Dispersion-based cognitive intra-individual variability in former American football players: Association with traumatic encephalopathy syndrome, repetitive head impacts, and biomarkers

<b>Background:</b> Exposure to repetitive head impacts (RHI), such as those experienced in American football, is linked to cognitive dysfunction later in life. Traumatic encephalopathy syndrome (TES) is a proposed clinical syndrome thought to be linked to neuropath­ology of chronic traumatic encephalopathy (CTE), a condition associated with RHI from football. Cognitive intra-individual variability (d-CIIV) measures test-score dispersion, indicating cognitive dysfunction. This study examined d-CIIV in former football players and its associations with TES diagnosis, RHI exposure, and DTI and CSF biomarkers. <b>Methods:</b> Data included 237 males (45–74 years) from DIAGNOSE CTE Research Project, including former professional and college football players (COL) (<i>n</i> = 173) and asymptomatic men without RHI or TBI (<i>n</i> = 55). Participants completed neuropsychological tests. TES diagnosis was based on 2021 NINDS TES criteria. Years of football play and a cumulative head impact index (CHII) measured RHI exposure. Lumipulse technology was used for CSF assays. DTI fractional anisotropy assessed white matter integrity. Coefficient of variation (CoV) measured d-CIIV. ANCOVA compared d-CIIV among groups (football versus control; TES-status). Pearson correlations and linear regressions tested associations between d-CIIV, RHI exposure, and CSF and DTI biomarkers. <b>Results:</b> Former professional players had higher d-CIIV than controls (F(7, 194) = 2.87, <i>p</i> = .007). d-CIIV was associated with TES diagnosis (F(8, 146) = 9.063, <i>p</i> &lt; .001), with highest d-CIIV in TES Possible/Probable-CTE. Higher d-CIIV correlated with higher CHII scores (<i>r</i> = 0.19), reduced CSF Aβ_1–42 (<i>β</i> = −0.302), increased p-tau₁₈₁ (<i>β </i>= 0.374), and reduced DTI FA (<i>β</i> = −0.202). <b>Conclusion:</b> d-CIIV is linked to RHI exposure and TES diagnosis in former football players, with associated changes in CSF biomarkers and white matter integrity.