Causes of ALS

Last updated Feb. 2, 2023, by Marisa Wexler, MS
Fact-checked by Ines Martins, PhD

The exact cause of amyotrophic lateral sclerosis (ALS) is largely unknown, but a number of factors including genetics, environmental exposures, and lifestyle habits have been linked to an increased risk of ALS.

Also known as Lou Gehrig’s disease, named after the famous baseball player who was diagnosed with the disorder in 1939, ALS is a neurodegenerative condition characterized by the progressive death of motor neurons — the specialized nerve cells that control muscle movement.

It affects both 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 and out to connect to all the muscles in the body. Upper motor neuron degeneration generally causes muscle tightness or spasticity, while lower motor neuron degeneration causes muscle weakness, muscle atrophy (shrinkage), and twitching.

Genetics and ALS

There is strong evidence that an individual’s genetics have an impact on the risk of developing ALS. Mutations in more than a dozen genes have been definitively linked with ALS, and many more genes have shown potential associations with disease risk. Some of the genes most strongly linked to ALS include:

• C9ORF72
• SOD1
• TARDBP
• FUS
• TBK1.

ALS can broadly be divided into two types: familial, meaning the disease affects more than one person in a family, and sporadic, when there’s no family history. Mutations in these genes are mostly found in people with the familial form of the disease, but about 10% of patients with sporadic ALS also carry a known ALS-associated genetic mutation.

Importantly, most ALS-associated mutations have incomplete penetrance and genetic pleiotropy. In other words, just because a person has a certain mutation does not mean that the individual is guaranteed to develop ALS; other factors also play a role.

Familial ALS

Due to its genetic component, ALS can run in families, with parents passing disease-associated mutations on to their biological children. When someone with an ALS diagnosis can show at least two cases of the condition in the family, that person has familial ALS — which accounts for roughly 5%-10% of all cases. A family history of ALS is one of the strongest risk factors associated with the disease.

Specific disease-associated mutations have been identified in approximately two-thirds of familial ALS cases. In other cases, the disease-related mutations remain unknown — possibly because those mutations have not yet been identified and linked to ALS.

Usually, people can develop the disease if they inherit only one copy of a mutated gene. For most genes, two copies are inherited, one from each biological parent.

Mutations in the C9ORF72 gene account for about 25%-50% of familial ALS cases, while mutations in SOD1 are found in 10%-20% of cases. Mutations in TARDB and FUS collectively account for 3%-5% of cases.

Sporadic ALS

If an individual with ALS does not have a family history of the disease, it’s referred to as sporadic ALS, meaning isolated or without clear patterns. Genetics are thought to play a role in determining disease risk in sporadic cases, though the precise effects still are incompletely understood.

Around 1 in 10 people with sporadic ALS has a known ALS-associated mutation. These mutations may be inherited from a parent who never developed the disease, or they may have developed spontaneously in the affected individual during early development.

Mutations in C9ORF72 are found in 7%-10% of sporadic ALS cases. Mutations in SOD1 are present in 1%-2% of cases, while mutations in other genes are generally found in less than 1% of sporadic ALS cases.

Environmental and lifestyle factors

While the genetic basis of ALS is relatively well established, gene mutations are not the sole determinants of disease risk. The likelihood of someone developing the disease is thought to result from the interaction between genetic alterations and environmental and lifestyle factors.

Studies have shown that a person’s experiences, habits, and career may influence the risk of ALS. These include exposures to chemicals, physical trauma, and lifestyle habits including smoking and exercise.

Military service

Veterans are about twice as likely to develop ALS as individuals in the general population — and the risk reportedly is higher for those deployed more recently. A 2019 study found the prevalence of ALS is about four times higher among military service members who were deployed to post-9/11 wars than those deployed in the Gulf War.

While it remains unclear exactly why this association exists, members of the military often are exposed to chemicals, strenuous physical conditions, and trauma, all of which may play a role. Most data on ALS and veterans come from the U.S., with little information about military service members in other countries.

Head injury and trauma

A history of traumatic injury, particularly head injuries, has shown an association with an increased risk of ALS. Data show that head injuries are linked with a 38% greater likelihood of developing ALS, with those changes increasing to 69% among people with severe head injuries.

This association may explain, at least in part, why people who played sports at a competitive level or who served in combat have a greater risk of ALS.

Electric shock and electromagnetic fields

Some studies have suggested that people with a history of electric shock and/or exposure to electromagnetic fields (EMFs) are more likely to develop ALS.

The risk of ALS is increased among individuals in professions related to electricity, such as electricians, train drivers, and people operating electric equipment, like welders or carpenters. This may be because people in these professions are more likely to experience electric shocks that contribute to high exposure of extremely low frequency EMFs.

Smoking

Smoking cigarettes is one of the most well-established lifestyle risk factors for ALS. Studies suggest that the risk of ALS is increased by more than 40% among people who have ever smoked cigarettes, compared to those who have never smoked.

Exposure to toxic chemicals

Exposure to certain toxic chemicals has been linked with an increased ALS risk, and may explain at least in part why ALS is more common among people in the military and certain other professions exposed to these substances. These include:

• heavy metals, particularly manganese, mercury, and zinc
• beta-methylamino-L-alanine (BMAA), a toxic compound made by algae
• formaldehyde
• pesticides.

Viral infections

A history of infection with certain viruses — in particular enteroviruses, a group that includes the virus that causes polio, as well as numerous other viruses that don’t usually cause serious diseases in people — has been linked with an increased risk of ALS.

Some herpes viruses also have been linked with ALS and HIV can trigger ALS-like symptoms that resolve after the viral infection is controlled.

However, the association between any infection and ALS risk remains unproven.

Excessive exercise

Many studies have suggested that people who are very physically active, regularly engaging in strenuous exercise, are more likely to develop ALS.

The risk of ALS is increased among people who play sports professionally, such as professional soccer players and football players, which may be attributable to physical activity or to other factors such as head trauma. However, ALS risk is not significantly altered for people who engage in recreational sports.

Biological factors

In ALS, a number of biological systems in the human body become dysregulated, which contributes to the onset and gradual progression of the disease. Some inherent traits, most caused by genetic variants known to contribute to ALS, may influence disease risk.

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 of 55 and 75, although there are reports of children who have developed ALS symptoms as early as age 3.

The disease also is about 20% more common in males than in females. This is more pronounced among younger patients, with differences between sexes decreasing 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 motor neuron degeneration that characterizes ALS.

Overactive immune response

Neuroinflammation — inflammation in the brain — is common among people living with ALS and is thought to contribute to the progression of the disease. This inflammation 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.

A few studies have suggested that people with autoimmune diseases — conditions in which the immune system attacks the body’s own healthy tissue — may be at an increased risk of ALS, though other research has shown no link. This potential connection is still being explored.

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 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 oxygen-containing molecules that can cause damage to DNA and other cellular structures. This type of damage is called oxidative stress.

Impaired neuronal transport

To carry out their normal functions, nerve cells need to be able to efficiently move molecular cargo from one part of the cell to another. One example of this is the signaling molecules used for communication. In ALS, the systems used to transport these molecules often are 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 often do not function correctly, which can contribute to oxidative stress and disease progression.

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