Plasma p-tau217/Aβ42 Test Accuracy Reduced in Patients With Traumatic Brain Injury
Key Clinical Summary
- Plasma p-tau217/Aβ42 ratio accurately detected amyloid-PET positivity in veterans without traumatic brain injury (TBI), but accuracy declined significantly in those with prior TBI.
- In a cross-sectional study of 272 older US veterans, reduced test performance was primarily driven by lower sensitivity, particularly in participants with more severe TBI.
- The findings suggest that TBI history and severity should be considered when interpreting Alzheimer disease (AD) blood biomarker results.
The US Food and Drug Administration (FDA)–approved plasma phosphorylated tau 217 (p-tau217)/amyloid-β42 (Aβ42) ratio demonstrated high diagnostic accuracy for detecting brain amyloid in older veterans without traumatic brain injury (TBI) but performed significantly worse in those with prior TBI, according to a cross-sectional diagnostic study published in JAMA Neurology. The findings indicate that TBI history may modify the clinical performance of emerging Alzheimer disease (AD) blood tests.
Study Findings
Researchers evaluated the diagnostic performance of the plasma p-tau217/Aβ42 ratio, plasma p-tau217, and the plasma Aβ42/40 ratio for detecting amyloid positivity on positron emission tomography (PET). The study analyzed existing data and banked plasma samples from the Alzheimer Disease Neuroimaging Initiative Department of Defense (ADNI-DOD) cohort.
The analysis included 272 Vietnam War veterans without dementia who were either cognitively unimpaired or had mild cognitive impairment. Participants had undergone amyloid-PET imaging and concurrent plasma collection between 2013 and 2020, while biomarker analyses were completed between 2024 and 2025. The mean age was 70 years, 99.3% were male, and 83 participants (30.5%) were amyloid-PET positive.
The plasma p-tau217/Aβ42 ratio achieved 90% accuracy (95% CI, 84%–96%) among veterans without TBI. Accuracy declined to 78% (95% CI, 69%–87%; P = .03 versus no TBI) in veterans with TBI involving loss of consciousness (LOC) of 0–5 minutes and to 63% (95% CI, 53%–73%; P < .001 versus no TBI) in those with LOC exceeding 5 minutes.
Investigators reported similar results for plasma p-tau217 alone and the plasma Aβ42/40 ratio. The findings remained consistent after excluding participants with TBI within the previous 10 years and when amyloid-PET positivity was defined using a quantitative threshold rather than consensus visual interpretation.
Clinical Implications
Blood-based biomarkers are increasingly being incorporated into the diagnostic evaluation of AD because they offer a less invasive and more accessible alternative to amyloid-PET imaging. Previous civilian studies have reported approximately 90% accuracy for the plasma p-tau217/Aβ42 ratio in detecting cerebral amyloid pathology.
This study suggests that clinicians should interpret these biomarkers cautiously in older patients with a history of TBI, particularly when injury severity included prolonged loss of consciousness. Among cognitively unimpaired individuals and those with mild cognitive impairment, reduced sensitivity may increase the likelihood of false-negative results despite underlying amyloid pathology.
The findings also indicate that both TBI history and injury severity may act as modifiers of blood biomarker performance. Although the plasma p-tau217/Aβ42 ratio remained highly accurate in those without TBI, clinicians should consider TBI history when evaluating negative blood test results and determining whether additional diagnostic assessment, including amyloid-PET, may be warranted.
Expert Commentary
“As AD biomarkers increasingly guide diagnosis and treatment eligibility, clinicians should be aware that this test may miss over half of Aβ-PET–positive cases in individuals with prior TBI,” wrote Yael Rosen-Lang, MPH, Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat-Gan, Israel, and study coauthors. “This diagnostic gap creates a hazard of excluding eligible patients from time-sensitive, disease-modifying therapies.”
“Further research should validate these findings in larger, more diverse cohorts and establish guidelines for using biomarkers to determine Aβ-targeted therapy in persons with TBI history,” the investigators concluded.
