ALS develops when nerve cells that control movement break down, but the exact reason this happens remains unknown

Amyotrophic lateral sclerosis (ALS) occurs when motor neurons—the nerve cells that send signals to your muscles—gradually die. This causes muscles to weaken, waste away, and eventually stop responding to commands from your brain and spinal cord. The disease is progressive, meaning it gets worse over time. What triggers this cell death in the first place is still not fully understood, even though researchers have identified several factors that appear to play a role.

About 90 percent of ALS cases are sporadic, meaning they occur randomly with no known family history. The remaining 10 percent are familial, inherited from a parent who carries a gene mutation. Even in familial cases, having the gene does not may provide you will develop the disease—penetrance varies, meaning some gene carriers never show symptoms.

Key Takeaways

  • ALS happens when motor neurons die, but scientists do not yet know why this process starts in most cases.
  • Genetic mutations cause about 10 percent of ALS cases, with the SOD1 gene being the most common known mutation.
  • Environmental exposures, inflammation, protein buildup, and problems with how cells handle waste may all contribute to motor neuron death.
  • Age, sex, and family history are risk factors, but none of them cause ALS on their own.
  • Research continues to identify new genes and mechanisms, but no single cause has been found that explains all cases.

Genetic mutations linked to familial ALS

When ALS runs in families, it is usually because of a mutation in a single gene that gets passed down. The SOD1 gene was the first one identified and accounts for about 20 percent of familial cases. Since then, researchers have found mutations in dozens of other genes—including C9orf72, FUS, TARDBP, and others—each accounting for smaller percentages of inherited ALS.

These genes normally produce proteins that help motor neurons survive and function. When mutated, the proteins either work poorly or accumulate in toxic clumps inside the cell. Some mutations cause the cell to struggle with clearing waste; others trigger inflammation or disrupt the cell's energy production. The specific mutation determines how quickly the disease progresses and which muscles are affected first, but the end result is the same: motor neuron death.

Having a familial ALS mutation does not mean you will definitely get sick. Some people with the mutation never develop symptoms, even into old age. Researchers call this incomplete penetrance, and it suggests that genes alone do not tell the whole story—something else must also be present for the disease to start.

Environmental and lifestyle factors under investigation

Researchers have looked for environmental triggers—things in your surroundings or habits that might increase risk. Studies have examined exposure to pesticides, heavy metals, military service, head trauma, intense physical activity, and smoking. Some of these show a possible link to ALS, but none has been proven to cause the disease on its own.

The strongest environmental finding so far involves military service, particularly among veterans who served in the Gulf War. Veterans have higher rates of ALS than the general population, but researchers have not pinpointed which specific exposure—whether it was depleted uranium, pesticides, vaccines, or something else—is responsible. This suggests that multiple exposures or a combination of factors may matter more than any single one.

Lifestyle factors like smoking and high BMI have been associated with earlier onset in some studies, but again, these are risk factors, not causes. Many people who smoke or have high BMI never develop ALS, and many people with ALS have neither risk factor.

Protein buildup and cellular damage

Inside motor neurons, two proteins—TDP-43 and SOD1—often accumulate in abnormal clumps. These protein aggregates appear in most ALS cases, whether or not a genetic mutation is present. The buildup seems to interfere with the cell's normal functions, but whether the protein clumps are the cause of cell death or a result of it is still debated.

When these proteins misfold and clump, they can trigger a cascade of problems: the cell's protein-disposal system gets overwhelmed, toxic stress builds up, and the cell's energy-producing structures (mitochondria) begin to fail. The cell may also lose the ability to communicate with other neurons and with muscles. Eventually, the accumulated damage becomes irreversible and the neuron dies.

Researchers are testing whether clearing these protein clumps can slow or stop the disease. Some experimental treatments aim to prevent the proteins from misfolding in the first place, while others try to help the cell dispose of clumps more efficiently.

Inflammation and immune system involvement

The immune system appears to play a role in motor neuron death, though whether it is a primary cause or a secondary response to dying neurons is unclear. In ALS brains and spinal cords, researchers find activated immune cells (microglia and astrocytes) clustered around dying motor neurons. These cells release inflammatory molecules that may accelerate nerve cell death.

Some people with ALS have antibodies in their blood that attack motor neurons or the proteins that help neurons communicate. This suggests that in at least some cases, the immune system may be mistakenly targeting the very cells it should protect. However, these antibodies are not present in all ALS patients, so they cannot be the whole explanation.

The inflammatory response could be triggered by protein clumps, by genetic mutations, by environmental toxins, or by some combination. Researchers are exploring whether reducing inflammation might slow disease progression, and several clinical trials have tested anti-inflammatory approaches.

Age and other risk factors

ALS typically appears between ages 40 and 70, with average onset around age 60. Age itself is a risk factor—the older you are, the higher your risk—but ALS is not a normal part of aging. Young people do develop ALS, though it is less common.

Men are diagnosed with ALS more often than women, though the reason is not clear. Some research suggests biological differences in how motor neurons age or respond to stress; other work points to differences in how the disease presents or gets diagnosed. Family history is also a risk factor: if a close relative has ALS, your risk is higher than the general population, even if you do not carry a known mutation.

These risk factors help identify who is more likely to develop ALS, but they do not explain why the disease starts. A 70-year-old man with a family history of ALS might never get sick, while a 45-year-old woman with no family history might. This unpredictability is one reason ALS remains so difficult to understand and prevent.

What researchers still do not know

Despite decades of research, the fundamental question remains unanswered: why do motor neurons die in ALS? The disease likely has multiple causes—different genetic mutations, different environmental exposures, different cellular mechanisms—that all lead to the same outcome. This is why a treatment that works for one person may not work for another.

New genes are still being discovered through large genetic studies. Advanced imaging and lab techniques are revealing more about what happens inside dying neurons. Animal models and cell cultures are helping researchers test whether blocking specific mechanisms can prevent cell death. But translating these discoveries into treatments that slow or stop human ALS has proven slow and difficult.

Understanding the cause matters because it points toward prevention and treatment. If researchers can identify what starts the cascade of motor neuron death, they may be able to stop it before symptoms appear—or at least slow it down after they do.

Frequently Asked Questions

Can you catch ALS from someone else?

No. ALS is not contagious. You cannot get it from contact with someone who has the disease, from their blood, or from their environment. The disease develops from changes within a person's own nervous system, either inherited or acquired over time.

If my parent has ALS, will I definitely get it?

Not necessarily. If your parent has familial ALS caused by a dominant gene mutation, you have a 50 percent chance of inheriting the mutation. But inheriting the mutation does not may provide you will develop symptoms—some people with the mutation never get sick. If your parent has sporadic ALS, your risk is slightly higher than the general population, but most children of ALS patients do not develop the disease.

Does stress cause ALS?

There is no evidence that stress causes ALS. Some people report that their symptoms appeared after a stressful event, but this is likely coincidence rather than cause. Stress may worsen symptoms in people who already have ALS, but it does not trigger the disease.

Can diet or supplements prevent ALS?

No diet or supplement has been shown to prevent ALS or slow its progression. Some people try various treatments based on anecdotal reports, but controlled research has not found that any dietary change reduces ALS risk. If you are interested in nutrition or supplements, discuss them with your doctor.

Why is ALS more common in some places than others?

ALS rates do vary geographically, and researchers have investigated whether local environmental exposures explain the differences. Some clusters have been linked to specific occupations or military service, but most geographic variation remains unexplained. It may reflect differences in how the disease is diagnosed and reported rather than true differences in how often it occurs.