Here's a party trick: your blood carries a library of tiny protein signatures that can rat out what's happening deep inside your skull, long before you forget where you left the car keys. Scientists have now read that library in the veins of former elite rugby players, and the story it tells is equal parts sobering and extraordinary.
The Scrum Inside Your Skull
A team led by Dr. Neil Graham at Imperial College London recruited 197 former elite rugby players and 33 controls for the Advanced Brain Health Clinic (ABHC) cohort, then ran their blood through a rather spectacular piece of kit called NULISA - a Nucleic acid Linked Immuno-Sandwich Assay that can detect proteins at concentrations so vanishingly small they make a needle in a haystack look conspicuous. We're talking attomolar sensitivity - roughly one molecule per drop of blood. The platform screened 124 brain-related proteins in each participant's plasma, hunting for molecular breadcrumbs left behind by years of repetitive head impacts (Graham et al., 2025).
The results? Former players carried a distinctive proteomic fingerprint compared to controls. Three proteins were noticeably reduced: GFAP (which supports brain cells like scaffolding around a crumbling building), SNAP25 (a synaptic protein that helps neurons pass notes to each other), and KLK6, an endothelial serine protease that, like a conscientious housekeeper, helps tidy up amyloid and other troublesome proteins in the brain (Prassas et al., 2015). Reduced KLK6 across the entire ex-player group was particularly intriguing - it suggests a shared biological shift, regardless of playing position.
Forwards March (Into Trouble)
Here's where it gets properly interesting. When the researchers split their rugby players by position, the forwards - those noble, bruised souls who spend matches with their heads wedged in scrums and their skulls collecting impacts like loyalty points - showed a distinctly different pattern from backs. Forwards had reduced levels of BACE1 and amyloid beta-38, enzymes and peptides involved in the amyloid processing pathway. They also showed elevated phospho-tau-181, a marker associated with the tangles of tau protein that characterise both Alzheimer's disease and chronic traumatic encephalopathy (CTE).
In other words, the players who absorb the most head impacts carry the most alarming molecular signatures. Your mother was right to worry every time you packed down in a scrum.
Why a Blood Test Changes Everything
CTE, the neurodegenerative disease haunting contact sports from rugby to American football to boxing, currently has a rather inconvenient diagnostic requirement: you have to be dead. It can only be confirmed by autopsy, which is, as diagnostics go, somewhat final. The search for living biomarkers has been described as the holy grail of sports neurology, and recent initiatives like the NIH's $15 million DIAGNOSE CTE Research Project are betting big on finding them (Halicki et al., 2023).
What Graham's team has done is demonstrate that ultrasensitive blood proteomics can detect meaningful biological differences in midlife, years before clinical dementia appears. Of the 197 ex-players studied, 24 (about 12%) met criteria for traumatic encephalopathy syndrome (TES) - the clinical counterpart of CTE - but critically, none had dementia. This is a window of opportunity, not a death sentence.
The Quiet Promise of KLK6
Among the findings, reduced plasma KLK6 stands out as potentially the most useful. Unlike the position-specific changes in forwards, KLK6 was reduced across all former players, suggesting it could serve as a broad screening biomarker for the effects of repetitive head impacts. Kallikrein-6 is abundantly expressed in the central nervous system, particularly in the brain stem, hippocampus and spinal cord, and has been previously linked to amyloid metabolism in Alzheimer's disease research (Diamandis et al., 2004). Its reduction in ex-players could signal disrupted protein clearance pathways - like the brain's janitorial service calling in sick.
What Happens Next
As Dr. Graham himself put it, these findings show "a distinctive fingerprint in ex-rugby players," though "clinical significance remains unclear." The companion study using SiMoA assays found that elevated phospho-tau-217 was associated with TES in the same cohort, reinforcing the proteomic findings from a different analytical angle (Graham et al., 2025).
The honest truth is that we're at the stage of reading tea leaves with extraordinary precision - we can see the patterns, but we don't yet know exactly what fortunes they predict. Longitudinal follow-up will be essential. But the fact that a simple blood draw in midlife can reveal the molecular aftermath of a rugby career, years before cognitive symptoms appear, is the kind of advance that Oscar Wilde might have appreciated: "The truth is rarely pure and never simple," he wrote, but sometimes it shows up in a vial of plasma.
References
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Graham, N., Zimmerman, K., Hain, J., et al. (2025). Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players. Journal of Neurology, Neurosurgery & Psychiatry. DOI: 10.1136/jnnp-2025-336593. PMID: 41047224
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Graham, N.S.N., Zimmerman, K., Hain, J., et al. (2025). Biomarker evidence of neurodegeneration in mid-life former rugby players. Brain, 148(8), 2684-2697. DOI: 10.1093/brain/awaf152. PMID: 40602789
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Halicki, M.J., Hind, K., & Chazot, P.L. (2023). Blood-Based Biomarkers in the Diagnosis of Chronic Traumatic Encephalopathy: Research to Date and Future Directions. International Journal of Molecular Sciences, 24(16), 12556. DOI: 10.3390/ijms241612556. PMID: 37628736. PMCID: PMC10454393
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Ashton, N.J., et al. (2025). Biomarker discovery in Alzheimer's and neurodegenerative diseases using Nucleic Acid Linked Immuno-Sandwich Assay. Alzheimer's & Dementia, 21(5), e14621. DOI: 10.1002/alz.14621. PMID: 40401628. PMCID: PMC12096316
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Prassas, I., et al. (2020). Involvement of Kallikrein-Related Peptidases in Nervous System Disorders. Frontiers in Cellular Neuroscience, 14, 166. DOI: 10.3389/fncel.2020.00166
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.