Immune Signatures Shape How Quickly ALS Progresses

Amyotrophic lateral sclerosis (ALS) patients typically live only three years after symptoms emerge, though some survive close to a decade. The reasons behind that wide gap have long puzzled scientists. A Northwestern Medicine study, published in Nature Neuroscience, offers new insight by tracing the disease through a domino-like sequence that starts inside motor neurons and is then amplified by the immune system.

"This study reveals 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," said co-corresponding author David Gate.

The team examined blood and spinal cord samples from nearly 300 living and deceased individuals with both genetic (linked to C9orf72) and non-genetic forms of ALS, alongside controls. Single-cell RNA sequencing was applied to blood from 40 living patients, while spatial transcriptomics mapped gene activity in spinal cord tissue from 18 deceased participants. RNA from postmortem tissue of 237 patients added depth to the inflammatory analysis. Gate noted that the work is the first in-depth molecular assessment of how the immune system behaves across different forms of ALS.

Immune cells clustered at sites of motor neuron loss and TDP-43 buildup, with distinct inflammatory patterns tied to ALS type and pace of progression. Patients whose disease advanced quickly displayed elevated activity in particular immune genes, and those with the genetic form showed a different set of altered genes. In worse clinical cases, complement genes—first-line defenders against pathogens or tissue damage—were notably more active. Gate added that the inflamed immune cells were tied to ALS pathology, lending support to the idea that the immune response is making the disease worse rather than helping.

"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," said co-corresponding author Evangelos Kiskinis. "If we can target these immune signatures therapeutically, we can slow down the rate of disease progression."

Future therapies may need to be tailored to specific ALS subtypes and stages to work effectively, the authors said. Gate's lab next plans to chart how immune activity spreads across the motor circuit from brain to muscles, while Kiskinis intends to test whether TDP-43 dysfunction directly triggers the inflammatory response driving faster decline.