakdown, making moisturizing and environmental temperature management practical concerns.
The Bedsore Question
One of the oldest observations about ALS skin is that patients seemed remarkably resistant to bedsores, even when completely immobilized in the late stages of the disease. Jean-Martin Charcot noted this in the 19th century, and the observation persisted in the clinical literature for well over a hundred years.6PubMed. Potential skin involvement in ALS: revisiting Charcot’s observation – a review of skin abnormalities in ALS The idea was that ALS skin, with its altered collagen and unusual texture, somehow resisted the pressure damage that plagues other bedridden patients.
More recent epidemiological data complicates this picture considerably. A large nationwide cohort study found that people with ALS actually have a substantially higher risk of developing pressure sores than the general population, with the risk particularly elevated in women and in younger patients. Women with ALS had more than 26 times the risk of pressure sores compared to controls, and people aged 20 to 54 with ALS had roughly 28 times the risk.7PubMed. Risk of developing pressure sore in amyotrophic lateral sclerosis patients – a nationwide cohort study The overall adjusted hazard ratio was close to nine times the risk seen in matched controls. These numbers are hard to reconcile with the older clinical impression of bedsore resistance.
What likely explains the discrepancy is a combination of observation bias and changing care contexts. Charcot’s observation was made in an era before prolonged mechanical ventilation, when ALS patients often died before the immobility reached the point where bedsores typically form. Modern patients who live longer with ventilatory support spend more time at high risk. The altered collagen and skin texture may offer some localized protection, but they are clearly not enough to override the risk that comes with extended immobility, reduced subcutaneous fat, and impaired circulation.
Collagen and Structural Changes
The structural changes in ALS skin are not trivial. Under light microscopy, collagen bundles in the dermis appear disoriented, separated, and fragmented, particularly in the upper layer of the dermis closest to the surface.8Journal of the American Academy of Dermatology. Skin changes in patients with amyotrophic lateral sclerosis: Light and electron microscopic observations The spaces between these disorganized collagen bundles contain elevated levels of glycosaminoglycans, a family of sugar-based molecules that normally help skin retain water and structure. Staining for these molecules becomes more intense as the disease progresses, suggesting that the collagen disruption worsens over time.9PubMed. Alterations of skin glycosaminoglycans in patients with ALS
One enzyme that appears to drive this collagen breakdown is MMP-9, a matrix metalloproteinase that chews up structural proteins in connective tissue. MMP-9 is elevated both in the central nervous system and in the skin of people with ALS. In the brain and spinal cord, it likely reflects ongoing nerve cell destruction and the inflammatory glial response. In the skin, elevated MMP-9 appears to break down type IV collagen specifically, which is a key component of basement membranes. Researchers have proposed that MMP-9 acts as a common link between the neurodegeneration in the brain and the structural deterioration of the skin, two seemingly distant aspects of the same disease.10Journal of the Neurological Sciences. Linking neuron and skin: Matrix metalloproteinases in amyotrophic lateral sclerosis (ALS) In an animal model of ALS, oxidative stress and inflammatory signals like IL-1β appeared to drive MMP levels higher, particularly in later disease stages.11Journal of the Neurological Sciences. MMP-2 and MMP-9 are elevated in spinal cord and skin in a mouse model of ALS
The collagen changes help explain both the altered texture that clinicians feel and the delayed return phenomenon. With fragmented, disorganized collagen and excess glycosaminoglycans filling the spaces between bundles, the skin behaves differently under mechanical stress. It stretches more easily but rebounds sluggishly, like a piece of leather that has lost its internal scaffolding.
Loss of Nerve Fibers in the Skin
ALS is defined by the death of motor neurons, but the disease also affects the tiny sensory nerve fibers that thread through the skin. In one study comparing ALS patients to age-matched controls, the density of nerve fibers penetrating the outer layer of skin at the lower leg was dramatically reduced: roughly 4.8 fibers per millimeter in ALS patients versus 12.2 in controls. About 79% of ALS patients in that study met the criteria for small-fiber neuropathy, compared to 12% of controls.12PubMed. Small-fiber neuropathy in patients with ALS
A larger study confirmed this pattern across multiple body sites. Nerve fiber density was markedly reduced at the leg, thigh, and fingertip in ALS patients compared to healthy controls. The percentage of patients showing fiber density below the normal threshold was 58% at the leg, 78% at the thigh, and 30% at the fingertip.13Brain. Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers This gradient, with more nerve loss closer to the trunk and less at the extremities, is itself an interesting finding, because it differs from the typical pattern seen in peripheral neuropathies where the longest nerves (to the feet and hands) tend to be affected first.
The loss of these small fibers has practical consequences. Small nerve fibers carry pain and temperature signals and help regulate blood flow and sweating. Their loss likely contributes to the sweating dysfunction described earlier and may affect how the skin responds to injury or pressure. People with ALS sometimes report unusual sensory experiences, tingling, or numbness that are difficult to explain through motor neuron loss alone. Small-fiber neuropathy in the skin provides a plausible explanation for at least some of these symptoms.
TDP-43 Deposits in the Skin
Perhaps the most striking finding in recent ALS skin research involves TDP-43, a protein that misfolds and clumps together inside nerve cells in the vast majority of ALS cases. Researchers have now shown that these same abnormal protein deposits are present in the skin. A study comparing ALS patients, people with other neurological conditions, and healthy controls found that phosphorylated TDP-43 deposits were present across the epidermis and dermis in ALS patients, while they were nearly absent in healthy controls.14PubMed. Phosphorylated TDP-43 Pathology in Skin and Muscle Tissue of Patients With Amyotrophic Lateral Sclerosis The deposits were found in keratinocytes, sweat glands, and cutaneous nerve fibers, suggesting that TDP-43 dysfunction is not restricted to the central nervous system.
Earlier work using confocal microscopy had already identified TDP-43 deposits in the nerve fibers of ALS skin, raising the possibility that skin biopsy could serve as a diagnostic marker.15PubMed. Cutaneous somatic and autonomic nerve TDP-43 deposition in amyotrophic lateral sclerosis The presence of the same pathological protein in both the brain and the skin reinforces the idea that ALS is a whole-body disease, not just a disease of the motor neurons. It also opens the door to a much less invasive way of detecting the disease’s molecular signature.
Skin Biopsy as a Diagnostic Window
ALS is notoriously difficult to diagnose. There is no single blood test or imaging scan that confirms it. Diagnosis relies on clinical assessment and the exclusion of other conditions, a process that can take a year or more. The discovery that ALS-associated protein pathology is present in the skin has generated serious interest in skin biopsy as a faster, less invasive diagnostic approach.
The most dramatic finding in this space comes from work examining skin biopsies taken from individuals who were not yet showing motor symptoms. In a validation cohort, TDP-43 pathology was present in all skin biopsies from all individuals examined, from as little as 213 days up to 26.5 years before the onset of motor symptoms. The median lead time between detectable skin TDP-43 pathology and motor symptom onset was about 10.6 years.16PubMed Central. Skin TDP-43 pathology as a candidate biomarker for predicting amyotrophic lateral sclerosis decades prior to motor symptom onset If this finding holds up in larger studies, it would mean that ALS leaves detectable traces in the skin a decade or more before anyone suspects the diagnosis.
The practical implications are significant. A small skin punch biopsy is a routine, low-risk procedure that any dermatologist can perform. If validated, it could be used not only to confirm a diagnosis in people who already show symptoms but also to screen people at genetic risk for ALS or to monitor disease progression in clinical trials. The combined assessment of nerve fiber density and TDP-43 pathology in skin biopsies is being actively studied as a prognostic biomarker that could predict how quickly the disease will advance.13Brain. Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers
Researchers have also explored skin-derived cells in a different way: taking fibroblasts from ALS patients’ skin and reprogramming them into stem cells that can then be turned into motor neurons in the lab. These lab-grown motor neurons develop the same TDP-43 protein clumps seen in postmortem brain tissue, providing researchers with a living model of the disease for drug screening.17Molecular and Cellular Neuroscience. A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells One such screen identified existing FDA-approved compounds that could modify TDP-43 aggregation, and a separate effort used patient-derived motor neurons to test retigabine, an anticonvulsant, which blocked abnormal nerve excitability and improved motor neuron survival in the lab setting.18Frontiers in Neuroscience. Current Advances and Limitations in Modeling ALS/FTD in a Dish Using Induced Pluripotent Stem Cells
Subcutaneous Fat Redistribution
The changes in ALS skin are not only about the skin itself. The layer of fat just beneath the skin also shifts. While total body fat in ALS patients may appear roughly similar to that of healthy controls, the distribution changes: visceral fat (the deep fat surrounding organs) expands while subcutaneous fat (the fat just under the skin) tends to decrease. The ratio between the two shifts toward visceral fat.19PLOS ONE. Adipose Tissue Distribution Predicts Survival in Amyotrophic Lateral Sclerosis This redistribution has real consequences: subcutaneous fat acts as a cushion over bony prominences, and losing it increases susceptibility to pressure injury. Combined with the collagen changes and nerve fiber loss described above, this helps explain why modern data shows elevated bedsore risk despite the historical impression of bedsore resistance.
Practical Skin Management
For people living with ALS and their caregivers, awareness of these skin changes translates into several concrete care priorities. Pressure sore prevention is the most urgent. Despite the old clinical lore, people with ALS are at high risk for pressure injuries, especially as mobility declines. Regular repositioning, pressure-relieving mattresses, and careful monitoring of skin over bony areas like the heels, sacrum, and hips are essential.
Sweating management varies by disease stage. Early on, when sweating may be excessive, breathable clothing, moisture-wicking fabrics, and good air circulation can help. Later, when sweating declines and the skin becomes drier, moisturizers become more important to prevent cracking and breakdown.
An often-overlooked source of skin damage comes from the medical devices used in ALS care. Noninvasive ventilation masks, worn for hours at a time, can cause pressure injury to the nasal bridge and face. In case reports of ALS patients who developed nasal bridge skin necrosis from continuous mask use, switching to a total face mask that avoids contact with the sensitive nasal area resolved the problem and allowed safe ventilation for days.20PubMed. Continuous noninvasive ventilation delivered by a novel total face mask: a case series report If you or someone you care for uses a ventilation mask and notices redness, pain, or skin breakdown around the nose, asking the respiratory team about alternative mask designs is a reasonable step.
The altered collagen and reduced elasticity of ALS skin also mean that wound healing may not proceed normally. Caregivers should flag any skin break, however small, to the medical team rather than assuming it will heal on its own. The combination of fragmented collagen, reduced nerve innervation, altered fat cushioning, and impaired autonomic regulation creates a skin environment where small injuries can escalate faster than expected.
From Skin Cells to Lab-Grown Motor Neurons
Skin cells from ALS patients are now being used in ways that go well beyond diagnosis. By taking fibroblasts from a simple skin punch biopsy and chemically reprogramming them into induced pluripotent stem cells, researchers can grow motor neurons that carry the patient’s own genetic background.21PubMed Central. Induced pluripotent stem cells from ALS patients for disease modeling These lab-grown neurons develop disease-relevant pathology, including the protein aggregation that defines ALS, making them useful for studying disease mechanisms and testing potential drugs in a dish before moving to clinical trials. The approach has been applied to both familial and sporadic forms of ALS, which is particularly valuable for the roughly 90% of cases that arise without a known genetic cause. For a disease that has historically been difficult to study outside of postmortem tissue and animal models, the ability to grow living human ALS neurons from a small piece of skin has been a meaningful advance.