Prior Traumatic Brain Injury and Alzheimer Disease Blood Biomarkers: Diagnostic Challenges and Clinical Implications

Highlights

• Traumatic brain injury (TBI) significantly reduces the diagnostic accuracy of plasma Alzheimer disease (AD) biomarkers such as the p-tau217/Aβ42 ratio for detecting brain amyloid pathology.
• In veterans with TBI history, the plasma p-tau217/Aβ42 ratio misses over half of amyloid-PET positive cases, contrasting with 90% accuracy in non-TBI populations.
• These findings underscore the need for cautious interpretation of AD blood biomarker results in individuals with prior TBI, with implications for clinical diagnosis and trial enrollment.

Background

Alzheimer disease (AD) remains a leading neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks including amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Recent advances in blood-based biomarkers have facilitated minimally invasive detection of AD pathology. Among these, the plasma phosphorylated tau 217 (p-tau217)/amyloid-β 42 (Aβ42) ratio has demonstrated approximately 90% accuracy for identifying brain amyloid in civilian cohorts, offering promise for screening and diagnosis.

Traumatic brain injury (TBI) is a known independent risk factor for dementia, including AD. Mechanistically, TBI may contribute to neurodegeneration through secondary inflammatory cascades, oxidative stress, axonal injury, and blood-brain barrier disruption. TBI is also reported to modulate levels of various AD biomarkers, posing challenges for interpreting biomarker test results. Despite growing clinical use, the impact of prior TBI on the diagnostic accuracy of emerging AD blood biomarkers has been inadequately characterized.

The study by Rosen-Lang et al. (2026) addresses this critical knowledge gap by evaluating blood biomarker accuracy in Vietnam War veterans with and without TBI, leveraging amyloid-positron emission tomography (PET) as the reference standard. This review synthesizes these findings, contextualizes them within broader AD biomarker research, and discusses translational considerations.

Key Content

Study Design and Population

The pivotal cross-sectional cohort study utilized data and banked plasma from the Alzheimer Disease Neuroimaging Initiative Department of Defense (ADNI-DOD) study. The cohort comprised 272 Vietnam War veterans aged around 70 years, predominantly male (99.3%), including cognitively unimpaired individuals and those with mild cognitive impairment (MCI), all without dementia at enrollment (2013-2020). Participants underwent amyloid-PET with consensus visual read and concurrent plasma collection.

Subjects were categorized by TBI history: no TBI, TBI with loss of consciousness (LOC) 0-5 minutes, and TBI with LOC >5 minutes. The primary biomarkers analyzed were FDA-approved plasma p-tau217/Aβ42 ratio, plasma p-tau217 alone, and the Aβ42/40 ratio, assessing their accuracy against PET amyloid status.

Findings: Impact of TBI on Biomarker Accuracy

The plasma p-tau217/Aβ42 ratio demonstrated excellent accuracy (90%, 95% CI 84%-96%) for detecting brain amyloid in veterans without TBI history. However, accuracy dropped significantly in TBI-exposed groups: 78% (95% CI 69%-87%) with LOC 0-5 minutes and further to 63% (95% CI 53%-73%) for LOC >5 minutes (P < .001 vs no TBI). Similar patterns were observed for plasma p-tau217 alone and Aβ42/40 ratio.

Notably, exclusion of veterans with recent TBI (<10 years) or the use of quantitative PET thresholds rather than consensus visual reads did not alter these differential accuracy rates, emphasizing the robustness of these observations.

This indicates that TBI history confounds AD blood biomarker levels, reducing sensitivity to underlying amyloid pathology, potentially due to chronic pathological processes or altered biomarker metabolism post-TBI.

Mechanistic and Translational Insights

Complementary literature suggests TBI induces sustained oxidative stress, neuroinflammation, and blood-brain barrier disruption, which may alter peripheral biomarker dynamics. For example, oxidative stress biomarkers are elevated in AD and may be confounded by TBI-related injury (Alves et al., 2026). Moreover, microbiota-gut-brain axis disturbances observed in AD could be exacerbated post-TBI, influencing systemic inflammation and neuronal integrity (Smith et al., 2026).

The diminished diagnostic accuracy in TBI-affected individuals raises important considerations for biomarker-based diagnosis and clinical trial inclusion criteria. Biomarker thresholds and interpretation guidelines may need adjustment or incorporation of TBI history for accurate AD diagnosis in these populations.

Expert Commentary

The study by Rosen-Lang et al. represents a crucial advance, highlighting a significant limitation of AD blood biomarkers in TBI-affected veterans. This contrasts with civilian cohorts where biomarker accuracy is high. Clinicians should maintain caution when interpreting plasma p-tau217/Aβ42 ratios in patients with prior TBI, particularly those with LOC.

Differential biomarker kinetics, ongoing neurodegeneration, and post-injury gliosis may contribute to biomarker variability and reduced concordance with PET amyloid. Longitudinal studies are needed to elucidate biomarker trajectories post-TBI and their relationship to cognitive decline.

The findings also underscore the importance of integrating multimodal assessments—including neuroimaging, cognitive testing, and detailed TBI history—in dementia evaluation.

Current guidelines (e.g., NIA-AA research framework) do not explicitly address TBI as a confounder in blood biomarker interpretation, indicating a gap in consensus recommendations that should be addressed.

Conclusion

While AD blood biomarkers like plasma p-tau217/Aβ42 ratio hold promise for non-invasive detection of amyloid pathology, prior TBI significantly compromises their diagnostic accuracy. This limitation is pronounced in veterans with TBI history and must be carefully considered in clinical and research settings.

Future research should focus on understanding the mechanistic underpinnings of biomarker alterations post-TBI, refining biomarker panels or algorithms that account for TBI effects, and establishing tailored interpretation guidelines. Multimodal biomarker strategies incorporating imaging and fluid markers may enhance accuracy in these complex patient subsets.

Overall, integration of TBI history is critical to improve the precision of AD biomarker-based diagnosis and optimize patient care in this vulnerable population.

References

• Rosen-Lang Y, Vrillon A, Pasternak S, et al. Prior Traumatic Brain Injury and Alzheimer Disease Blood Biomarkers. JAMA Neurol. 2026;XXX:1-11. PMID: 42371653. https://pubmed.ncbi.nlm.nih.gov/42371653/
• Alves, J. et al. Oxidative stress biomarkers and flavonoids in Alzheimer’s disease: current clinical evidence and therapeutic perspectives. Redox Rep. 2026;31(1):2677396. PMID: 42187062. https://pubmed.ncbi.nlm.nih.gov/42187062/
• Smith, R. et al. Microbiome functional gene pathways are indicative of cognitive performance in older adults at risk for Alzheimer’s disease. Gut Microbes. 2026;18(1):2676162. PMID: 42178714. https://pubmed.ncbi.nlm.nih.gov/42178714/