Most people who develop ALS have no family history of the disease and no single identifiable cause. Roughly 80% to 90% of cases are classified as sporadic, meaning they appear without a clear genetic link. The remaining cases are familial, inherited through gene mutations passed from parent to child. For the majority of people, ALS likely results from a combination of genetic susceptibility, environmental exposures, and biological processes that together trigger the death of motor neurons.
Sporadic vs. Familial ALS
The traditional estimate holds that about 10% of ALS cases are familial and 90% sporadic, but more recent population-level research suggests the true familial rate is higher. A study tracking ALS cases in Ireland over two decades found that when researchers applied strict diagnostic criteria, the familial rate was about 11%. But when they accounted for related conditions within extended families, that number climbed to around 30%. Many people carrying a genetic predisposition simply have no known family history because the gene may not have caused disease in previous generations.
At least 30 genes have been linked to familial ALS. The most common genetic cause is a repeat expansion in the C9orf72 gene, which also contributes to a related condition called frontotemporal dementia. This mutation causes cells to produce abnormal proteins that accumulate and interfere with normal brain function. It is particularly active in microglia, the brain’s immune cells, which may help explain the inflammatory damage seen in ALS.
What Happens Inside Motor Neurons
Regardless of whether ALS is genetic or sporadic, the disease converges on a shared biological problem. In about 97% of patients, a protein called TDP-43 misfolds and clumps together inside motor neurons. Normally, TDP-43 stays in the nucleus of a cell and helps manage RNA, which carries instructions for building other proteins. In ALS, TDP-43 leaks out of the nucleus into the surrounding cell fluid, where it folds incorrectly, fragments, and forms toxic clusters. Gene mutations and environmental stressors can both promote this mislocalization. Once the clumps form, they disrupt normal cell operations and eventually kill the neuron.
A second key mechanism is excitotoxicity. Motor neurons communicate using a chemical signal called glutamate, and in ALS, excess glutamate overstimulates neurons to the point of damage. When too much glutamate floods the space around a neuron, it activates receptors outside the normal communication zones, triggering cell-death signaling. This was one of the earliest disease mechanisms identified in ALS and remains a target for treatment.
Environmental and Occupational Exposures
Several environmental factors have been linked to increased ALS risk, though none on its own is considered a definitive cause. A case-control study examining residential exposure to air toxicants found that people in the highest exposure quartile for vinyl chloride had six times the odds of developing ALS compared to those with the lowest exposure. Elevated risk was also associated with higher exposure to cyanide compounds, cadmium, carbon disulfide, and chlorinated solvents. Occupational exposure to insecticides, metals, and industrial solvents has shown similar associations across multiple studies.
Military service is a recognized risk factor. A CDC study of veterans deployed in post-9/11 conflicts found an ALS prevalence of 19.7 per 100,000 over 14 years. Air Force personnel had the highest prevalence at 33.2 per 100,000, and tactical operations officers had 2.2 times the odds of developing ALS compared to administrative officers. The suspected contributors include exposure to electromagnetic fields, high-intensity radar, jet engine exhaust, and other occupational hazards specific to those roles.
Smoking, Head Injuries, and Other Risk Factors
Smoking is one of the more consistently supported lifestyle risk factors. A large European study found that people in the highest category of lifetime cigarette consumption had a 26% greater risk of ALS compared to people who never smoked. Current smokers faced roughly 47% higher odds, and some analyses have reported nearly double the risk of dying from ALS among active smokers at the time of study enrollment. The risk appears to increase with the total amount smoked over a lifetime.
Head injuries, particularly repeated ones, have also drawn attention. Data from the National ALS Registry found that people who sustained head injuries between ages 18 and 30 had an increased risk of being diagnosed with ALS before age 60. Those with five or more head injuries, and those injured during childhood, showed a higher risk as well. Notably, a separate military study found that traumatic brain injury on its own, when adjusted for other factors, was not independently associated with ALS diagnosis, suggesting the relationship may depend on timing, frequency, or interaction with other exposures.
Who Gets ALS
ALS is most common in older adults. The highest prevalence, about 20.2 cases per 100,000 people, occurs in the 70 to 79 age group. It is rare before age 40, with a prevalence of just 0.5 per 100,000 in the 18 to 39 range. Men develop ALS more often than women at a ratio of roughly 1.6 to 1, though the reasons for this disparity are not fully understood.
How ALS First Appears
The disease starts in one of two general patterns. About three-quarters of cases begin with limb onset, where the first symptoms show up in the arms or legs. This can look like muscle cramps, twitching, weakness in the hands or feet, loss of grip strength, or difficulty with fine motor tasks like buttoning a shirt. Some people first notice tripping, stumbling, or problems with balance.
The remaining quarter begin with bulbar onset, where the muscles of the face, throat, and tongue are affected first. Early signs include slurred speech, difficulty chewing or swallowing, excessive choking, and changes in voice quality such as hoarseness or reduced volume. Bulbar onset ALS tends to progress faster than limb onset, though the pace varies from person to person. In both forms, the disease eventually spreads to affect motor neurons throughout the body.