Could CTE Be Analyzed Before an Individual Kicks the bucket? This Protein May Be the Key
Could CTE Be Analyzed Before an Individual Kicks the Bucket? From 2019's Tau Clue to Today's Living Diagnosis Revolution
Let's be honest: there's something deeply unsettling about a disease that can only be diagnosed after you're dead. It's like being told you failed the exam, but you won't find out until you've already graduated, gotten married, and retired—oh, and by the way, you can't do anything about it. For decades, chronic traumatic encephalopathy (CTE)—the degenerative brain disease linked to repeated head impacts in sports, military service, and other activities—has existed in this maddening diagnostic limbo. The only way to know for sure if someone had CTE was to examine their brain tissue under a microscope, which obviously requires the patient to have, well, kicked the bucket. But a quiet revolution has been unfolding over the past seven years, and we are now closer than ever to diagnosing CTE in living people—and maybe, just maybe, doing something about it before it's too late.
Back in 2019, when this article was first published, a team of researchers led by Dr. Carmela Tartaglia at the University of Toronto had just identified a promising lead. They found that 12 out of 22 former professional athletes (54%) with a history of multiple concussions had elevated levels of a protein called tau in their cerebrospinal fluid (CSF). Those with higher tau performed worse on tests of executive function—attention, memory, and planning—and showed changes in the brain's white matter that mirrored what pathologists see in post‑mortem CTE cases. "We are optimistic that we are drawing nearer to finding a biomarker for CTE," Tartaglia said at the time, "which will enable researchers to study how tau influences brain function." The study was small, the biomarker was far from perfect, and the diagnosis still required a lumbar puncture (a needle in the spine—not exactly a walk in the park), but it was a crack in the door. And in the years since, that door has been kicked wide open.
"We are optimistic that we are drawing nearer to finding a biomarker for CTE, which will enable researchers to study how tau influences brain function."
The Tau Trail: From Spinal Taps to PET Scans
If 2019 was the "proof of concept" year for tau as a CTE biomarker, the years since have been an all‑out sprint to refine the tools and expand the evidence. The biggest leap forward has come from positron emission tomography (PET) scanning—a technology that lets scientists actually see tau deposits in living brains. Two major studies, both published in 2025, have transformed our understanding of what's possible.
First, a landmark study using an experimental PET tracer called flortaucipir (also known as 18F‑AV‑1451) scanned the brains of 26 former NFL players with cognitive and neuropsychiatric symptoms. The results were striking: the players had elevated tau levels in the same brain regions where pathologists find tau deposits in CTE—specifically, areas deep in the brain's folds where the disease takes root. Crucially, the scans showed tau elevation but not amyloid‑beta, the sticky protein that defines Alzheimer's disease. This is a huge deal. It means that CTE's tau signature is distinct from Alzheimer's, and we can now see it in living people. "The test is an important advance towards our progress in developing a diagnostic biomarker for CTE," said lead scientist Dr. Robert Stern of Boston University. But he was quick to add a crucial caveat: "We need to refine how we analyze the tau data to be better able to detect elevations on an individual level. We are not there yet. This experimental PET scan ligand is not ready for use in the clinic."
Second, a separate study using an even more advanced tracer called 18F‑MK‑6240 scanned 30 former NFL players and found increased tau uptake in the entorhinal cortex and parahippocampal gyrus—brain regions critical for memory. Higher tau levels in these areas correlated with worse performance on memory and verbal fluency tests. The study also confirmed, through post‑mortem tissue analysis, that MK‑6240 actually binds to the specific tau deposits found in CTE, not just Alzheimer's tau. This is the molecular equivalent of a fingerprint match. We're no longer guessing—we're confirming that what we see on the scan matches what we see under the microscope. As one researcher put it, "We present evidence of in‑vitro binding to post‑mortem CTE tissue and in vivo PET binding in former football players." That's science‑speak for "this stuff actually works."
The implications are enormous. For the first time, we have tools that can measure tau pathology in living people suspected of having CTE. The scans aren't ready for individual diagnosis—the variability from person to person is still too high, and we don't yet have standardized cutoffs for what constitutes "abnormal"—but they are powerful research tools that are already reshaping how we study the disease. As Dr. Stern noted, "The findings from this study bring us one important step closer to being able to diagnose CTE during life. There are now biomarkers to help diagnose Alzheimer's disease and we need similar biomarkers for CTE."
The Blood Test Revolution: Neurofilament Light and Beyond
If PET scans are the Cadillac of CTE diagnostics—powerful, precise, and expensive—then blood tests are the everyday sedan that could make diagnosis accessible to everyone. And the past year has seen explosive progress on this front. The star of the show is a protein called neurofilament light chain, or NfL for short. NfL is a structural protein that holds neurons together like scaffolding. When neurons are damaged or die—whether from a concussion, a neurodegenerative disease, or just the wear and tear of aging—NfL leaks out into the blood and CSF, where it can be measured.
A growing body of evidence shows that NfL is a sensitive marker of brain injury. In 2025, researchers demonstrated that NfL could be reliably measured in both blood and CSF using high‑throughput immunoassays, paving the way for its use in clinical research. More recently, scientists have developed DNA aptamers—basically, custom‑built molecular "Velcro"—that can grab onto NfL with high specificity, potentially enabling a simple, cheap blood test for neurodegeneration. And NfL isn't the only player. Other blood‑based markers, including phosphorylated forms of tau (p‑tau181, p‑tau217, p‑tau231), glial fibrillary acidic protein (GFAP), and various inflammatory cytokines, are being investigated as part of a "biomarker panel" that could one day distinguish CTE from Alzheimer's, Parkinson's, and other dementias.
The DIAGNOSE CTE Research Project, a massive NIH‑funded multicenter study, is at the forefront of this effort. The project's second phase, launched in 2025, will follow 225 former football players, 75 controls, and 50 Alzheimer's patients, collecting blood, CSF, MRI scans, and tau PET images to build a comprehensive picture of how CTE develops and progresses. Blood samples will be analyzed for six different p‑tau epitopes, Aβ40/42, neuroinflammation markers, and white matter injury markers. The goal is nothing less than a "liquid biopsy" for CTE—a simple blood draw that could tell you whether you're on the path to neurodegeneration years before symptoms appear.
Let's pause for a moment to appreciate how wild this is. In 2019, we had a single study of 22 Canadian athletes and a lumbar puncture. Today, we have PET scans that can see tau deposits in living brains, blood tests that can measure neuronal damage with a finger prick, and a nationwide research project tracking hundreds of athletes over years. The pace of progress is staggering. And yet, we're not quite at the finish line. "The hope is to eventually use neuropsychological tests, brain imaging such as specialized MRI and other biomarkers to diagnose CTE," the Mayo Clinic notes. "But there is no way to definitively diagnose CTE during life." The gold standard remains the autopsy. But the gap between "definitive" and "good enough to guide treatment" is shrinking fast.
"The findings from this study bring us one important step closer to being able to diagnose CTE during life. There are now biomarkers to help diagnose Alzheimer's disease and we need similar biomarkers for CTE."
The NINDS Criteria: Defining the "Clinical" Side of the Equation
Biomarkers are only half the story. To diagnose a disease in a living person, you need clinical criteria—a checklist of symptoms and history that defines who is likely to have the condition. In 2025, the National Institute of Neurological Disorders and Stroke (NINDS) published the first expert consensus criteria for Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE. This was a milestone. For the first time, researchers had a standardized way to identify people who might have CTE based on their symptoms and exposure history, even without a brain scan or a blood test.
But the criteria came with some surprises. First, they are explicitly not intended for clinical use—at least not yet. They are designed to facilitate research, helping scientists enroll the right patients in studies and track how the disease progresses. Second, and perhaps most counterintuitively, concussions are not part of the diagnostic criteria. Instead, the criteria focus on "substantial exposure to repetitive head impacts (RHI)"—defined, for football players, as at least five years of organized play, with two or more of those years at the high school level or beyond. As Dr. Stern explained, "It's not about concussions. As far as we know, CTE is not directly associated with the number of concussions. It is more associated with the overall exposure over a period of several years to repetitive impacts on the head, which may or may not result in symptomatic concussions."
Another surprise: depression, anxiety, and suicidality are not core diagnostic features. They are considered "supportive features," but the core criteria focus on specific types of cognitive impairment and a neuropsychiatric syndrome called "neurobehavioral dysregulation"—essentially, problems with emotional control, impulsivity, and aggression. This is a critical refinement. Many people with depression do not have CTE, and using mood symptoms as a primary diagnostic tool would lead to massive overdiagnosis. By focusing on the unique combination of cognitive and behavioral changes that characterize CTE, the NINDS criteria aim to separate the signal from the noise.
The criteria are not perfect, and they will undoubtedly evolve as biomarkers improve. But they represent a crucial step forward. As one neurologist put it, "The public has been begging for something like this. It had to be addressed, and this was a rigorous process with the right team of people to do it." The NINDS criteria give researchers a common language and a common framework—and that, in turn, accelerates the search for treatments.
The Prevention Horizon: Can We Stop CTE Before It Starts?
Diagnosis is important, but prevention is the holy grail. And here, too, the past few years have delivered genuinely exciting news. A 2025 NIH‑funded study from Boston University found that repeated head impacts cause early and lasting changes in the brains of young athletes—changes that occur years before the hallmark tau tangles of CTE appear. The researchers discovered a striking 56% loss of a specific type of neuron in the brain region that takes the hardest hits during impacts, even in athletes who had no tau buildup. They also found that the brain's immune cells, called microglia, became increasingly activated in proportion to the number of years of contact sports exposure. In other words, the damage starts early—and it's not just about tau.
This has profound implications for prevention. If we can detect these early cellular changes, we might be able to intervene before irreversible neurodegeneration sets in. Several promising avenues are already being explored. Researchers at Case Western Reserve University have shown that a brief two‑week treatment with a peptide called P110, which blocks excessive mitochondrial fission (a cellular process that goes haywire after brain injury), can prevent long‑term cognitive impairment, oxidative damage, and blood‑brain barrier deterioration in mice—and the protection lasts for the equivalent of decades in human terms. "Brief P110 treatment during the acute time period after TBI permanently normalized mitochondrial fission/fusion and prevented subsequent harm to the brain," explained senior author Dr. Andrew Pieper. "The same treatment administered much later, however, had no protective effect. Thus, there is a critical time window after TBI wherein this treatment can be effective."
Another approach targets the PREP–PP2A pathway, a molecular cascade that contributes to tau pathology and neurodegeneration. A proprietary PREP ligand developed by Polku Therapeutics has been shown to prevent long‑term memory loss after repeated mild traumatic brain injury in animal models. And there is growing interest in repurposing existing drugs—including fenofibrate, a common cholesterol medication—that may reduce neuroinflammation and protect cognitive function after TBI. None of these treatments are ready for prime time yet, but the pipeline is filling up. For the first time, we're talking not just about diagnosing CTE, but about actually doing something about it.
And then there's the simplest prevention strategy of all: reduce exposure. The science is unequivocal that CTE is caused by repetitive head impacts, not necessarily concussions. This has led to policy changes across youth and professional sports—limits on full‑contact practices, new rules to reduce head‑to‑head collisions, and increased scrutiny of heading in soccer. A 2025 study found that repetitive soccer heading damages a brain region critical for memory and learning, with the junction between white and gray matter sustaining the most injury. The message is clear: we can't eliminate risk entirely, but we can reduce it. And for millions of athletes, from pee‑wee football to the pros, that reduction could make all the difference.
"Brief P110 treatment during the acute time period after TBI permanently normalized mitochondrial fission/fusion and prevented subsequent harm to the brain, including oxidative damage, blood‑brain barrier deterioration, axonal degeneration, and cognitive impairment, 17 months later. This is equivalent to many decades in people."
The Complexity Factor: Why CTE Is Trickier Than Alzheimer's
If all of this sounds too good to be true, well, there's a reason CTE has been so hard to pin down. The disease is maddeningly complex. The DIAGNOSE CTE Research Project found that among former football players, estimates of repetitive head impact exposure were not generally associated with CSF tau levels—meaning that the relationship between how many hits you took and how much tau you have is not straightforward. And while the study confirmed that CSF amyloid‑β levels are reduced in former players (a pattern also seen in Alzheimer's), the lack of a clear tau signature in CSF suggests that "the pathological features of CTE reflected in fluid biomarkers are complex and require further study."
Neuroinflammation adds another layer of complexity. A 2025 review argued that inflammatory mechanisms could serve as a viable source for novel CTE‑specific biomarkers, pointing to candidates like CCL11 (eotaxin‑1), CCL21, and GFAP. The idea is that the brain's inflammatory response to repetitive head impacts may have a unique "signature" that distinguishes CTE from other neurodegenerative diseases. If we can identify that signature, we might have a new class of diagnostic tools—and potentially new therapeutic targets. But we're still in the early days. "Although further research is necessary to validate immune mediators," the authors concluded, "the latter show promise as diagnostic biomarkers for CTE and may also eventually serve as therapeutic targets."
And then there's the problem of comorbidity. Many people at risk for CTE are also at risk for Alzheimer's disease, and the two pathologies often coexist in the same brain. The DIAGNOSE CTE study found that traumatic brain injury is associated with increased risk of Alzheimer's and may lead to comorbid neuropathology. This means that a living patient with cognitive decline and a history of head impacts could have CTE, Alzheimer's, or both. Untangling that knot requires a multi‑pronged approach—combining tau PET, amyloid PET, MRI, blood biomarkers, and clinical assessment—to get a complete picture. We're building the toolkit, but it's not yet a single, simple test.
What the Skeptics Say—and Why They're Right (for Now)
To be clear, we are not there yet. The Mayo Clinic's official position remains unchanged: "There is no way to definitively diagnose chronic traumatic encephalopathy, also known as CTE, during life." The gold standard is still the autopsy. And while the NINDS criteria for TES are a huge step forward, they are explicitly "not intended for use in the clinic, at least not yet." Why? Because we still don't know how well the criteria predict actual CTE pathology at autopsy. Without that validation, using the criteria to tell a living patient they have CTE is ethically fraught and scientifically premature.
There's also the issue of specificity. Tau PET scans can detect tau deposits, but they can't always tell you which flavor of tau it is. Is it CTE tau? Alzheimer's tau? Age‑related tau? The tracers are getting better—MK‑6240 appears to bind CTE tau in at least some cases—but we're not at the point where a scan can definitively rule CTE in or out. And blood biomarkers like NfL are sensitive to neuronal injury but not specific to CTE. A high NfL level could mean CTE, or it could mean Alzheimer's, or it could mean you had a concussion last week. The dream of a single, definitive blood test for CTE remains just that—a dream.
But here's the thing: we don't need a perfect test to make progress. We need a good enough test. A test that, when combined with clinical history and other biomarkers, can give doctors and patients a reasonable level of confidence. And we are getting close. As one researcher put it, "The ability to make an accurate diagnosis of CTE is needed to facilitate research on risk factors, mechanisms, prevention, and treatment." The goal isn't just to give people a label; it's to understand the disease well enough to intervene. And on that front, the progress since 2019 has been nothing short of remarkable.
The Road Ahead: What Does 2030 Look Like?
If current trends continue, the CTE landscape in 2030 will look radically different from today. Imagine a former college football player, now in his 50s, who notices he's been more irritable and forgetful lately. He goes to his doctor, who orders a blood test that measures a panel of biomarkers—p‑tau217, NfL, GFAP, and a few inflammatory cytokines. The results come back with a "CTE risk score" that, combined with his exposure history and a brief cognitive assessment, suggests a high probability of underlying CTE pathology. He's referred for a tau PET scan, which confirms elevated tau in the characteristic CTE pattern. He doesn't have Alzheimer's; his amyloid scan is clean. Armed with this information, he enrolls in a clinical trial testing a drug that targets neuroinflammation, or perhaps a therapy that promotes mitochondrial health. He also makes lifestyle changes—better sleep, more exercise, a brain‑healthy diet—that we know can slow cognitive decline. He doesn't have a cure, but he has a plan. And he has hope.
This is not science fiction. The pieces are falling into place. The DIAGNOSE CTE Research Project‑II will provide critical validation of biomarkers and clinical criteria over the next five years. New PET tracers with even better specificity for CTE tau are in development. Blood‑based biomarker panels are being refined and validated in large cohorts. And the first disease‑modifying therapies—targeting everything from mitochondrial dysfunction to neuroinflammation to tau aggregation—are moving through the pipeline. The FDA has not yet approved any treatment for CTE, but the groundwork is being laid. As the UCSF trial description notes, "Results will provide insight into the detection, diagnosis, and prognosis for people living with CTE, paving the way for treatment trials."
The biggest remaining challenges are not scientific but practical. PET scans are expensive and not widely available. Lumbar punctures are invasive and uncomfortable. Blood tests are promising but not yet validated. And even when we have a reliable diagnostic test, we'll need to figure out what to do with the information. Telling a 45‑year‑old that they likely have CTE is a heavy burden, and we don't yet have proven treatments to offer. But as any neurologist will tell you, knowledge is power. Knowing you're at risk allows you to plan, to make lifestyle changes, to participate in research, and to advocate for yourself and your family. The alternative—waiting until an autopsy confirms what you already suspected—is no longer acceptable.
When this article was first published in 2019, the idea of diagnosing CTE in living patients was a distant hope. Today, it is an imminent reality. The tau clue that Tartaglia and her colleagues uncovered has blossomed into a full‑fledged research enterprise, spanning PET imaging, blood biomarkers, clinical criteria, and experimental therapies. We are not there yet—the autopsy remains the gold standard, and we must be cautious about overpromising—but the trajectory is unmistakable. We are moving from a world where CTE is a post‑mortem mystery to one where it is a manageable, perhaps even preventable, condition. And that, dear reader, is worth getting excited about. So the next time you hear someone say CTE can't be diagnosed until you kick the bucket, you can smile and say, "Not for long." Because the bucket is getting kicked further down the road every day.
Key Takeaways: The CTE Diagnostic Revolution
- The 2019 tau CSF study was a watershed moment: Researchers found that 54% of former athletes with multiple concussions had elevated tau in their spinal fluid, and those with higher tau performed worse on cognitive tests. This cracked open the door to living diagnosis.
- PET scans can now see tau deposits in living brains: Using tracers like flortaucipir and MK‑6240, scientists have imaged CTE‑like tau patterns in former NFL players—and confirmed that the tau signature is distinct from Alzheimer's. The scans aren't yet ready for individual diagnosis, but they are powerful research tools.
- Blood tests are coming: Neurofilament light chain (NfL) is a promising marker of neuronal injury, and panels including p‑tau, GFAP, and inflammatory cytokines are being validated in large studies. A "liquid biopsy" for CTE may be closer than you think.
- The NINDS published the first consensus criteria for Traumatic Encephalopathy Syndrome (TES) in 2025: These research criteria focus on repetitive head impact exposure and specific cognitive/behavioral changes—not concussions or depression. They give researchers a standardized way to identify likely CTE patients.
- Prevention is becoming a reality: NIH research shows that repeated head impacts cause early neuron loss and inflammation years before tau tangles appear. Experimental treatments like P110 and PREP ligands have prevented long‑term neurodegeneration in animal models.
- CTE is more complex than Alzheimer's: The relationship between head impacts and tau is not straightforward, and neuroinflammation plays a key role. Comorbid Alzheimer's pathology is common, making diagnosis a multi‑pronged challenge.
- The DIAGNOSE CTE Research Project‑II is the largest study of its kind: Tracking 225 former football players over five years, it will validate biomarkers, refine clinical criteria, and pave the way for treatment trials.
- We are not there yet—but we are close: The autopsy remains the gold standard, and no test can definitively diagnose CTE during life. But a combination of PET imaging, blood biomarkers, and clinical assessment is rapidly approaching "good enough" to guide care and research.
Sources and Further Reading
- Journal of Neurotrauma (2026): Alterations in CSF Amyloid‑β and Tau Biomarkers in Former Football Players — DIAGNOSE CTE Project findings on CSF biomarkers and RHI exposure.
- DOAJ (2025): Neuroinflammatory mechanisms may help identify candidate biomarkers in CTE — Review of inflammatory markers like CCL11, CCL21, and GFAP.
- Mayo Clinic: Chronic Traumatic Encephalopathy – Diagnosis and Treatment — Current clinical approach and research directions.
- Neurology Today (2025): PET Scans Show Higher Tau Levels in Former NFL Players — Flortaucipir PET study findings and Stern's commentary.
- Molecular Neurodegeneration (2025): 18F‑MK‑6240 tau PET in patients at‑risk for CTE — MK‑6240 PET study showing binding to CTE tau and correlations with cognition.
- UCSF Clinical Trials: DIAGNOSE CTE Research Project‑II — Ongoing 5‑year NIH‑funded study of biomarkers and clinical course.
- Polku Therapeutics (2025): PREP ligand prevents long‑term memory loss after TBI — Preclinical data on a novel CTE‑relevant therapeutic pathway.
- Case Western Reserve University (2024): Chronic neurodegeneration can be prevented after TBI — P110 peptide study showing permanent protection after brief post‑injury treatment.
- NIH (2025): Repeated head impacts cause early neuron loss and inflammation in young athletes — 56% neuron loss found in brain regions affected by CTE, even without tau buildup.
- Neurology Today (2025): New NINDS Consensus Criteria for Traumatic Encephalopathy Syndrome — First expert consensus criteria for TES, designed for research use.
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