ALS (amyotrophic lateral sclerosis) has no single cause. In most cases, the disease develops from a combination of genetic vulnerability and environmental exposures that together damage motor neurons, the nerve cells controlling voluntary movement. About 5 to 10 percent of cases run in families, while the remaining 90 to 95 percent appear without any family history. Even in those “sporadic” cases, subtle genetic factors and environmental triggers likely work together behind the scenes.
What Happens Inside the Body
ALS kills motor neurons in the brain and spinal cord, which means the muscles they control gradually weaken and waste away. The underlying biology involves several overlapping problems, not just one broken switch.
The most consistent finding across nearly all ALS cases is the buildup of a protein called TDP-43. This protein normally works inside the cell’s nucleus, helping manage genetic instructions. In ALS, TDP-43 gets displaced from the nucleus into the surrounding cell fluid, where it misfolds and clumps into toxic deposits. These clumps interfere with the cell’s normal operations and eventually kill it. Preventing this misfolding or helping cells clear these clumps is considered one of the most important therapeutic targets.
Motor neurons are also unusually sensitive to a chemical messenger called glutamate. Glutamate is the brain’s main excitatory signal, but in ALS, excess glutamate overstimulates motor neurons to the point of damage. This process, called excitotoxicity, is one reason motor neurons die while other cell types survive. On top of that, mitochondria (the structures that produce energy inside cells) malfunction early in the disease. Damaged mitochondria produce harmful molecules called reactive oxygen species, starve the cell of energy, and disrupt its ability to manage calcium levels. This mitochondrial breakdown is one of the earliest detectable events in ALS, sometimes appearing before symptoms do.
The Role of Genetics
In roughly 15 percent of all ALS cases, doctors can identify a specific gene mutation driving the disease. The most common culprit is a mutation in a gene called C9orf72, which accounts for 7 to 41 percent of familial cases (depending on the population studied) and about 5 percent of cases with no family history. Several other genes, including SOD1, FUS, and TARDBP, also contribute, though each explains a smaller slice of cases.
Having a family member with ALS increases your risk, but it doesn’t guarantee you’ll develop the disease. Many people carry ALS-linked mutations and never become ill, which tells researchers that genes alone aren’t usually enough. Something else, whether an environmental exposure, a lifetime of cellular stress, or simple chance, tips the balance. Even in sporadic ALS, common genetic variations may make motor neurons slightly more vulnerable without being powerful enough to cause disease on their own.
Environmental Exposures Linked to ALS
Researchers have identified several environmental factors that appear to raise ALS risk, though none of them cause the disease in every exposed person.
- Lead and pesticides. A CDC-backed case-control study using the National ALS Registry found increased ALS risk among people with occupational exposure to lead and agricultural chemicals. These exposures are thought to raise oxidative stress, the same kind of cellular damage seen in ALS motor neurons.
- Cyanobacterial toxins. A compound called L-BMAA, produced by blue-green algae (cyanobacteria), has been found in the brain tissue of ALS patients at autopsy. In laboratory studies, L-BMAA exposure causes TDP-43 to move out of the nucleus and form the same toxic clumps seen in ALS. The link was first proposed after researchers noticed high ALS rates on the island of Guam, where people consumed cycad seeds containing L-BMAA. Cell studies show the toxin has a synergistic effect in people who already carry ALS-related mutations, amplifying damage beyond what either factor causes alone.
- Head injuries. Data from over 3,400 people in the National ALS Registry showed that head injuries sustained between ages 18 and 30 increased the risk of being diagnosed with ALS before age 60. Five or more head injuries, or injuries during childhood, raised the risk further.
Who Is at Higher Risk
ALS can strike anyone, but certain groups face higher odds. Men develop ALS more often than women, though the gap narrows with age. The disease is most commonly diagnosed between the mid-50s and mid-70s, though younger onset does occur.
Military veterans are a notably higher-risk group. A large population-based study found that men who served in the military had roughly a 23 percent higher ALS death rate compared to men who never served. A separate analysis from the Cancer Prevention Study 2 put the increased risk even higher, at 53 percent. The risk was most pronounced among those who served during World War II, with a 47 percent increase, and early reports on Gulf War veterans suggested they were about twice as likely to develop ALS as nondeployed veterans. The reasons aren’t fully clear, but likely involve a combination of physical exertion, toxic exposures (such as heavy metals, fuel fumes, or pesticides), and possibly head trauma.
Global incidence varies significantly by region, ranging from about 0.26 per 100,000 people per year in Ecuador to as high as 23.46 per 100,000 in Japan. Some of this variation reflects differences in genetic background, some reflects diagnostic access, and some may point to environmental factors that differ by geography.
How ALS Is Diagnosed
There is no single blood test or scan that confirms ALS. Diagnosis is clinical, meaning neurologists piece it together by observing a pattern of progressive muscle weakness affecting both upper and lower motor neurons, while ruling out other conditions that can mimic those symptoms.
The current standard is the Gold Coast Criteria, introduced in 2020 to simplify and speed up diagnosis. These criteria have a sensitivity of about 94 percent, meaning they correctly identify ALS in the vast majority of people who have it. Earlier diagnostic frameworks were more conservative and often missed the disease in its initial stages, delaying treatment. Even with the Gold Coast Criteria, reaching a diagnosis typically takes months because doctors need to document progression over time and exclude lookalike conditions through imaging, nerve conduction tests, and blood work.
Why Most Cases Have No Clear Explanation
The honest answer to “how do you get ALS” is that, for most people, no single cause can be identified. The current scientific understanding points to a threshold model: genetic vulnerabilities, environmental insults, aging, and cellular stress accumulate over a lifetime until motor neurons can no longer cope. Some people reach that threshold because of a powerful gene mutation. Others may reach it through decades of low-level exposures, repeated injuries, or simply biological bad luck. This is part of what makes ALS so difficult to predict or prevent. Two people with identical exposures can have completely different outcomes, because their underlying genetic resilience differs in ways that are still being mapped.