Menardi et al. 2026; Functional dispersion within amyloid-present contexts
Chloe Chen; 17
Neil S N Graham, Karl A Zimmerman, Jessica Hain, Erin Rooney, Ying Lee, Martina Del Giovane, Thomas Parker, Mathew G Wilson, Paresh Malhotra, Michael C B David, Magdalena Kolanko, Maneesh Patel, Elena Veleva, Owen Swann, Amanda Heslegrave, Henrik Zetterberg, Daniel Friedland, Richard Sylvester, David J Sharp, Biomarker evidence of neurodegeneration in mid-life former rugby players, Brain, Volume 148, Issue 8, August 2025, Pages 2684–2697, https://doi.org/10.1093/brain/awaf152
The purpose of this study was to determine whether mid-life former elite rugby players show biological evidence of neurodegeneration associated with repetitive head impacts and traumatic brain injury. While epidemiological studies suggest increased long-term neurological risk in contact-sport athletes, objective in-vivo biomarker evidence in relatively young, non-demented former players has been limited. The authors aimed to address this gap using advanced blood-based and neuroimaging markers.
The study included 200 former elite rugby players (median age 44 years) and 33 age-matched controls without exposure to contact sports. Participants underwent blood sampling to measure plasma biomarkers of neurodegeneration and brain injury, including phosphorylated tau-217 (p-tau217), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β, using ultrasensitive assays. Structural 3-Tesla MRI was used to assess brain volumes, and participants completed neuropsychological and clinical assessments, including evaluation for traumatic encephalopathy syndrome (TES). Statistical models examined group differences and associations between biomarkers, clinical features, and brain structure.
Results showed that former rugby players had significantly higher plasma p-tau217 levels than controls, with nearly one-quarter showing abnormal elevations on an individual basis. A smaller proportion showed elevated NfL, while overall biomarker levels were lower than those typically seen in Alzheimer’s disease, suggesting a distinct pathological process. MRI analyses revealed reduced frontal and cingulate cortical volumes, and longer playing careers were associated with lower hippocampal and white-matter volumes.
Clinically, 12% of former players met criteria for TES, although none had dementia. Elevated p-tau217 was more common in those with TES, and higher NfL levels were associated with greater mood symptoms. Overall, the findings provide converging biomarker and imaging evidence of early neurodegenerative changes in mid-life former rugby players, supporting the use of fluid and MRI biomarkers to detect long-term brain effects of repetitive sports-related head impacts.
Author's Note
I was intrigued by the methodology of this study--the selection of p-tau217, NfL, GFAP, and amyloid-Beta, as well as TES and MRI tests. I'm only familiar with quantifying p-tau217 and amyloid-Beta from my personal AD research, so I found it fascinating how they used additional biomarkers. This methodology has given me some personal inspiration for the next steps of my research and how I can personally integrate more biomarkers for analysis (hopefully, I have the resources to do so next year).
Back to the content itself: Although the rugby players didn't have dementia, the development of AD-like biomarkers and neurodegeneration highlighted to me the severity of head impacts. As a volleyball athlete myself, I've been hit in the head many times, so this paper really reinforced my instinct to protect my brain, specifically my hippocampal and white-matter volumes.
I'm curious how the placebo effect was prevented in this study--how did they integrate blocking? I feel like its common knowledge that repeated head trauma will indeed lead to a certain level of brain damage, so when the participants took the TES exam, I wonder if there was any perceived "right answer".
Rating: This study was easily worded, and the underlying theme is novel in context but the more complicated nuances are explained well.