Q&A Part 1: CTE Prevalence, Brain Donation Findings in Former NFL Players: Thayne Munce, PhD

A new retrospective population-based cohort study is adding to the growing body of research examining chronic traumatic encephalopathy (CTE) among former NFL players, while raising important questions about how the disease can be studied and its prevalence estimated. The research examined former players who died between 2008 and 2021, using postmortem neuropathological assessments alongside population-level mortality data.

CTE remains a complex area of research, in part because definitive diagnosis currently relies on neuropathological examination after death. As interest continues to grow around the potential long-term neurological consequences of repetitive head impacts, researchers have increasingly sought to better understand the relationship between CTE pathology, clinical symptoms, and neurodegenerative conditions such as dementia.

In the first part of this 2-part Q&A with NeurologyLive, Thayne Munce, PhD, a member of the leadership council at the Wu Tsai Human Performance Alliance, discusses the study's approach to examining CTE in former NFL players, the broader significance of its findings, and the challenges involved in interpreting brain-donation research. Munce, who is also the site director of the Alliance at the University of Kentucky, also offered perspective on what the study may contribute to the ongoing understanding of CTE and its potential clinical manifestations.

NeurologyLive: Can you provide an overview of the study and its key objectives for those who may not be familiar with the research?

Thayne Munce, PhD: What the researchers did in this study was access the brains of former NFL players who had passed away between 2008 and 2021. They performed neuropathological evaluations of their brains to identify the presence of chronic traumatic encephalopathy, or CTE, in those former players.

One thing that was unique about this study is that they also accounted for all of the deaths that occurred among former NFL players during that same period of time. They then used the number of postmortem CTE diagnoses from their donor population to estimate what the true prevalence of CTE may have been in that cohort of former NFL players.

There are a couple of unknowns. They didn't know how representative their donor sample was of the broader group of former NFL players who passed away during that period of time. They ended up having a pretty wide range of estimates as to what the actual prevalence of CTE was among the donor brains that they had available.

The pathologists examined nearly all of the brains—I don't remember the exact number, but it was in the high 90% range—and most of those brains showed signs of CTE. They staged the disease across the 4 stages of CTE.

Most of the brains that had been donated did show signs of CTE. That resulted in the researchers saying that, very conservatively, if all of the former football players who died during this period of time happened to be those who donated their brains for research, and if those were the only cases of CTE that we happened to have examined, then because they had about 20% to 25% of the sample of all of the players, they would say conservatively about roughly 1 in 4.

That was the headline from the study: 25%, or at least 25%, or at least 1 in 4 former NFL players who passed away during this period of time.

They narrowed the bands a little bit to a more specific analysis, I believe between 2016 and 2021, where they ended up with a lot of their analysis. That was a period of time when they got the most brain donations. So, conservatively, if their donation sample happened to capture almost all of the cases of CTE, then that probably would have represented about 25% of that entire population.

However, if their donor sample was more representative of the players they didn't have access to, whose brains they weren't able to examine, then that true rate of CTE prevalence in that cohort could have been up into the mid to upper 90% range. We don't know how representative that donor sample was. That's why the researchers were left with this really wide estimate of between 25% and, I believe, 95% to 98% of former NFL players in the age range who passed away during those years potentially having CTE.

They also looked at associations with dementia within their donor group. Clinicians looked at their medical records, and I believe they also had some interview information to be able to diagnose postmortem whether those individuals likely had dementia. They then looked at correlations between not having CTE at all and the different stages of CTE with dementia.

They found that the more advanced stages, like stage 4 CTE, did convey considerably higher, significantly higher, risk of dementia among that donor group.

What were the most important findings from this study, and which could have the greatest implications going forward?

This replicates some work that many of these researchers and authors had presented with other groups of brain donors and former NFL players who had donated their brains for research. It confirms that among those players who either elect, while they're still living, or whose families volunteer to have their brains donated after death to be examined, a very, very high percentage—above 90%—and nearly 100% of those brains are being found to have CTE.

One of the big questions in this type of research is always, how biased is that sample, and how representative is that sample?

There's a lot of thought that if somebody has cognitive issues, dementia, or even behavioral or mood changes while living, and they were a former football player and they've heard a little bit about CTE, they may suspect that maybe they have CTE. Perhaps their family suspects they do, or after death there's more of a reason for them to want to volunteer their brains.

People who are having issues in life are going to be more likely to donate their brains. Other players who may be living well, happy, healthy, normal lives have no reason to suspect that there'sanything wrong with their brains. They may not want to have their family go through the trouble of having their brains examined and autopsied, so they don't donate their brains.

You may end up with this very biased sample, where only the people who donate their brains are the ones who are actually having issues in real life. But we don't really know that unless you're able to autopsy and evaluate all of the former NFL players who passed away during that period of time. You wouldn't know what the true CTE prevalence is, nor would you know how biased or how representative that donor sample is.

In terms of the main findings, I think it reinforces what some of the brain-donor studies have shown in the past: a really high prevalence of CTE among those former NFL players who have donated their brains. It advances some of our understanding of the link between particularly late-stage or more advanced CTE and increased risk of dementia, as was characterized in this particular study.

One note of context for the broader interpretation of this study is to recognize that this is historical, in the sense that the former players who were evaluated passed away between 2008 and 2021. The average age, I believe, in the entire sample was around 70 years of age. So, when they would have played in the NFL was predominantly in the 1960s and 1970s, just if you look at the averages and the math.

We're looking at football players from an era half a century ago in terms of when they were playing in the NFL. It's still really important work because former NFL players are a very select, elite group of individuals, and there just aren't a lot of those individuals available to study.

Any work that we can do to try to understand some association between their sport participation and injury risk or late-life consequences is really valuable and really important. This study certainly is. It's trying to really tease out and understand some of those relationships between exposure to repetitive head impacts or perhaps concussion and neurodegenerative disease, and how that may link to clinical manifestations in life. That work is super important.

The caveat, of course, is what does that tell us about current players? That's where we need to be cautious about saying that current players and the exposure that they have, the rules that they play under, the equipment that they wear, and the sports medicine care available to them are vastly different from what they would have been for players from 50 years ago.

How does the association between stage 4 CTE and increased dementia risk advance our understanding of CTE pathology and its clinical impact?

It helps to fill in some gaps because there's a lot of differences of opinion or controversy about this neurodegenerative, neuropathological condition known as CTE, which can only be diagnosed after death.

It's characterized by structural changes in the brain and how that is linked to behavior, memory, mood changes, psychological conditions, and mental health in the living. That hasn't always been clearly linked. There have been individuals who have been diagnosed with CTE who didn'texhibit any outward signs or symptoms of disease while living, and vice versa. People who may have dementia doesn't necessarily mean that they have CTE.

I think one of the things that this study helps us to understand is that perhaps, like other conditions, this is more of a threshold-type phenomenon. Early stages may have some changes in brain structure that initially may not result in different changes in function or behavior. But perhaps when you get to later stages, more advanced stages, and reach a certain threshold, then the probability or likelihood that that's going to be severe enough to actually cause dementia or cognitive decline, or an Alzheimer disease-related type of condition, is increased.

I say that because people may recognize what those symptoms would be, and that happens more regularly. It may not just be a linear progression. Any type of CTE development that we, again, can't see in the living, if it's taking place, doesn't necessarily mean that that's going to result immediately in any clinical issues. It may take a certain threshold above which and beyond then the risk is certainly heightened.

Transcript edited for clarity.

REFERENCES
1. Daneshvar D, Nowinski C, Abdolmohammadi B, et al. Prevalence of chronic traumatic encephalopathy at death in National Football League players: retrospective population based cohort study, 2008-21. BMJ. 2026;394. doi: 10.1136/bmj-2026-100418