Most people who develop ALS, also known as Lou Gehrig’s disease, get it without any clear cause. About 90% of cases are considered sporadic, meaning the disease appears at random in people with no family history and no obvious explanation. The remaining 10% are familial, passed down through inherited gene mutations. Even after decades of research, the full picture of what triggers ALS remains incomplete, but scientists have identified several genetic, biological, and environmental factors that raise the risk.
What Happens Inside the Body
ALS destroys motor neurons, the nerve cells in the brain and spinal cord that control voluntary muscle movement. As these neurons die, the muscles they control weaken, waste away, and eventually stop working. The disease is progressive, meaning it gets worse over time, and it affects everything from walking and gripping objects to speaking and swallowing.
In about 97% of ALS patients, regardless of whether their case is sporadic or inherited, researchers find the same abnormality in affected tissue: a protein called TDP-43 has moved out of its normal position inside the cell nucleus and clumped together in the surrounding fluid. TDP-43 normally helps process RNA, the molecular instructions cells use to build proteins. When it misfolds and accumulates in the wrong part of the cell, it stops doing its job and becomes toxic. The cell’s cleanup systems can’t keep up with the buildup, and motor neurons gradually die.
There’s also a chemical component. Glutamate, the brain’s main excitatory signaling molecule, builds up to excessive levels around motor neurons in ALS. Normally, nearby support cells absorb glutamate after it’s been used, but in ALS this recycling system breaks down. The result is chronic overstimulation: motor neurons fire too much, become hyperexcitable, and trigger internal damage pathways that lead to cell death. This process, called excitotoxicity, is one reason the disease progresses relentlessly once it starts.
The Genetic Side
In the 10% of cases that run in families, specific gene mutations are responsible. The best-studied ones involve four genes: C9orf72, SOD1, TARDBP, and FUS. A mutation in C9orf72, which produces an abnormal repeat expansion in the DNA, is the most common genetic cause in people of European descent. SOD1 mutations were the first discovered and remain significant across populations worldwide.
These mutations don’t all cause damage the same way. Some lead directly to the TDP-43 protein buildup described above. Others impair the cell’s ability to process RNA or break down waste proteins. The C9orf72 mutation, for example, produces toxic repeat sequences that jam up RNA processing machinery inside the cell and also triggers TDP-43 accumulation. Having one of these mutations doesn’t guarantee you’ll develop ALS, but it dramatically increases the odds, and symptoms tend to appear earlier in life compared to sporadic cases.
Genetic testing can identify these mutations in people with a family history. But here’s what makes ALS genetics complicated: some people with sporadic ALS, those with no family history at all, also carry mutations in these same genes. The line between “inherited” and “random” is blurrier than the 90/10 split suggests.
Environmental and Occupational Risk Factors
For the vast majority of people with ALS who have no genetic explanation, researchers have been searching for environmental triggers. Several have emerged as likely contributors, though none has been proven to cause the disease on its own.
Exposure to heavy metals is one of the most studied links. Lead, mercury, cadmium, and zinc have all been found at elevated levels in the blood or spinal fluid of ALS patients compared to healthy controls. Lead is a well-established neurotoxin, and higher concentrations have been measured in ALS patients repeatedly. Zinc exposure has been shown in laboratory studies to cause oxidative damage specifically in spinal cord motor neurons, reducing their survival. Cadmium, a contaminant in cigarettes and certain industrial settings, also has established neurotoxic effects.
Pesticide exposure and agricultural work have been associated with higher ALS rates in multiple studies. So has smoking, intense physical activity, and physical trauma, though the evidence for each of these varies in strength.
One of the more striking environmental findings involves a toxin called BMAA, produced by blue-green algae (cyanobacteria). The strongest evidence comes from the Chamorro people of Guam, who historically had extraordinarily high rates of ALS. Researchers traced this to chronic dietary exposure to BMAA through contaminated cycad flour and flying foxes that fed on cycad seeds. BMAA was found in the brain tissue of Chamorro villagers who died of the disease but was largely absent in healthy individuals from other populations. Similar clusters of ALS have been identified near cyanobacterial blooms in France, where the local population consumed large quantities of shellfish year-round, and BMAA was confirmed in the mussels and oysters. Proximity to cyanobacterial blooms has been correlated with higher ALS rates in several additional studies.
Military Service and ALS
Military veterans face a meaningfully higher risk of developing ALS than the general population. A pooled analysis of nine studies found that military service was associated with roughly a 1.3-fold increased risk. The link appears strongest among veterans of World War II and the Gulf War. The exact reason isn’t settled, but researchers suspect a combination of factors: exposure to chemicals and heavy metals, intense physical exertion, traumatic injuries, and potentially other service-related environmental exposures. The U.S. Department of Veterans Affairs recognizes ALS as a service-connected disease for all veterans with 90 days or more of continuously active service.
Who Gets ALS
Globally, about 58,000 people are diagnosed with ALS each year, with an incidence of roughly 0.78 per 100,000 people. That makes it relatively rare, but not as rare as many people assume. At any given time, an estimated 331,000 people worldwide are living with the disease.
ALS most commonly appears between ages 55 and 75, and men are affected slightly more often than women. About two-thirds of cases begin in the limbs, typically with weakness in a hand, arm, or leg. The remaining third start with bulbar symptoms, meaning difficulty speaking or swallowing. Limb-onset and bulbar-onset ALS progress somewhat differently, but both forms involve the same underlying motor neuron loss.
How ALS Is Diagnosed
There is no single blood test or scan that confirms ALS. Diagnosis relies on clinical evaluation, and the process often takes months because doctors must rule out other conditions that can mimic it. The current standard, known as the Gold Coast criteria, requires three things: progressive loss of motor function that was previously normal, evidence of both upper and lower motor neuron damage in at least one body region, and test results that exclude other explanations.
Upper motor neuron damage shows up as abnormally brisk reflexes, stiffness, or clumsy movements. Lower motor neuron damage appears as muscle weakness, visible wasting, or characteristic electrical patterns on an EMG test (a needle-based test that measures muscle activity). Doctors may also order MRI scans, blood work, and spinal fluid analysis to cross other diseases off the list. The process can be frustrating, but the criteria exist to prevent misdiagnosis of treatable conditions.
Why Most Cases Remain Unexplained
The honest answer to “how do you get ALS” is that, for most people, we don’t fully know. The leading theory is that ALS results from a combination of genetic susceptibility and environmental exposures that together push motor neurons past a tipping point. Someone might carry gene variants that make their motor neurons slightly more vulnerable, then encounter environmental stressors over a lifetime, whether toxins, physical stress, or something not yet identified, that trigger the disease process. This “multiple hit” model would explain why ALS appears random in most cases: different people reach the threshold through different combinations of risk factors, none of which is sufficient on its own.
What researchers do know is that once the process begins, the common pathway in nearly all cases converges on the same protein abnormality and the same pattern of motor neuron death. Understanding why that process starts in any given person remains one of the central unsolved problems in neuroscience.