CTE and normal aging are difficult to distinguish, new study finds
Brain protein tied to CTE not elevated in former amateur football players
Northwestern University
- Analyzed 174 donated brains, including from former high school, college football players
- Larger studies needed to understand how p-tau relates to aging and the extent to which repetitive impact from contact sport predisposes to p-tau accumulation
- Whether such changes cause or are associated with clinical problems during life remains unclear
CHICAGO --- In recent years, some scientists and advocates have warned that playing contact sports like football and hockey may increase the risk of brain diseases like Alzheimer’s disease or chronic traumatic encephalopathy (CTE) due to a buildup of a specific protein in the brain.
But a new Northwestern Medicine study of 174 donated brains, including some from former high school and college football players, pumps the brakes on that theory.
“The long and short of it is no, this protein in this specific brain region is not increased in people who played football at the amateur level. It throws a little bit of cold water on the current CTE narrative,” said corresponding author Dr. Rudolph Castellani, professor of pathology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neuropathologist.
The study was recently published in the Journal of Alzheimer’s Disease. It raises important questions about how scientists interpret subtle brain changes associated with aging, Alzheimer’s disease and repetitive head impacts.
How the study worked
The study analyzed brain tissue from the Lieber Institute for Brain Development, which collects brain donations from people who had psychiatric conditions (e.g. schizophrenia, major depression, general anxiety, substance use disorder, etc.) throughout their life. Of the 174 samples collected from older adult men (with a median age of 65 at death), 48 men participated in football in high school or college while 126 had no history of playing a contact or collision sport.
The study did not include brains from professional athletes.
The scientists focused on a small memory-related brain region called CA2, part of the hippocampus. This region has been shown to accumulate phosphorylated tau (p-tau) protein — which is often present in neurodegenerative disease — in a variety of contexts, including normal aging, Alzheimer’s disease and in individuals with a history of repetitive head impacts.
But the findings suggest p-tau buildup in CA2 isn’t specific to contact sports. The scientists found no over-representation of CA2 p-tau in individuals with a history of youth football participation. Instead, the presence of p-tau in this region was statistically associated with age.
“What’s novel here is a return to the null hypothesis — that there may be no link between repeated head injuries and p-tau buildup in this location,” said Castellani, who also is the neuropathology core director of the Northwestern University Alzheimer’s Disease Research Center. “Rather than assuming p-tau in CA2 is inherently pathological, we’re asking whether it might be part of normal aging or a non-specific response to environmental factors.”
The study also highlights broader challenges in the field of neurodegeneration research. In particular, the authors point to the difficulty of assigning clinical meaning to subtle pathological findings. The paper’s section, “Knowledge gaps and implications for future research,” underscores how even expert consensus groups struggle to define CTE in clinically meaningful terms.
“Modern studies on CTE may be expanding the boundaries of what’s considered normal variability in the human brain,” Castellani said. “This work reminds us to be cautious in interpreting pathology without clear clinical correlation.”
The authors call for larger studies to better understand how p-tau relates to aging and head injuries, while urging the scientific community to critically evaluate assumptions about what constitutes neurodegenerative disease.
The study is titled “Postmortem tau in the CA2 region of the hippocampus in older adult men who participated in youth amateur American-style football.”
Journal
Journal of Alzheimer’s Disease
Article Title
Postmortem tau in the CA2 region of the hippocampus in older adult men who participated in youth amateur American-style football
A key role of brain protein in learning and memory is deciphered by scientists
Rutgers-led research reveals potentially profound implications in treating neurodegenerative diseases and brain injuries
Rutgers University
Scientists have discovered how a key protein helps maintain strong connections between brain cells that are crucial for learning and memory.
Results of the study, published in the journal Science Advances, could point the way to new treatments for traumatic brain injuries and diseases, such as Parkinson’s and Alzheimer’s, the scientists said.
Their research, led by a Rutgers University-New Brunswick professor, uncovered a previously unknown role for cypin, a brain protein. Members of the research team found that cypin promotes the presence of tags on specific proteins at synapses, namely the tiny gaps where the brain cells, known as neurons, communicate. The marking helps ensure that the right proteins are in the right place, allowing the synapses to work properly.
The researchers said the insight has potentially profound implications for the treatment of brain disorders.
“Our research indicates that developing treatments or therapies that specifically focus on the protein cypin may help improve the connections between brain cells, enhancing memory and thinking abilities,” said Bonnie Firestein, a Distinguished Professor in the Department of Cell Biology and Neuroscience in the School of Arts and Sciences and an author of the study. “These findings suggest that cypin could be used to develop treatments for neurodegenerative and neurocognitive diseases, as well as brain injuries.”
Firestein has been studying cypin for more than two decades. Her latest work uncovered several important aspects of how cypin functions and why it is significant for brain health.
One of the crucial discoveries is that cypin helps add a special tag to proteins in synapses connecting neurons. This tag ensures proteins are correctly positioned and able to send signals effectively. Proper tagging and movement of proteins are essential for the neurons to function correctly.
Another important finding is that cypin interacts with a complex of proteins, known as the proteasome, which is responsible for breaking down proteins. When cypin attaches or binds to the proteasome, it slows down this breakdown process, leading to an accumulation of proteins. This buildup can positively affect various cellular functions, which are important for the communication between neurons.
Firestein's research also shows that when there is more cypin present, the levels of important proteins in the synapses increase. These proteins are vital for effective communication between neurons, empowering learning and memory.
Additionally, cypin increases the activity of another protein called UBE4A, which also helps with the tagging process. This indicates that cypin's influence on synaptic proteins is partly because of its effect on UBE4A.
The work highlights the importance of cypin in maintaining healthy brain function and its potential as a target for therapeutic interventions.
“Even though this study is what we call ‘basic research,’ it eventually can be applied in practical, clinical settings,” said Firestein, who already is conducting such “translational” work in parallel. Translational research is a type of research that takes discoveries made in the lab and turns them into practical treatments or solutions to improve human health.
Cypin’s significant role in the workings of the brain’s synapses makes it highly relevant to the potential treatment of neurodegenerative diseases and traumatic brain injury, she said. For example, healthy synaptic function is often disrupted in diseases such as Alzheimer’s and Parkinson’s.
In addition, the protein’s role in promoting synaptic plasticity – the ability of synapses to strengthen or weaken over time – means it may be used to help counteract the synaptic dysfunction seen in neurodegenerative diseases and brain injuries.
The study was supported in part by the National Institutes of Health (NINDS), the Coalition for Brain Injury Research, a charitable foundation dedicated to the memory of Dennis John Benigno, who suffered a traumatic brain injury in junior high school; and private donors Jamuna Rajasingham and Dyan Rajasingham.
Other scientists from Rutgers involved in the study include Kiran Madura, a professor in the Department of Pharmacology at Robert Wood Johnson Medical School; Srinivasa Gandu, Mihir Patel, Ana Rodriguez, former doctoral students in the Department of Cell Biology and Neuroscience.
Jared Lamp and Irving Vega of Michigan State University also contributed to this research.
Explore more of the ways Rutgers research is shaping the future.
Journal
Science Advances
Method of Research
Observational study
Subject of Research
Cells
Article Title
Cypin regulates K63-linked polyubiquitination to shape synaptic content
Article Publication Date
11-Jul-2025
COI Statement
Cypin regulates K63-linked polyubiquitination to shape synaptic content
