Inflammation may explain why ALS progression is faster for some

Differences in the inflammatory activity of certain immune cells may explain why amyotrophic lateral sclerosis (ALS) progresses faster in some people than others, according to a study.

The findings suggest that it may be possible to slow ALS progression by targeting specific inflammatory disease markers.

“The intensity of spinal cord inflammation doesn’t determine when someone develops ALS — it determines how fast the disease progresses and how long they survive,” Evangelos Kiskinis, PhD, co-author of the study and associate professor at Northwestern University Feinberg School of Medicine, said in a university news story. “If we can target these immune signatures therapeutically, we can slow down the rate of disease progression.”

The study, “Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming,” was published in Nature Neuroscience. The work was funded in part by the National Institutes of Health.

ALS is a neurological disorder in which motor neurons, the nerve cells that control movement, become damaged and die. The loss of motor neurons leads to muscle weakness, making it progressively more difficult to move, speak, swallow, and breathe. ALS symptoms worsen over time, but not at the same rate for everyone. In many people, ALS progresses very quickly and leads to death a few years after onset, but others may live for decades after disease onset. Why the disease progresses at different rates in different people has been a longstanding scientific mystery.

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Pinpointing gene activity

The team at Northwestern showed that differences in the activity of certain immune cells may explain, at least in part, the different disease progression rates.

Seeking to better understand how the immune system goes haywire in ALS, the researchers conducted in-depth analyses of genetic activity using blood samples from living people with or without ALS, paired with analyses of spinal cord tissue from deceased donors. The study included people with non-genetic forms of ALS, as well as some with ALS caused by a mutation in the C9ORF72 gene. 

“For ALS, this work is highly novel,” said David Gate, PhD, study co-author and assistant neurology professor at Feinberg. “This is the first in‑depth molecular assessment of how the immune system behaves across different forms of ALS, using technologies that allow us to pinpoint which immune genes are active in patient tissues, and where.”

The researchers found that ALS patients showed signs of atypical inflammatory activity. In particular, a group of immune proteins known as the complement cascade was elevated in immune cells from people with ALS. These inflamed immune cells were found in the spinal cord next to damaged motor neurons with abnormal TDP-43 protein clumps, a molecular hallmark of ALS

“We found the immune cells we detected in the blood of people living with ALS were inflamed, and we found the genes that mediate their inflammatory response in the spinal cord at the site of motor neurons,” Gate said. “These inflamed immune cells were associated with [ALS-related nerve damage], giving some credence to our theory that the immune system is detrimental.”

The researchers found evidence of inflammatory dysregulation in people with all forms of ALS, though specific patterns differed between individuals with or without the C9ORF72 mutation. And among people with non-genetic forms of ALS, the team found that complement activity was significantly elevated in patients whose disease progressed faster, though it showed no clear association with age at disease onset.

Gates said the data suggest “that ALS is not a single event but a domino-like cascade that begins inside motor neurons with TDP-43 pathology and is then amplified by a damaging immune response in the bloodstream and spinal cord.”

If it’s true that certain types of immune activation lead to faster ALS progression, then treatments aimed at dampening these specific immune programs might help slow the disease. The researchers said the data “highlight immune pathways with potential for biomarker development and therapeutic intervention.”

The researchers are working to better understand this immune dysregulation and how it might be targeted therapeutically.

“Our next step is to map exactly how this immune reaction spreads throughout the entire motor circuit: from the brain, down through the spinal cord and out to the muscles,” Gate said. “By profiling the motor circuit in depth, we’ll get a much clearer picture of where and when inflammation drives faster progression, which should help us develop immune-targeted therapies that slow the disease and extend survival across ALS subtypes.”