Lou Gehrig’s disease, known medically as amyotrophic lateral sclerosis (ALS), has no single known cause. For the vast majority of people diagnosed, roughly 90% of cases, the disease appears without any family history or clear genetic link. The remaining 5-10% of cases run in families. What researchers do understand is a growing web of genetic, environmental, and cellular factors that converge to kill motor neurons, the nerve cells that control voluntary movement.
Genetic Mutations Behind Familial ALS
When ALS runs in families, specific gene mutations are usually involved. The most common is a repeat expansion in a gene called C9orf72, which accounts for 30-50% of all familial cases and about 20-30% of those where a family connection is known. It also shows up in roughly 5% of people with no family history of the disease, blurring the line between inherited and seemingly random cases.
Another well-studied mutation involves the SOD1 gene, which normally helps cells neutralize damaging molecules called free radicals. When SOD1 is mutated, it appears to do the opposite: zinc separates from the enzyme, ramping up the production of toxic molecules like hydrogen peroxide and peroxynitrite inside motor neurons. More than 30 genes have now been linked to ALS, but C9orf72 and SOD1 remain the most significant.
What Happens Inside Motor Neurons
Regardless of whether ALS is inherited or sporadic, 97% of patients share one striking feature: clumps of a misfolded protein called TDP-43 accumulate in their affected nerve cells. Under normal circumstances, TDP-43 helps manage RNA, the molecular messenger that carries instructions from DNA to the cell’s protein-building machinery. When TDP-43 misfolds, two things go wrong simultaneously. First, it can no longer do its job of transporting RNA properly, a loss of function. Second, the misfolded proteins clump together and recruit healthy TDP-43 molecules into the aggregates, creating a toxic snowball effect. This dual problem, losing a critical function while gaining a toxic one, is now considered central to how ALS destroys motor neurons.
These protein clumps trigger a cascade of damage. Mitochondria, the structures that generate energy inside cells, become misshapen and stop producing adequate fuel. They also lose their ability to manage calcium levels, which is essential for nerve signaling. The result is a buildup of reactive oxygen species (free radicals) that damage proteins, membranes, and DNA. Motor neurons are especially vulnerable because they are large cells with enormous energy demands, and mitochondria lack catalase, one of the key enzymes that normally neutralizes hydrogen peroxide.
Glutamate and Overstimulation
Glutamate is the brain’s primary excitatory chemical messenger. In ALS, several processes conspire to flood motor neurons with too much of it. Astrocytes, the support cells surrounding neurons, lose their ability to clear glutamate from the gaps between nerve cells. At the same time, the presynaptic neuron releases more glutamate than normal, and the inhibitory neurons that would normally dial signaling down become less effective.
The excess glutamate forces calcium to pour into the motor neuron through specialized receptors. This calcium overload overwhelms the mitochondria, which are already compromised, pushing them to produce even more free radicals. The cycle feeds on itself: damaged mitochondria produce less energy and more toxic byproducts, further weakening a neuron that’s already under siege. This process, called excitotoxicity, is one reason ALS progresses so relentlessly once it begins. It’s also the target of riluzole, the first drug approved for ALS, which works by reducing glutamate signaling.
Environmental and Occupational Risk Factors
Since 90% of ALS cases lack a clear genetic cause, researchers have focused heavily on environmental exposures. Neurotoxic pesticides show a consistent positive association with sporadic ALS in population-level studies, though proving direct causation remains difficult. Heavy metals and industrial chemicals are also under investigation.
One of the more striking environmental leads involves BMAA, a toxin produced by 95% of cyanobacteria (blue-green algae) genera tested. The connection first emerged in Guam, where the indigenous Chamorro people developed a condition resembling ALS at 50 to 100 times the worldwide rate. Researchers traced the exposure to cycad seeds, whose roots harbor BMAA-producing cyanobacteria. When scientists later tested brain tissue from ALS patients in North America, they found high BMAA concentrations, while age-matched healthy controls had none. In New Hampshire, people living within half a mile of lakes with a history of cyanobacterial blooms had 2.3 times the expected ALS risk, and residents around one particular lake had up to 25 times the expected rate. The evidence is compelling but not yet conclusive, and large-scale epidemiological studies are still needed.
Military veterans face elevated risk as well. A large study following participants in the American Cancer Society’s cohort found that people who reported any military service were 1.5 times more likely to die of ALS than those with no service history, even after adjusting for age, smoking, education, alcohol use, pesticide exposure, and occupation. The specific military exposures responsible remain unclear, though chemical and biological warfare agents, certain vaccines, and various occupational hazards during service have all been proposed.
Who Gets ALS
ALS is most commonly diagnosed around age 65, with about 80% of cases occurring between ages 50 and 79. The disease peaks in the 70-79 age group. Men are affected slightly more often than women, making up about 55% of cases, which translates to roughly 1.25 times the risk. Cases have been diagnosed as young as 18 and as old as 96, but onset before 45 is uncommon. The higher rate in men narrows with age, and by the oldest age groups the gap nearly disappears, suggesting that hormonal or occupational factors may play a role in the disparity.
Why Diagnosis Takes Time
ALS is diagnosed primarily through clinical observation and electrical testing of nerve and muscle function, not a single blood test or brain scan. A diagnosis requires evidence that both upper motor neurons (in the brain) and lower motor neurons (in the spinal cord) are deteriorating, and that the damage is spreading across multiple body regions. Because early symptoms like muscle twitching, weakness in one hand, or slurred speech overlap with many other conditions, the average time from first symptoms to confirmed diagnosis is often 12 months or longer. Doctors must also rule out other causes, making the process feel frustratingly slow for patients and families.
The Bigger Picture
ALS almost certainly results from multiple hits rather than one cause. A person might carry a genetic vulnerability that remains harmless for decades until an environmental exposure, aging-related cellular stress, or accumulated protein damage tips the balance. The convergence of misfolded TDP-43, mitochondrial failure, glutamate toxicity, and oxidative stress in nearly all cases, regardless of the initial trigger, suggests these pathways reinforce each other in a vicious cycle. Understanding how to interrupt that cycle at any point is the driving question behind current treatment efforts.