Clinicopathological study of chronic traumatic encephalopathy pathology in a population-based cohort

INTRODUCTION

Chronic traumatic encephalopathy neuropathological changes (CTE-NC) is a progressive neurodegenerative disease currently defined neuropathologically as a region-specific accumulation of hyperphosphorylated tau protein (p-tau) with the mandatory finding of p-tau aggregates in neurons at the depth of a cortical sulcus and around small blood vessels.¹ CTE-NC has garnered increasing attention due to its high prevalence in individuals exposed to contact sports and to a lesser extent, military service.^2,3 Clinically, CTE-NC typically manifests with a range of cognitive, behavioral, and mood symptoms that develop gradually over time. A greater severity of CTE-NC pathology has been associated with increased risk of dementia,^4,5 but low levels of CTE-NC can also be found incidentally.^1,6

The marked overrepresentation of CTE-NC among individuals exposed to repetitive head impacts (RHIs) supports a causal role for RHI in the development of CTE-NC.^7–11 Nonetheless, critics point to the long latency between exposure and clinical disease and to occasional cases without documented RHI, leaving open whether additional etiologies contribute.¹² A decisive way to adjudicate the role of RHI is to estimate the frequency of CTE-NC in populations not selected for RHI exposure. If the population frequency is substantially lower than in RHI-enriched cohorts, that pattern would reinforce RHI as the predominant driver; if it is not rare, it would suggest additional factors worth systematic study. Determining this baseline frequency is therefore essential, though challenging because definitive diagnosis currently requires postmortem neuropathological examination.¹³

A few clinicopathological studies have attempted to address this question by examining cohorts without known exposure to RHI. These studies report very low CTE-NC frequencies—0% to <1% across approximately 1800 individuals.^14–20 However, these cohorts are not population-based: most are drawn from dementia clinics or from community samples heavily enriched for non-Hispanic White individuals with high educational attainment and very advanced age at death, often ascertained through clinical pathways. Such selection and survivorship biases limit generalizability to more diverse and socioeconomically disadvantaged populations who may face higher risks of both dementia and head trauma.²¹ To fill this gap, we conducted a comprehensive review of histological slides from 1151 individuals in the Biobank for Aging Studies at the University of São Paulo (BAS-USP), a population-based cohort composed of diverse individuals with a broad range of educational backgrounds and socioeconomic statuses (SESs). This represents the largest single cohort evaluated for CTE-NC to date.

METHODS

RESULTS

DISCUSSION

This study presents a comprehensive clinicopathological investigation of CTE-NC frequency in a large, population-based, admixed cohort from São Paulo, Brazil. Our findings reveal a notably low prevalence of CTE-NC, observed in only 0.6% of the 1151 individuals examined. This frequency aligns with other population-based studies that have reported similarly low rates ranging from 0% to <1%.^14,17–19 While our results are consistent with previous reports, this study also extends the current understanding of CTE-NC by examining a demographically and socioeconomically distinct population. Unlike many prior cohorts from high-income countries, our sample includes individuals from an admixed population in a middle-income country, with generally lower SES, age at death, and educational attainment. The low frequency of CTE-NC in this population, 1 not enriched for contact sports participation or other sources of RHI/TBI, adds further support to the notion that CTE-NC remains rare in the general population and is more commonly observed in individuals with known exposure to RHIs.

Interestingly, while most of the cases in our series were classified as early-stage CTE (stage I or II, with only 2 cases reaching stage III), application of the severity criteria proposed by the Second NINDS/NIBIB Consensus Meeting yielded a different perspective, with 6 out of 7 cases categorized as having a high burden of pathology. Differences reflect that the 2021 NINDS/NIBIB severity algorithm weights medial temporal/diencephalic/cerebellar NFTs; thus, limited cortical distribution (McKee stage II) can still meet high severity when deep region involvement is present. A brain with 3 cortical foci (stage II) could still score high if it also shows NFTs in several deep regions. This discrepancy highlights a potential divergence between the staging and severity frameworks, particularly when applied to samples drawn from the general population rather than from highly selected, sports-related cohorts. Further work is needed to clarify which of these classification schemes better capture the clinicopathological spectrum of CTE, and to determine their relative value in predicting clinical outcomes and public health implications.

Although the overall frequency of CTE-NC in our cohort was low, the sex-related disparity was notable: 6 of the 7 CTE-NC cases were male. This finding reinforces previous reports demonstrating a very low incidence of CTE-NC in females in studies that included women in their samples.^14,17–19 This disparity circles back to the question of CTE-NC etiology and its likely association with repetitive TBI. Lower rates of CTE-NC in females are thought to reflect reduced exposure to contact sports and combat training.^34,35 Two additional reports have identified CTE-NC in females with documented histories of chronic exposure to domestic violence.^36–38

Regarding the female with stage I CTE-NC identified in our cohort, a postmortem interview conducted at the time of autopsy indicated that she was never married and had lived alone independently. We attempted, unsuccessfully, to contact the next of kin listed in the autopsy records to obtain information about any potential history of TBI. Similarly, we were unable to reach the next of kin for the other 6 individuals with CTE-NC. Of the 2 individuals known to have played soccer, which may be associated with CTE-NC,^39,40 neither had a history of TBI. However, the absence of a recorded TBI history does not necessarily imply the absence of TBI exposure, especially considering the 5 out of 7 cases collected before 2019. Studies in American athletes have shown that, despite concussion education, the majority of concussions go unreported and undiagnosed.⁴¹ Furthermore, approximately 20% of athletes diagnosed with CTE had no documented history of TBI.⁴² It is presumed that many of these individuals, who sustained thousands of head impacts over the course of their athletic careers, did not report their symptoms or experienced subclinical repetitive TBIs.³⁴

We found no significant differences in the prevalence of common cerebrovascular risk factors, including hypertension, diabetes, smoking, and alcohol abuse, between individuals with and without CTE-NC pathology. Regarding the latter, although there is no direct scientific evidence linking alcohol abuse to the development of CTE, some opinion pieces and observational studies have proposed that alcohol misuse may contribute to TBI independent of contact sports exposure, particularly among college athletes due to increased risk of falls and accidents.^43,44 In our cohort, despite a relatively high prevalence of alcohol abuse (approximately 25%), the frequency of CTE-NC remained extremely low.

Co-pathology was common in our CTE-NC cases, with most individuals also exhibiting additional tau-related changes, consistent with prior cohorts.^45–47 While not unexpected, this underscores a key methodological challenge for population- or community-based samples: low-burden CTE-NC can be overlooked when overlapping tauopathies, such as ARTAG, AD, or AGD, are present. Given our sample composition (7 CTE-NC vs 545 ARTAG), we are not powered to determine whether ARTAG patterns differ between normal aging and CTE-NC; this is an important question for targeted, prospectively sampled studies. Although the prevalence of multiple pathologies increases with age, TBI has also been associated with higher risk of other neurodegenerative pathologies, including AD and LBD.^48,49 These coexisting pathologies may obscure or mimic the subtle features of CTE-NC, reinforcing the need for comprehensive and nuanced neuropathological assessments in nonselected populations.

There is evidence linking lower SES to increased risk of TBI.⁵⁰ People from disadvantaged backgrounds are more likely to face environmental and occupational hazards, such as dangerous work conditions, poor housing, limited safety equipment, and higher rates of violence. Lower SES is also associated with reduced access to health care and prevention, which can delay diagnosis and worsen TBI outcomes. However, in our population-based cohort, individuals with CTE-NC pathology tended to have higher SES and identified as White. While this may seem counterintuitive, it may reflect differences in the type, frequency, or context of TBI exposure not captured by SES alone. For example, individuals with higher SES may be more likely to participate in organized, RHI sports (eg, amateur or professional football, rugby, martial arts), which are more strongly associated with CTE-NC than to isolated or accidental injuries.

In addition to the diversity and population-based nature of the cohort, a key strength of this study is the prospective neuropathological examination of all cases for CTE and ARTAG using freshly prepared, simultaneously stained slides. All slides were processed with the same antibody clone, lot, and protocol, and were reviewed by a single observer to reduce interrater variability. This methodological consistency enhances the reliability of our findings, particularly in distinguishing between CTE and ARTAG, 2 pathologies with overlapping features. Notably, previous studies have suggested that the use of looser diagnostic criteria can lead to misclassification of ARTAG as CTE, potentially inflating CTE prevalence.^51,52 However, our study has several limitations. The retrospective nature of the clinical data and reliance on informant interviews introduce the potential for recall bias, which may affect the accuracy of reported medical and exposure histories. Additionally, the lack of systematic data on sports participation and TBI history for most subjects limits our ability to fully assess these specific risk factors. Nonetheless, this limitation would be a major concern only if the frequency of CTE-NC in our cohort were high, as it would hinder our ability to explore potential etiologies. Given the very low prevalence observed, this limitation does not undermine the central finding: in populations not enriched for TBI exposure, the prevalence of CTE-NC is very modest.

In summary, this study reinforces that CTE is a rare finding in the general population and aligns with previous studies from high-income countries, suggesting that CTE is not widespread in the absence of significant rTBI exposure. Continued research in varied populations is critical to uncover the full spectrum of CTE pathology and its implications for public health.

FUNDING

The Biobank for Aging Studies and LIM-22 of the University of São Paulo supported by Fundação de Apoio a Pesquisa do Estado de São Paulo (FAPESP: 2006/55318, 2009/09134-4, 2012/07526-5, and 2024/03917-7), Conselho Nacional de Desenvolvimento Científico e Tecnológico (466763/2014-0, 465355/2014-5, and 403502/2020-9), and Alzheimer’s Association (AARG-20-678884 and 24CBIDR-1185483). This study received funds from the Concussion Legacy Foundation, and by Alzheimer’s Association (AARF 18-566005). L.T.G. is partially funded by National Institutes of Health (NIH) K24AG053435.

CONFLICTS OF INTEREST

CJN is a volunteer member of the Mackey-White Health & Safety Committee of the National Football League Players Association for which he receives travel support; he has received travel support from the NFL, NFL Players Association, World Rugby, WWE, Total Nonstop Action and AEW for lectures or conference. CJN is an advisor and options-holder with Oxeia Biopharmaceuticals, LLC, and StataDx; and CJN has served as an expert witness in cases related to concussion and CTE and is compensated for speaking appearances and serving on the Players Advocacy Committee for the NFL Concussion Settlement. CJN is employed by the Concussion Legacy Foundation, a 501(c)(3) non-profit which receives charitable donations. LTG is a member of the Medical and Scientific Advisory Board for the Alzheimer Association and member of the Governing Board of the Global Brain Institute at UCSF to which she has received travel support. She receives honorarium from Orator Inc for educational-related (commercial-free) talks about Alzheimer disease. The other authors have no conflicts of interest to declare.