CTE May Be Driven by Inflammation-Linked DNA Damage in Neurons, Study Finds

New research suggests that chronic traumatic encephalopathy (CTE) — the degenerative brain disease associated with repeated head impacts — may arise when trauma triggers inflammation that accelerates DNA damage inside neurons. The pattern of genetic lesions observed in CTE resembles that reported in Alzheimer’s disease, pointing to a potentially shared pathway of neurodegeneration.

What researchers did

The team used single-cell whole-genome sequencing to examine individual neurons from postmortem brains. They analyzed neurons from 15 people diagnosed with CTE and from four people who had experienced repetitive head impacts but did not have CTE, comparing both groups with neurons from healthy control brains and from people with Alzheimer’s disease.

Key findings

Neurons from CTE-affected brains carried substantially more DNA mutations than neurons from healthy brains — on average about 114 extra single-letter (point) changes per neuron. By contrast, neurons from individuals with repeated head impacts but without CTE did not show an increased mutation burden compared with healthy controls.

In addition to single-letter changes, the investigators found many more small insertions and deletions (indels) in neurons from both CTE and Alzheimer’s brains than in healthy tissue. In some CTE cases, individual neurons contained more than a thousand indels — a mutational load comparable to what might accumulate over more than a century of normal aging.

"We used to think neurons had the most stable genomes in the body," said Dr. Christopher Walsh, a geneticist at Boston Children's Hospital and a co-author on the study. "But it turns out, they pick up mutations year after year, and those mutations accelerate in neurodegenerative disease."

Inflammation as a likely driver

Although the genomic analysis did not directly measure inflammatory molecules within the sequenced neurons, previous work by co-authors Dr. Ann McKee and John Cherry documented widespread microglial activation — a sign of inflammation — in CTE brain tissue. The authors hypothesize that repeated head trauma combined with chronic inflammation may subject neuronal DNA to damaging biochemical processes, analogous to the way ultraviolet light or tobacco exposure damages DNA in other tissues.

Implications and next steps

These results support a model in which head trauma initiates injury and inflammation, and those inflammatory processes accelerate accumulation of DNA damage that impairs neuron function and can lead to cell death. The research team is now investigating whether a similar inflammation → DNA damage → neuron loss cascade occurs in other neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease, with the long-term goal of identifying points where intervention could prevent or slow degeneration.

Takeaway: Repeated head impacts may set off chronic inflammation that promotes a heavy burden of DNA mutations in neurons. That damage could help explain progressive neuron loss in CTE and may overlap mechanistically with other neurodegenerative disorders.