Solving the mystery of ALS survival differences with new biological insights

A new Northwestern Medicine study provides new insight, identifying evidence that ALS unfolds through a domino‑like sequence of events that begins with an early breakdown inside motor neurons and is followed by a damaging inflammatory response. The findings help explain why the disease worsens over time, why some patients progress faster than others and how future treatments could be more personalized.

The domino effect

Using cutting-edge techniques, the scientists analyzed blood and spinal cord samples from almost 300 patients - living and deceased - with both non-genetic and genetic (caused by changes in the C9orf72 gene) forms of ALS, as well as controls.

"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 pathology, giving some credence to our theory that the immune system is detrimental. It's responding to pathology, and it's causing the disease to be worse."

Sophisticated scientific techniques

"For ALS, this work is highly novel," said Gate, also an assistant professor of neurology 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."

Patients whose disease advanced quickly showed heightened activity in certain immune genes, while those with the genetic form had a different array of altered immune genes. In the spinal cord, these activated immune cells gathered directly at the locations of motor neuron loss and near the toxic protein buildups characteristic of ALS.

"We saw that people with worse clinical ALS had more expression of complement genes, which are proteins that become activated as the body's first-line immune defense against a pathogen or damage to the body," Gate said.

Next steps for the research

Having identified a direct link between the immune system and ALS, Gate said the next step for his lab is to expand the research to include more patients and to more closely study the motor circuit, which is the neural command system that carries signals from the brain, through the spinal cord, to the muscles.

Source:

Northwestern University

Journal references:

Zhang, Z., et al (2026). Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming. Nature Neuroscience. DOI: 0.1038/s41593-026-02300-5. https://www.nature.com/articles/s41593-026-02300-5.