Alzheimer’s pathology is associated with altered cognition, brain volume, and plasma biomarker patterns in traumatic encephalopathy syndrome

Breton M. Asken, Jeremy A. Tanner, Leslie S. Gaynor, Lawren VandeVrede, William G. Mantyh, Kaitlin B. Casaletto, Adam M. Staffaroni, Corrina Fonseca, Ranjani Shankar, Harli Grant, Karen Smith, Argentina Lario Lago, Haiyan Xu, Renaud La Joie, Yann Cobigo, Howie Rosen, David C. Perry, Julio C. Rojas, Bruce L. Miller, Raquel C. GardnerKevin K.W. Wang, Joel H. Kramer, Gil D. Rabinovici

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background: Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer’s disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer’s neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls. Methods: We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ[+]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ[+]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ[+]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ[+] or Aβ[−] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen’s d > 0.50) were interpreted as potentially meaningful. Results: Cognitively, within the TES group, Aβ[+] RHI/TES performed worse than Aβ[-] RHI/TES on visuospatial (p =.04, d = 0.86) and memory testing (p =.07, d = 0.74). Comparing voxel-wise brain volume, both Aβ[+] and Aβ[−] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ[+] RHI/TES had higher plasma GFAP than HC (p =.01, d = 0.88) and did not significantly differ from AD. Conversely, Aβ[−] RHI/TES had higher NfL than HC (p =.004, d = 0.93) and higher IL-6 than all other groups (p’s ≤.004, d’s > 1.0). Conclusions: Presence of Alzheimer’s pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ[−] RHI/TES. Measuring well-validated Alzheimer’s biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

Original languageEnglish (US)
Article number126
JournalAlzheimer's Research and Therapy
Issue number1
StatePublished - Dec 2023


  • Amyloid
  • Biomarker
  • Brain injury
  • Chronic traumatic encephalopathy
  • GFAP
  • NfL
  • PET
  • Plasma
  • Repetitive head impacts
  • Traumatic encephalopathy syndrome

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Cognitive Neuroscience


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