Amyotrophic lateral sclerosis (ALS) has no single cause. In about 90% of cases, the disease appears without any family history, and researchers still cannot point to one definitive trigger. What they have identified is a web of genetic, cellular, and environmental factors that converge to destroy motor neurons, the nerve cells that control voluntary movement. Understanding these factors helps explain why the disease develops and who faces the highest risk.
Familial vs. Sporadic ALS
ALS splits into two broad categories. Familial ALS, where other family members have had the disease, accounts for roughly 10% to 20% of cases depending on how strictly researchers define “family history.” When broader neuropsychiatric conditions within families are included, that figure can climb to 30%. The remaining cases are classified as sporadic, meaning no clear inherited pattern is present.
That distinction is less clean than it sounds. Many people with sporadic ALS carry gene variants also found in familial cases. The difference often comes down to whether those variants are strong enough on their own to cause disease or whether they need additional triggers, like environmental exposures or accumulated cellular damage, to push motor neurons past the breaking point.
Genes Linked to ALS
More than 30 genes have been tied to ALS, but a handful dominate. The most common is a mutation in the C9orf72 gene, which shows up in roughly 40% of familial cases and about 7% of sporadic ones. This mutation produces an abnormal repeat in the DNA sequence that leads to toxic protein buildup inside neurons.
The second most recognized gene is SOD1, found in about 12% of familial and 2% of sporadic cases. SOD1 normally produces an enzyme that neutralizes harmful molecules called free radicals. When the gene is mutated, this protective function breaks down, and the misfolded proteins themselves become toxic to motor neurons. Two other genes, TARDBP and FUS, each account for around 4% of familial and 1% of sporadic cases. Both are involved in how cells process RNA, the molecular instructions used to build proteins.
Having one of these mutations doesn’t guarantee you’ll develop ALS. Many carriers never show symptoms, a phenomenon called reduced penetrance. This is part of what makes genetic counseling for ALS families so complicated: the same variant can cause aggressive disease in one person and remain silent in another.
How Motor Neurons Die
Regardless of whether the trigger is genetic or environmental, the end result in ALS is always the same: motor neurons in the brain and spinal cord progressively break down. Several interconnected processes drive this destruction.
Glutamate Overload
Glutamate is the brain’s primary excitatory chemical messenger. In a healthy nervous system, it fires signals between neurons and is quickly cleared away. In ALS, glutamate accumulates in the spaces between cells, overstimulating motor neurons. This flood of signaling forces too much calcium into the cell, which activates enzymes that chew apart the cell’s internal structures. One critical target is the machinery that keeps mitochondria, the cell’s energy factories, fused together and functional. Once mitochondria fragment, the neuron loses its energy supply and begins to die.
Mitochondrial Failure and Oxidative Stress
Mitochondria do more than generate energy. They also manage the balance of reactive oxygen species, which are chemically aggressive molecules produced as a byproduct of normal metabolism. In ALS, mitochondria become damaged and leak excess electrons, generating a surge of these reactive molecules. This is oxidative stress, and it corrodes proteins, membranes, and DNA inside the cell.
Brain imaging studies in people with ALS have shown that the severity of this oxidative damage in the motor cortex correlates directly with how advanced the disease is. The worse the mitochondrial dysfunction, the faster the degeneration progresses. This makes oxidative stress not just a bystander but an active driver of the disease.
Inflammation From Support Cells
Motor neurons don’t exist in isolation. They’re surrounded by support cells, including microglia (the brain’s immune cells) and astrocytes (cells that maintain the chemical environment around neurons). In ALS, these support cells shift from protective to destructive.
Microglia normally respond to injury by cleaning up debris and releasing signals that promote repair. In ALS, they become chronically activated and begin pumping out inflammatory molecules and additional reactive oxygen species. This creates a toxic feedback loop: damaged neurons trigger inflammation, and inflammation accelerates neuronal damage. Astrocytes join in, amplifying the inflammatory environment. In mouse models carrying ALS-linked mutations, microglia have been shown to directly promote motor neuron death through inflammatory signaling pathways. The disease, in other words, is not just a problem of neurons. It’s a problem of the entire cellular neighborhood.
Environmental and Occupational Risk Factors
For the majority of people with sporadic ALS, genetics alone can’t explain the disease. Environmental exposures appear to play a significant role, though pinning down exactly which ones has proven difficult.
Lead exposure is one of the more consistent findings. A case-control study examining lifetime neurotoxin exposure found that ALS was associated with both blood and bone lead levels, as well as occupational lead exposure. The bone measurement is particularly telling because it reflects cumulative exposure over decades, not just recent contact. Mercury, solvents, and pesticides have also been investigated, though results are less consistent.
Military service carries a notably elevated risk. A large prospective study found that men who served in the military had a 53% higher rate of ALS mortality compared to men who never served. The increase appeared across nearly every branch: Army, Navy, Air Force, and Coast Guard all showed elevated rates. Potential explanations include exposure to aerosolized lead from weapons fire, the insect repellent DEET, other industrial chemicals common in military settings, traumatic injuries, and intense sustained physical exertion. No single exposure has been isolated as the cause, suggesting that military service creates a combination of risk factors.
Who Is Most at Risk
ALS most commonly strikes between the ages of 40 and 70, with an average diagnosis age of 55. It is 20% more common in men than women, though that gap narrows with age, suggesting that hormonal or lifestyle factors may play a role earlier in life.
Beyond age and sex, certain populations face disproportionate risk. People of European descent have higher rates of ALS than other ethnic groups, though it’s unclear how much of this reflects genetic susceptibility versus differences in diagnosis and reporting. A family history of ALS or frontotemporal dementia (a related neurodegenerative condition) raises risk substantially, particularly if the C9orf72 mutation is present in the family, since that same gene variant accounts for about 25% of familial frontotemporal dementia cases as well.
Why a Single Cause Remains Elusive
One of the most frustrating aspects of ALS research is that the disease likely requires multiple hits to develop. A person might carry a genetic risk variant, encounter occupational toxins, experience mitochondrial wear from aging, and develop chronic low-grade neuroinflammation. Individually, none of these may be enough. Together, they overwhelm the motor neuron’s ability to survive.
This “multiple hit” model explains why ALS can run in families yet skip generations, why identical twins don’t always share the diagnosis, and why most people exposed to the same environmental risks never develop the disease. It also explains why, after more than 150 years of study, no single preventive strategy exists. The cause of ALS is not one thing. It is a convergence of vulnerabilities, each contributing a piece to a collapse that, once started, the body cannot reverse.