Can You Diagnose CTE While Alive? The Current Science

As of now, no test, scan, or blood draw can definitively confirm chronic traumatic encephalopathy in a living person. The only way to reach a certain diagnosis is through a post-mortem brain autopsy, where a neuropathologist looks for a very specific pattern of abnormal tau protein clustered around blood vessels deep in the brain’s grooves. That said, the science is not standing still. Researchers have developed a clinical framework called traumatic encephalopathy syndrome (TES) to identify people who likely have CTE based on their symptoms and exposure history, and several experimental tools are inching closer to detecting the disease’s biological fingerprints during life.

What Makes CTE Unique Under a Microscope

The reason a living diagnosis remains so elusive starts with what CTE actually looks like in brain tissue. CTE is defined by a hallmark lesion: clumps of phosphorylated tau protein that accumulate around small blood vessels at the bottom of the cortical sulci, the deep folds on the brain’s surface. This pattern is distinct from every other known brain disease. Alzheimer’s disease involves tau as well, but the tau in CTE has a different structural configuration at the molecular level and shows up in different locations.¹ Any living diagnostic tool has to somehow detect or approximate that very specific signature without the benefit of slicing and staining brain tissue. That is the core challenge researchers are trying to solve.

Traumatic Encephalopathy Syndrome as a Clinical Stand-In

Because a definitive diagnosis is off the table during life, researchers at the National Institute of Neurological Disorders and Stroke (NINDS) created formal consensus criteria for what they call traumatic encephalopathy syndrome, or TES. TES is not the same as a CTE diagnosis. It is a clinical label that captures the syndrome believed to be associated with the underlying CTE pathology. The criteria require four things: substantial exposure to repetitive head impacts (from contact sports, military service, or other causes); core clinical features of cognitive impairment in memory or executive functioning, or neurobehavioral problems like impulsivity and aggression; a progressive course where symptoms get worse over time; and the absence of another condition that fully explains the symptoms.²

For patients who meet TES criteria, the framework also assigns a provisional level of certainty for CTE pathology based on how much head impact exposure they had, how severe their symptoms are, and whether additional features like delayed symptom onset or motor problems are present. Earlier proposals had broken TES into subtypes: a behavioral/mood variant (marked by explosivity, depression, and hopelessness), a cognitive variant (memory loss and executive dysfunction), a mixed variant, and a dementia subtype.³ The subtype idea reflects a real clinical observation: two people with CTE can look very different. One may primarily struggle with rage and impulsivity while another slowly loses the ability to remember conversations. This variability makes TES useful as a research tool but frustrating as a diagnostic one, because the symptoms overlap heavily with other conditions.

The Problem of Lookalike Diseases

CTE’s symptom profile overlaps with a long list of other diagnoses, including Alzheimer’s disease, behavioral variant frontotemporal dementia, Parkinson’s disease, ALS, mood disorders, and PTSD.⁴ The overlap is not just clinical. Many of the biomarkers researchers have studied for CTE are also elevated in those other conditions, which limits their usefulness for telling CTE apart from, say, early Alzheimer’s.⁵

Making matters worse, autopsy studies show that CTE rarely travels alone, especially in older individuals. People with CTE pathology frequently also have Alzheimer’s-type plaques, TDP-43 protein deposits, or other neurodegenerative changes piled on top of the CTE. One case report of a former professional soccer player who died in his mid-sixties illustrates this complexity: his clinical picture looked like Alzheimer’s disease, but amyloid PET imaging during life showed no elevated beta-amyloid plaques. At autopsy, he had severe CTE-related tau pathology and also TDP-43 inclusions in the frontal lobe and hippocampus.⁶ A broader study of these mixed pathologies concluded that the diverse combinations of brain disease accompanying CTE make it unwise to attribute cognitive or neurological symptoms in older patients solely to presumptive CTE.⁷ The implication for living diagnosis is sobering: even if you could perfectly detect CTE tau in the brain, you might still be missing other pathologies driving the patient’s symptoms.

Tau PET Scans and What They Can and Cannot See

The most talked-about experimental tool for detecting CTE during life is tau PET imaging. This technique uses a radioactive tracer, most commonly flortaucipir, that binds to tau protein in the brain and lights up on a scan. A study of former NFL players found that average flortaucipir signal was higher in former players than in controls across several brain regions, including the superior frontal cortex and medial temporal lobe. The signal also correlated with years of football played, suggesting a dose-response relationship between head impacts and tau accumulation.⁸

Those group-level findings are encouraging, but tau PET has real limitations for individual diagnosis. A small study that compared end-of-life flortaucipir PET scans to post-mortem brain tissue in six former football players found a strong correlation between PET signal and actual tau density in cortical and limbic regions. However, the scans showed modest signal overall, and some CTE and non-CTE cases had overlapping scan values, meaning the scan alone could not cleanly separate who had the disease from who did not.⁹ The tracer also has known off-target binding in certain brain regions like the thalamus, which can muddy the picture. And since flortaucipir was originally designed to detect Alzheimer’s-type tau, it may not be perfectly tuned to CTE’s distinct tau configuration. Researchers are working on next-generation tracers, but none have yet been validated for CTE specifically.

What Brain Scans Reveal About Structure

Standard MRI cannot diagnose CTE, but structural brain scans in former contact sport athletes consistently show patterns of shrinkage that differ from healthy controls. Data from the DIAGNOSE CTE Research Project, a large multicenter study involving 170 former American football players and 54 unexposed controls, found that former players had reduced cortical thickness and volume in the hippocampus, amygdala, entorhinal cortex, and several other regions.¹⁰ Those happen to be brain areas where CTE pathology concentrates, which is suggestive but not proof of CTE in any individual.

White matter, the brain’s wiring, also shows changes. In former NFL players, increased volume of white matter signal abnormalities on MRI was linked to higher cumulative head impact scores and worse performance on tests of processing speed and executive function.¹¹ Diffusion tensor imaging, which measures the integrity of white matter tracts, has shown some differences in former players as well, though the findings have been limited and inconsistent across studies.¹² The problem with all structural imaging is the same: the changes overlap with normal aging, Alzheimer’s, and other conditions. An MRI might support a clinical picture consistent with TES, but it cannot confirm CTE on its own.

Blood and Spinal Fluid Biomarkers

The dream scenario for CTE detection would be a simple blood test. Researchers have investigated several candidates, with phosphorylated tau (p-tau) variants getting the most attention. Unfortunately, two of the most studied forms, p-tau181 and p-tau217, have not panned out for CTE. A study of patients meeting TES criteria found no support for either as an in vivo biomarker of CTE-related tau.¹³ A 2025 study reached a similar conclusion about p-tau217, though it did find that the marker could be useful for ruling out Alzheimer’s-type amyloid pathology in people at risk for CTE, which at least helps narrow the differential diagnosis.¹⁴

Cerebrospinal fluid (CSF) testing tells a slightly different story. Former professional athletes with multiple concussions had total tau levels in their spinal fluid that were roughly twice those of healthy controls, though still well below levels typical of Alzheimer’s disease. Higher CSF tau was also linked to worse white matter integrity and poorer performance on executive function tests.¹⁵ CSF testing is more informative than blood testing in some respects, but it requires a lumbar puncture, which is invasive enough that it is unlikely to become a routine screening tool. The broader takeaway from the biomarker field so far is that no single fluid marker reliably identifies CTE, and researchers widely agree that a combination of markers will probably be needed.¹⁶

Neuroinflammation as a Possible Window

One of the more recent angles in CTE biomarker research focuses on the brain’s immune response. Neuroinflammation appears to be an early and driving component of CTE, not just a bystander effect. A pilot study using a specialized PET tracer called [11C]DPA-713, which binds to a protein expressed during brain injury and repair (TSPO), found significantly increased signal in brain regions like the supramarginal gyrus and right amygdala in former NFL players compared to controls.¹⁷

The excitement around neuroinflammation is not just about another PET tracer. Researchers have argued that the specific pattern of immune activation in CTE may differ from the patterns seen in Alzheimer’s or frontotemporal dementia, potentially offering a disease-specific “signature.” Inflammatory markers like CCL11, CCL21, and GFAP have been proposed as candidate biomarkers worth investigating in clinical trials.¹⁸ The evidence is early-stage, and few studies have rigorously tested immune mediators as CTE-specific markers. But the logic is compelling: if CTE’s inflammatory fingerprint is distinct enough, it could be the piece that separates CTE from other tauopathies in a living patient.

Experimental Proteomic and Retinal Approaches

Beyond the major imaging and fluid biomarker tracks, researchers are exploring less conventional routes. One study analyzed proteins carried by tiny cellular packages called extracellular vesicles in the blood of former NFL players. Using machine learning, the team found that a combination of three proteins (COL6A3, COL6A1, and reelin) could distinguish former NFL players from controls with about 85% accuracy.¹⁹ That is a promising signal for a blood-based test, though the study compared former NFL players to unexposed controls, not to people with other neurodegenerative diseases. The harder test will be distinguishing CTE from Alzheimer’s or frontotemporal dementia using these markers.

The eye has also attracted interest. Because the retina is an extension of the central nervous system, researchers have explored whether retinal changes detectable by optical coherence tomography (OCT) could serve as a surrogate marker for brain damage from repetitive head impacts. A study of Olympic boxers found that retinal nerve fiber layer thickness and macula density changed significantly over an 18-month period and were thinner than in healthy non-athletes, suggesting that OCT could one day be useful as a quick, noninvasive screening tool.²⁰ This is exploratory work, and no one is claiming retinal scans can diagnose CTE. But as a cheap, fast, and completely painless test that could flag people for more in-depth evaluation, the concept has appeal.

Genetic Factors That Complicate the Picture

Not everyone who sustains years of repetitive head impacts develops CTE, and genetics almost certainly plays a role in who is vulnerable. One gene that has emerged from CTE research is TMEM106B, which is involved in how brain cells process proteins and manage their internal cleanup systems. In brain bank studies, carrying the risk version of a TMEM106B variant was associated with higher CTE stage in donors over 65, with an odds ratio of roughly 2.7, comparable in effect to playing more than eight years of contact sports.²¹ In younger donors (65 and under), the same variant was associated with much higher odds of dementia. Conversely, an earlier study found that the protective version of this same gene variant was linked to less tau pathology, less neuroinflammation, and reduced odds of dementia among people who already had CTE at autopsy.²²

Genetic variation like this matters for living diagnosis in two ways. First, it might eventually help clinicians estimate an individual’s risk profile more accurately. Second, and perhaps more importantly, it underscores why exposure alone cannot predict who will develop CTE. Two athletes with identical playing careers can have very different trajectories based on their genetic makeup. This is part of why a simple exposure-based diagnostic test has never worked.

How Head Impact Exposure and Cognitive Reserve Factor In

Cumulative head impact exposure remains one of the strongest predictors of later-life cognitive and behavioral problems in former athletes. A study of former high school and college football players found a threshold dose-response relationship between a cumulative head impact index and risk for cognitive impairment, executive dysfunction, depression, and apathy. The cumulative index outperformed simpler measures like total concussions or years of play.²³ This matters because most CTE-related damage likely comes from the accumulated subconcussive hits, not just diagnosed concussions.

On the other side of the equation, cognitive reserve, the brain’s built-up resilience from education, occupational complexity, and intellectual engagement, appears to delay the onset of CTE symptoms. In a study of people with autopsy-confirmed CTE, high occupational achievement predicted later age at onset of both cognitive and behavioral symptoms.²⁴ The disease was still there in the brain, but its clinical effects took longer to surface. For clinicians trying to assess a patient during life, this adds another layer of complexity: a high-functioning person could harbor significant CTE pathology without yet showing the symptoms that would trigger a TES diagnosis.

The DIAGNOSE CTE Project and the Path Forward

The largest coordinated effort to crack the living diagnosis problem is the DIAGNOSE CTE Research Project, a multicenter study designed to develop and validate in vivo biomarkers for CTE. The study enrolled 240 male participants aged 45 to 74, including 120 former professional football players, 60 former collegiate players, and 60 controls with no history of contact sports. Each participant underwent an extensive battery of tests: neuropsychological exams, tau and amyloid PET scans, MRI, lumbar puncture, blood draws, and standardized self-report measures.²⁵ The project is also building a shared bank of anonymized data and biological samples for the wider research community.

Early results from DIAGNOSE CTE have already contributed to several of the structural imaging and biomarker findings discussed throughout this article. The hope is that by following participants over time and eventually correlating their living data with post-mortem neuropathology (for those who donate their brains), the study can identify which combination of tests most reliably predicts CTE. This longitudinal design is critical. Cross-sectional studies comparing former athletes to controls can show group-level differences, but what clinicians actually need is a test that accurately classifies an individual patient. That higher bar has not been met yet for any tool or combination of tools, but the data pipeline to get there is actively being built.

Why a Single Test Probably Will Not Be Enough

Across all of these research tracks, one theme keeps recurring: no single biomarker, scan, or clinical checklist is likely to be sufficient on its own. CTE shares too many features with other diseases, from tau accumulation (also present in Alzheimer’s) to brain atrophy (present in nearly every neurodegenerative condition) to behavioral symptoms (present in psychiatric disorders and frontotemporal dementia). The eventual living diagnosis of CTE will almost certainly require a panel approach, combining head impact exposure history, clinical presentation, tau PET, fluid biomarkers, structural imaging, and possibly genetic risk profiling into an integrated assessment.¹⁶ Machine learning tools may ultimately be what synthesizes all that data into a probability score, since no human clinician can weigh dozens of variables simultaneously with the precision the problem demands. For now, anyone evaluated for possible CTE during life is getting a best-guess clinical assessment, not a confirmed diagnosis. That reality frustrates patients, families, and clinicians alike, but it is also what makes this one of the more active and fast-moving areas in neurodegenerative disease research.