Chronic traumatic encephalopathy (CTE) progresses through four pathological stages, numbered I through IV, based on how much abnormal tau protein has built up in the brain and how far it has spread. This staging system, proposed by neuropathologist Ann McKee and colleagues in 2013, tracks the disease from isolated clusters of tau in a few regions to a devastating, brain-wide accumulation that produces dementia. Because CTE can only be definitively confirmed after death through brain examination, the stages describe what pathologists see under the microscope, though the symptoms that tend to accompany each stage are increasingly well documented.
The McKee Staging Framework
The staging scheme classifies CTE severity by the density and regional spread of hyperphosphorylated tau, a form of the tau protein that clumps abnormally and disrupts brain-cell function. Stage I represents mild tau deposits, and stage IV represents severe, widespread accumulation.1PubMed Central. Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme This is not a timeline with fixed years attached to each stage. Two people with similar head-impact histories might be at different stages at the same age, and progression speed varies. The framework is better understood as a map of how widespread the damage is at the moment a brain is examined, not a prediction of when each phase will begin.
One thing worth noting is that tau in CTE deposits in a distinctive pattern that sets it apart from other neurodegenerative diseases. It tends to cluster around small blood vessels at the depths of the brain’s folds, called sulci. That perivascular signature is the defining neuropathological feature of CTE and is present even in the earliest stage.
Stages I and II
In stage I, tau deposits are sparse and focal. They appear in isolated spots, typically at the depths of cortical sulci in the frontal lobe. These early clusters are often too limited to produce dramatic symptoms, but they are not completely silent. A large case series found that the most common symptoms associated with stage I were headache and difficulty with attention and concentration.2PubMed Central. The spectrum of disease in chronic traumatic encephalopathy Many people at this stage might attribute those problems to stress, aging, or lingering effects of individual concussions rather than an ongoing degenerative process.
Stage II involves more tau deposits spreading beyond the initial frontal-lobe hotspots. Tau begins showing up in additional cortical areas and sometimes in deeper brain structures. The symptom profile broadens to include depression, explosivity, and short-term memory loss.2PubMed Central. The spectrum of disease in chronic traumatic encephalopathy The mood and behavioral changes at this stage can be significant enough to disrupt relationships and daily life. Some individuals become impulsive or emotionally volatile in ways that feel out of character, and the short-term memory deficits go beyond normal forgetfulness.
Stages III and IV
Stage III marks a substantial jump in both the extent of tau pathology and the severity of cognitive problems. Tau has now reached the medial temporal lobe, the region critical for memory formation, including the hippocampus and surrounding cortex. Stereological analyses of brain tissue show significantly more tau-positive neurons and damaged neurites in the entorhinal cortex, perirhinal cortex, and hippocampal regions at stage III compared to stage II.3BioMed Central / Acta Neuropathologica Communications. Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study Clinically, executive dysfunction and broader cognitive impairment become apparent. People at stage III often struggle with planning, organizing, and problem-solving in ways that interfere with work and independent living.2PubMed Central. The spectrum of disease in chronic traumatic encephalopathy
Stage IV is the most severe. Tau pathology is widespread throughout the cortex, deep brain nuclei, and brainstem. The brain itself is visibly shrunken, with prominent atrophy in frontal and temporal regions and noticeably enlarged ventricles. MRI studies of donors later confirmed to have advanced CTE show marked atrophy of the orbital-frontal, dorsolateral frontal, and anterior and medial temporal lobes, with substantially larger lateral and third ventricles compared to unimpaired individuals.4PubMed Central. Structural MRI profiles and tau correlates of atrophy in autopsy-confirmed CTE Symptoms at this stage include dementia, word-finding difficulty, and aggression.2PubMed Central. The spectrum of disease in chronic traumatic encephalopathy Many people require full-time care. The personality changes and cognitive losses are profound enough that family members often describe the person as fundamentally different from who they once were.
Why the Damage Starts Where It Does
One of the more interesting questions about CTE is why tau first shows up at the bottom of the brain’s cortical folds rather than, say, on the surface or uniformly across the brain. The answer appears to be mechanical. When the head absorbs an impact, the brain does not experience uniform stress. The geometry of sulci, the grooves between folds, creates stress concentrations at their depths, much the way a crack in a material focuses force at its tip.
Computational modeling of head impacts shows that the sulci geometry produces complex stress waves that interact with one another, creating shear stresses at the depths of sulci that are dramatically larger than in analyses modeled without those folds.5PubMed. A mesoscale finite element modeling approach for understanding brain morphology and material heterogeneity effects in chronic traumatic encephalopathy Separate modeling work confirmed that both strain and strain rate were greatest in the sulci, distributed symmetrically at the depths of these grooves, matching the pattern of early CTE pathology observed in brain banks.6Brain. Computational modelling of traumatic brain injury predicts the location of chronic traumatic encephalopathy pathology In other words, the brain’s own folded architecture makes certain spots uniquely vulnerable to repeated impacts. That is where CTE begins, and from there it spreads outward.
What Drives Progression
The most straightforward predictor of how far CTE progresses is cumulative exposure to repetitive head impacts. A study of ice hockey players found a clear dose-response relationship: each additional year of play increased the odds of a CTE diagnosis by about a third, and each year also corresponded to a measurable increase in overall tau burden throughout the brain.7JAMA Network Open. Duration of Ice Hockey Play and Chronic Traumatic Encephalopathy More years of head-impact exposure means more tau, and more tau means a higher stage.
But exposure alone does not tell the whole story. The brain’s immune cells, called microglia, appear to play an active role in driving tau accumulation. Research in CTE brains has shown that activated microglia and tau deposits feed off each other in a positive feedback loop: more tau triggers more microglial activation, and more microglial activation leads to even more tau.8PubMed Central. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy About 14% of the effect that repetitive head impacts have on tau buildup appears to work through this microglial inflammation pathway, with the rest being a direct effect of the impacts themselves.8PubMed Central. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy The microglia drive continuous, low-level inflammation that persists long after the last hit, which helps explain why CTE can worsen years or decades after someone stops playing a contact sport.9PubMed Central. The Role of Microglia in the Etiology and Evolution of Chronic Traumatic Encephalopathy
Emerging research also implicates disruption to the brain’s waste-clearance systems. Traumatic brain injury appears to impair the glymphatic system, a network that flushes proteins and metabolic waste from brain tissue using cerebrospinal fluid. When this system is compromised, harmful proteins including tau accumulate around blood vessels instead of being cleared, potentially accelerating the perivascular tau deposits that define CTE.
How CTE Differs From Alzheimer’s Disease
Because both CTE and Alzheimer’s disease involve tau tangles in the brain, people sometimes wonder whether they are really the same condition or whether a CTE diagnosis might be confused with Alzheimer’s. They are distinct diseases with different tau patterns, even when they overlap in the same brain. In the hippocampus, CTE shows high levels of tau in the CA2 and CA3 subfields, whereas Alzheimer’s tends to hit CA1 and the subiculum harder. Direct comparison confirms that CTE has greater tau density in CA4 and CA2/3, while Alzheimer’s shows more in the subiculum.10PubMed Central. Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease These differences in where tau concentrates within hippocampal subfields could eventually be useful for distinguishing the two diseases in living people as imaging tools become more precise.
The diseases also differ in the type of tau involved and its relationship to blood vessels. The hallmark perivascular pattern of tau at the base of cortical sulci is specific to CTE and is not seen in Alzheimer’s. Alzheimer’s disease also involves amyloid-beta plaques as a core feature, which, while sometimes found alongside CTE, are not required for a CTE diagnosis. Still, the two conditions can coexist, and advanced CTE with concurrent Alzheimer’s pathology is not uncommon in older individuals, complicating the clinical picture.
Diagnosing CTE in Living People
The biggest frustration about the CTE staging system is that it currently requires a post-mortem brain examination to apply. You cannot get a definitive CTE stage while alive. Researchers are working hard to change that. One proposed clinical framework, called traumatic encephalopathy syndrome (TES), uses a person’s history of head-impact exposure combined with clinical signs to estimate whether someone likely has CTE. It is not a pathological diagnosis, but it gives clinicians something to work with.
Imaging biomarkers are a promising area. A study of active and retired combat-sport fighters found that those meeting TES criteria had mammillary bodies roughly 15% smaller and fornix volumes about 24 to 29% smaller than fighters without TES and healthy controls.11PubMed. Volume Loss in the Mammillary Bodies, Fornix, and Other Papez Circuit Structures in Fighters with Traumatic Encephalopathy Syndrome These structures are part of the brain’s memory circuit, and their shrinkage can be detected on standard MRI. If validated in larger populations, this kind of imaging could eventually help identify CTE-related changes before symptoms become severe, though we are not there yet.
PET scans that bind to tau protein are another active research frontier. Several tau tracers are being tested, but none has been approved specifically for CTE diagnosis. The challenge is that CTE tau and Alzheimer’s tau have slightly different molecular structures, so a tracer that lights up Alzheimer’s tangles may not bind as well to CTE tangles. The field is getting closer, but for now, a living person can receive a clinical assessment and imaging consistent with CTE without receiving a confirmed pathological stage.
Genetic Factors That Influence Severity
Not everyone with the same head-impact history ends up at the same CTE stage, which raises the question of genetic vulnerability. The most studied gene in this context is APOE, particularly the ε4 variant that is already well known for increasing Alzheimer’s risk. Among brain-bank donors older than 65, carrying at least one copy of APOE ε4 was associated with more than double the odds of a higher CTE stage and significantly greater tau burden in the frontal lobe.12PubMed Central. Association of APOE Genotypes and Chronic Traumatic Encephalopathy The association was specific to older individuals, which suggests that the gene’s effect may become more important as the brain ages and its ability to cope with accumulated damage diminishes.
Age at first exposure to head impacts also matters independently of total years of play. In a study of symptomatic former NFL players, younger age at first exposure to repetitive head impacts was associated with smaller thalamic volume later in life, and the effect of starting age was almost twice as strong as the effect of total playing years.13PubMed Central. Age at First Exposure to Repetitive Head Impacts Is Associated with Smaller Thalamic Volumes in Former Professional American Football Players Smaller thalamic volume, in turn, was linked to worse visual memory and more mood and behavioral symptoms. The developing brain appears to be more vulnerable to the kind of structural damage that sets the stage for later CTE progression.
CTE Beyond Contact Sports
CTE was first recognized in boxers decades ago, and most research has focused on athletes in contact and collision sports. But the condition is not exclusive to the playing field. Examination of post-mortem brains from U.S. military veterans exposed to blast injuries and concussive impacts revealed CTE pathology similar to what is seen in young amateur football players and professional wrestlers.14PubMed Central. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model The blast wave from an explosion creates mechanical forces in the brain that, while different in character from a helmet-to-helmet collision, can produce the same type of perivascular tau deposits at the base of sulci.
Cases have also been documented in people with histories of domestic violence, epilepsy-related repeated head impacts, and head-banging behavior. The common thread is not any particular sport or activity but cumulative exposure to repetitive head trauma, regardless of the source. The staging system applies the same way in all these populations: it describes how far tau has spread, not how it got there.
Motor Symptoms and the TDP-43 Connection
The four-stage framework focuses on tau, but CTE sometimes involves a second abnormal protein called TDP-43. When TDP-43 pathology accompanies CTE, motor symptoms can emerge, including parkinsonism, meaning movement difficulties such as tremor, stiffness, and slowed gait, and in rare cases something resembling motor neuron disease.15PubMed Central. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma Not everyone with CTE develops motor symptoms, and not all CTE brains contain TDP-43, but when it appears, the clinical picture becomes more complex than the tau-based staging alone would suggest.
Recent research examining spinal cord tissue from people with confirmed CTE found TDP-43 pathology in half the cases, with the prevalence rising to about two-thirds among those aged 65 or older.16JAMA Neurology. Spinal Cord Tau and Protein Copathologies Associated With Chronic Traumatic Encephalopathy The presence of TDP-43 in the spinal cord helps explain why some CTE patients develop weakness and motor decline that goes beyond what you would expect from brain tau alone. This is an area where the staging system’s focus on tau may understate the full range of disease. Clinicians and researchers are beginning to think of CTE as a condition that can involve multiple pathological proteins, with tau being the most consistent but not always the only one.
Psychiatric Symptoms and the Suicidality Question
Depression, irritability, impulsivity, and apathy appear throughout the CTE staging spectrum, from early stages onward.15PubMed Central. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma These behavioral and mood changes can be among the most distressing aspects of the disease for both the affected person and their family, and they sometimes appear years before cognitive decline becomes obvious.
Suicide is a common cause of death among people later found to have CTE at autopsy, which has led to public speculation that CTE directly causes suicidal behavior. The reality is more complicated. Brain-bank studies inherently have a selection problem: autopsies are more likely to be performed after a suicide, especially when the family suspects CTE, which inflates the apparent association. The 2021 diagnostic criteria for TES did not include suicidality as a clinical feature of CTE because there is no direct evidence yet that the neuropathology itself drives suicidal behavior as opposed to the depression, impulsivity, and life disruption that accompany it.17JAMA Neurology. Perceived CTE and Suicidality—Is Perception Reality? This does not mean CTE is unrelated to suicide risk. It means the relationship is tangled up with mood symptoms, personality changes, substance use, and the psychological burden of living with a progressive brain disease, and it is difficult to isolate CTE neuropathology as the direct cause. For anyone struggling with these symptoms, treatment of the depression and behavioral changes matters regardless of whether a formal CTE diagnosis is possible.
What a Staging System Cannot Tell You
The four-stage model is the best tool neuropathologists have for describing CTE severity, but it has real limitations that are worth understanding. It was developed from brain-bank samples, which skew heavily toward people who were symptomatic or died under circumstances that prompted donation. The full spectrum of CTE in the general population, including how many people with head-impact histories have early-stage pathology without symptoms, remains unknown. Some researchers have found tau deposits consistent with stage I in people who had no reported cognitive or mood symptoms during life, raising the possibility that the earliest pathology can exist subclinically for years or even indefinitely in some individuals.
The staging system also describes a single snapshot at death. It does not tell you how quickly someone moved from stage II to stage III, or whether some people plateau at a given stage. Animal models of repetitive mild traumatic brain injury show persistent neuroinflammation and elevated tau for months after the last injury, but whether that inflammation eventually resolves or only accelerates remains an open question in humans.18PubMed Central. The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy Prevention through reducing head-impact exposure is currently the only reliable strategy. There are no approved treatments that slow or reverse CTE progression, and until living diagnosis becomes routine, clinical trials will remain extremely difficult to design.19PubMed Central. Chronic traumatic encephalopathy: a review The staging system gives researchers a shared language for describing what they find, but the gap between describing the disease and being able to intervene in it is still wide.