Approximately 5 to 10 percent of amyotrophic lateral sclerosis (ALS) cases are familial, meaning that they are inherited and linked to a known genetic mutation. Within familial ALS (fALS), about two-thirds have an identifiable genetic cause, most commonly from mutations in these genes:

• C9orf72, which accounts for nearly 33 percent of identified fALS cases;
• SOD1, which accounts for about 15 percent of fALS cases; and
• TARDBP and FUS, which each account for about 3 to 4 percent of fALS cases 

“So far, we have identified about 30 genes that are linked to ALS, now that technology has advanced to the point where we can sequence whole genomes and do the statistical analysis necessary to identify changes in the DNA,” says Terry Heiman-Patterson, MD, professor of neurology at the Lewis Katz School of Medicine at Temple University and director of the Temple MDA/ALS Center of Hope. “They point to different pathways in the body that, when damaged, can lead to motor neuron deterioration and loss.” 

While a small percentage of people with non-familial ALS also have been found to have mutations in these genes, the majority of people with the disease, like influencer Brooke Eby, have what is known as “sporadic” ALS—that is, there are no known genetic underpinnings to their condition. 

“But the overlap between familial cases with genetic changes and sporadic ALS cases with no known genetic abnormalities suggests that these pathways are relevant to both sporadic and familial ALS, which gives us clues as to pathways to target for treatment,” Dr. Heiman-Patterson says. “Even in people without a family history, we’ve identified at least 10 of these pathways.”

Eva Feldman, MD, PhD, an endowed professor of neurology and director of the ALS Center of Excellence at Michigan Neuroscience Institute of the University of Michigan, is investigating what’s known as the “ALS exposome”—the environmental exposures a person with ALS has in their life until they develop the disorder. 

“That includes what you put on your skin, what you breathe, what you eat and drink, and so on,” she says. “And we have shown that in the blood and urine of our patients with ALS, there are significantly increased levels of legacy pesticides, selective persistent organic pollutants, and metals.”

But that is just an association. To try to determine if and how these exposures possibly contribute to the development of ALS, Dr. Feldman and her colleagues are studying the epigenome of ALS patients—the collection of chemical changes to their DNA that modify how it functions without changing its underlying sequence. 

“Our early research has found that there are clear epigenetic markers of these specific pesticides and pollutants altering DNA function, causing an increase in what is known as your ‘GrimAge,’” she explains.

GrimAge is a measure of aging based on epigenetic changes that calculates whether an individual is biologically “older” or “younger” than their chronological age. In a study published in November 2024, Dr. Feldman reported that people with ALS have a significantly higher GrimAge compared to normal controls. 

“The next step is to understand what exact genes are being marked by these epigenetic changes, what pathways are becoming more dysfunctional, and how specific exposures, such as to organochlorine pesticides, affects these pathways,” she says.

New research from Dr. Feldman’s group, published in April 2025, also suggests that sporadic ALS may be linked to underlying immune dysfunction. It has long been thought that the immune abnormalities found in the central nervous system of people with ALS was a sign of the immune system reacting to neurodegenerative changes. But this research suggests that it could be the other way around—that these immune system changes could represent a causative role in the disease, rather than just a reactive response.

“In patients with sporadic ALS, we identified numerous immune markers that were dysregulated early on in ALS that later predicted disease progression,” Dr. Feldman says. “The immune system seems to be highly active in a dysfunctional way early on, and then the disease follows. Those individuals with higher levels of immune dysfunction have a more progressive course of the disease. This suggests potential immune-specific targets for therapy.”

Given the recent breakthroughs in gene therapy, improved clinical trial design, increase in funding, and progress towards precision medicine, there is a growing sense of optimism in the ALS community. With deeper understanding of the disease, ongoing research, and collaboration across research centers, the path toward meaningful therapies has never looked so promising.