Causes of ALS

The exact cause of amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic, environmental, and lifestyle factors are all believed to play a role.

The neurodegenerative disease is characterized by the death of motor neurons, which are the nerve cells that control muscle movements.

Also known as Lou Gehrig’s disease, ALS affects both the upper motor neurons, which connect the brain to the spinal cord, and the lower motor neurons, which are in the spinal cord and brainstem and go down to innervate muscles and glands. Upper motor neuron degeneration generally causes muscle tightness known as spasticity, while lower motor neuron degeneration causes muscle weakness, muscle atrophy (shrinkage), and twitching.

ALS can be broadly divided into two types: familial and sporadic. In familial ALS, the disease develops as a direct result of genetic mutations that a person inherits from his or her biological parents.

In sporadic ALS, there is no one obvious cause of the disease, although many environmental factors have been linked to it. These include toxins such as beta-methylamino-l-alanine (BMAA), found in commercial seafood, as well as pesticides, viruses, and radiation and electromagnetic fields.

Genetics and ALS

Mutations in more than 30 different genes have been linked to ALS.

In some cases, genetic mutations directly cause the disease and, since these mutations can be passed from parents to their biological children, such cases are referred to as familial ALS. Familial ALS accounts for about 5 to 10% of all cases.

Usually, only one copy of a mutated gene is sufficient to cause the disease (for most genes, two copies are inherited, one from each biological parent). Mutations in more than a dozen genes have been found to cause familial ALS. Notably, many of these mutations have incomplete penetrance and genetic pleiotropy. In other words, just because a person has a certain mutation does not guarantee that he or she will develop ALS.

About 25 to 40% of all familial cases are caused by a mutation in a gene called C9orf72. Another 12 to 20% result from mutations in the gene SOD1.

Mutations in the genes TARDBP and FUS also can cause familial ALS.

The C9orf72SOD1TARDBP, and FUS genes all are key to the normal functioning of motor neurons. Mutations in these genes disrupt this normal functioning, though the specific effects of individual mutations are still being investigated by researchers. Collectively, mutations in these four genes account for nearly three out of every four cases of familial ALS.

Genetics also play a role in sporadic ALS, albeit indirectly. Specific genetic variations may influence a person’s susceptibility to ALS, even if they don’t directly cause the disease.

Apart from genetic mutations, a variety of biological, lifestyle, and environmental factors are thought to play a role in the development of ALS.

Environmental and lifestyle factors

Military service and trauma

Veterans are about twice as likely to develop ALS as compared with the general population, though it remains unclear why this association exists. Of note, most data on ALS and veterans come from the U.S., with little information about military service members in other countries.

A history of electrical shocks has been linked with an increased risk of ALS. So has a history of traumatic injury, particularly head injuries — this may explain, at least in part, why people who played sports at a competitive level or who served in combat also appear to have a greater risk of ALS.

Smoking and other toxins

Smoking cigarettes has been linked to an increased risk of ALS. Exposure to other toxins, such as some heavy metals or pesticides, also may increase a person’s risk of developing the disease.

Viral infections

Certain viruses, including HIV and the virus that causes polio, have been linked with ALS-like symptoms.

Biological factors

Age and Sex

ALS can develop in people of any age, but it is more common with increasing age. Most people who develop ALS do so between the ages 40 to 70.

The disease is also about 20% more common in males than in females. This difference is more pronounced among younger patients, and decreases with increasing age.

Chemical imbalance

People with ALS generally have higher than normal levels of glutamate, a chemical messenger in the brain and in the spinal fluid around nerve cells. High levels of glutamate can cause nerve cells to be “overstimulated,” which is toxic to the cells and may contribute to the neurodegeneration that causes ALS.

Overactive immune response

Another biological process that contributes to nerve cell damage in ALS is an increased level of inflammation in the brain. This is often triggered by astrocytes and microglia, which normally are supportive cells of the nervous system but acquire a pro-inflammatory behavior in ALS patients.

Molecular mishandling

ALS often is characterized by the production of irregular proteins that have an abnormal structure or accumulate in atypical parts of the cell. This can lead to disruption of the cellular machinery that normally works to produce proteins and to recycle unneeded proteins, which ultimately results in damage to nerve cells.

When cells make proteins, they “read” their DNA to produce a molecule called messenger RNA, or mRNA, which is then used as the template for the cell’s protein-making machinery to make the actual protein. Abnormal mRNA processing also is common in ALS.

Another molecular phenomenon common in ALS cells is the increased production of free radicals, which are highly reactive molecules that can cause damage to DNA and other cellular structures. This is called oxidative stress.

Impaired neuronal transport

In order to carry out their normal functions, nerve cells need to be able to efficiently move molecular cargo — for example, signaling molecules used for communication — from one part of the cell to another. In ALS, the systems used to transport these molecules are often compromised, which is thought to play a role in the disease.

Mitochondrial problems

Mitochondria are cellular structures often referred to as the “powerhouse of the cell” because they play a key role in generating energy. However, mitochondria also are critical for other cellular functions, such as making certain amino acids, which are the building blocks of proteins. In the nerve cells of people with ALS, mitochondria may not function correctly, which can contribute to the disease.

Research continues to learn more about the causes of ALS.


Last updated: June 8, 2021


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