ALS (amyotrophic lateral sclerosis) has no single known cause. In about 90% to 95% of cases, the disease appears without any family history or clear trigger, a form called sporadic ALS. The remaining 5% to 10% of cases are familial, meaning a genetic mutation was inherited from a parent. Even in sporadic cases, researchers have identified a web of biological processes that converge to kill motor neurons, the cells that control voluntary movement. What follows is what science currently understands about why ALS happens.
Genetics and Inherited Risk
Four genes account for the majority of known ALS-linked mutations: C9orf72, SOD1, TARDBP, and FUS. Which gene matters most depends on ancestry. In people of European descent, C9orf72 mutations are the leading genetic cause, found in roughly 60% of familial cases and about 8% of sporadic ones. In Asian populations, SOD1 mutations dominate, appearing in around 40% of familial cases and 3% of sporadic cases, with FUS and TARDBP following behind.
Having one of these mutations doesn’t guarantee someone will develop ALS. Penetrance, the likelihood a mutation actually triggers disease, varies by gene and even by the specific change within a gene. Some people carry a known ALS mutation and never develop symptoms. This suggests that genes load the gun, but other factors pull the trigger.
Protein Misfolding and TDP-43
A protein called TDP-43 is at the center of most ALS cases. In healthy cells, TDP-43 sits inside the nucleus, where it helps manage RNA, the molecular instructions cells use to build other proteins. In ALS, TDP-43 gets displaced from the nucleus and clumps together in the surrounding cell fluid (the cytoplasm). These clumps become chemically altered, making them resistant to the cell’s normal cleanup machinery.
This creates a double problem. First, the nucleus loses TDP-43 and its RNA-management abilities, disrupting the cell’s ability to function. Second, the toxic clumps accumulate and may actively damage the cell. Researchers are still debating which of these two effects, the loss of normal function or the gain of toxic function, does more harm. It may be both. Notably, this clumping pattern spreads over time from the motor neurons in the spinal cord and brain outward to other brain regions, and this spread tracks closely with how ALS symptoms progressively worsen.
Excitotoxicity: Nerve Cells Stimulated to Death
Glutamate is the main chemical signal that excites nerve cells. After one neuron fires a glutamate signal, nearby cells are supposed to quickly absorb the excess. In ALS, that cleanup system is impaired. Glutamate lingers in the space between neurons and overstimulates receptors that were only meant to handle brief bursts of activity. This prolonged stimulation floods motor neurons with calcium, triggering internal damage cascades that eventually kill the cell.
This process, called excitotoxicity, was one of the earliest disease mechanisms identified in ALS. It’s the reason riluzole, the first drug approved for the disease, works the way it does: by reducing glutamate signaling. Motor neurons carrying SOD1 mutations appear especially vulnerable to this kind of overstimulation, but the glutamate recycling system is disrupted broadly across ALS patients regardless of their genetic profile.
Mitochondrial Damage and Oxidative Stress
Mitochondria are the structures inside cells that produce energy. In ALS, mitochondria malfunction in multiple ways: their membranes lose integrity, their energy output drops, and they begin producing excess reactive oxygen species (free radicals). These free radicals are chemically unstable molecules that damage proteins, fats, and DNA throughout the cell.
This creates a vicious cycle. Damaged mitochondria produce more free radicals, which damage mitochondria further. Oxidative stress also warps the shape of normal proteins, potentially feeding into the same protein-clumping problem seen with TDP-43. Studies of spinal cord tissue, brain tissue, and blood cells from ALS patients all show reduced activity in the mitochondrial machinery responsible for generating energy. The motor neurons that ALS targets are especially large cells with high energy demands, which may help explain why they fail first when the energy supply breaks down.
The Brain’s Immune System Turns Harmful
The brain and spinal cord have their own resident immune cells called microglia. Early in ALS, microglia actually try to help. They adopt a protective state, releasing anti-inflammatory signals and growth factors that support neuron survival. But as the disease progresses, they shift into an aggressive, inflammatory state, releasing toxic chemicals and free radicals that accelerate motor neuron death.
This shift is driven in part by TDP-43 itself, which activates a master inflammation switch inside cells. So the same protein clumping that directly harms motor neurons also recruits the immune system to compound the damage. In mouse models of ALS, disrupting the communication between neurons and microglia led to faster disease progression and shorter survival, highlighting how important this immune relationship is to the pace of the disease.
Environmental Exposures
Most sporadic ALS cases have no identified genetic mutation, which has pushed researchers to look at environmental triggers. Military service is one of the most studied risk factors. CDC data on veterans deployed after 9/11 found an ALS prevalence of 19.7 per 100,000 over 14 years, with Air Force personnel showing the highest rates (33.2 per 100,000). Tactical operations officers had 2.2 times the odds of developing ALS compared to administrators, pointing to occupational exposures like electromagnetic fields, radar waves, jet emissions, and diesel exhaust as potential contributors.
A naturally occurring toxin called BMAA, produced by blue-green algae (cyanobacteria), has also drawn attention. BMAA was found in postmortem brain tissue from ALS patients, and it produced motor-system disease when given to monkeys in lab studies. The toxin appears to cause harm through multiple routes at once: it overstimulates glutamate receptors (mimicking excitotoxicity), it depletes the cell’s antioxidant defenses (worsening oxidative stress), and it can get mistakenly built into new proteins in place of normal amino acids, promoting the kind of protein misfolding central to ALS. BMAA also concentrates as it moves up the food chain; one study documented a 10,000-fold increase in free BMAA from cyanobacteria to the animals that eventually consumed them.
Other environmental factors under investigation include pesticide exposure, heavy metals like lead and mercury, and intense physical activity, though none of these have been confirmed as definitive causes.
Who Is Most Affected
ALS is not evenly distributed across the population. Men develop the disease about 1.6 times more often than women, though this gap narrows in older age groups. The disease is rare in people under 40, with a prevalence of just 0.5 per 100,000 in the 18-to-39 age group. Risk climbs sharply with age, peaking at 20.2 per 100,000 among people in their 70s.
Why men are affected more frequently remains unclear. Hormonal differences, occupational exposures, and genetic factors on the X chromosome have all been proposed, but none fully explain the gap. The age pattern fits with the idea that ALS results from accumulated cellular damage over a lifetime, with motor neurons eventually crossing a threshold where they can no longer compensate.
Why There’s No Single Cause
What makes ALS so difficult to understand, and to treat, is that these mechanisms don’t operate independently. Protein misfolding triggers inflammation. Inflammation generates oxidative stress. Oxidative stress damages mitochondria. Mitochondrial failure produces more free radicals, which warp more proteins. Excitotoxicity floods cells that are already struggling to produce enough energy to survive. Each pathway feeds the others, creating a self-reinforcing collapse of motor neuron health.
In familial cases, a genetic mutation may kick off this cascade earlier or more aggressively. In sporadic cases, some combination of environmental exposures, aging, and possibly unidentified genetic susceptibilities may slowly push motor neurons past the point of no return. The disease likely begins years before symptoms appear, during a long silent phase when compensatory mechanisms still hold. By the time muscle weakness or speech changes become noticeable, significant motor neuron loss has already occurred.