A history of traumatic brain injury (TBI) may reduce the accuracy of an FDA-approved blood test used to detect Alzheimer’s disease (AD)-related amyloid pathology, potentially leading to false-negative results in patients with prior TBI.

In a cross-sectional study of 272 older US veterans, the FDA-approved plasma phosphorylated tau 217 (p-tau217)/amyloid-beta-42 ratio achieved 90% accuracy in identifying amyloid PET positivity among participants without a history of TBI but fell to 78% in those with TBI and loss of consciousness (LOC) lasting 0-5 minutes and 63% in those with LOC lasting more than 5 minutes. The reduction in accuracy was driven primarily by lower sensitivity rather than specificity.

“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,” the investigators led by Yael Rosen-Lang, MPH, of Joseph Sagol Neuroscience Center, Sheba Medical Center in Ramat-Gan, Israel, and colleagues, wrote.

“This diagnostic gap creates a hazard of excluding eligible patients from time-sensitive, disease-modifying therapies,” they added.

The study was published online on June 29 in JAMA Neurology.

TBI and Test Accuracy

Blood-based biomarkers are changing the way clinicians evaluate AD, offering a less invasive way to detect cerebral amyloid pathology compared with cerebrospinal fluid testing and amyloid PET imaging.

The recent May 2025 FDA approval of the Lumipulse G p-tau217/amyloid-beta-42 ratio test for adults aged 55 years or older with mild cognitive impairment (MCI) or mild dementia has further expanded the role of blood biomarkers in routine diagnostic evaluations.

However, the accuracy of these tests may vary across patient populations. TBI is known to cause long-term changes in several AD-related biomarkers, including p-tau, total tau, and neurofilament light chain (NfL). Whether these biological changes affect the ability of AD blood tests to identify amyloid pathology accurately has remained unclear.

To assess this, the investigators evaluated whether TBI history and severity influenced the ability of plasma p-tau217/amyloid-beta-42 ratio testing to predict amyloid PET positivity, using PET imaging as the reference standard.

The study included 272 Vietnam War veterans (mean age, 70 years; 99.3% men; White, 85%) enrolled in the Alzheimer Disease Neuroimaging Initiative-Department of Defense study between 2013 and 2020.

Plasma biomarker analyses were conducted between 2024 and 2025. Among participants, 83% were cognitively unimpaired, whereas 17% had MCI; individuals with dementia were excluded. Overall, 30.5% of participants were amyloid PET positive.

The investigators categorized participants into three groups based on TBI history and LOC duration, using the Ohio State University TBI Identification Method: no history of TBI (n = 93), TBI with LOC lasting 0-5 minutes (n = 89), and TBI with LOC lasting longer than 5 minutes (n = 90). 

Blood Test Accuracy Declines After TBI

The plasma p-tau217/amyloid-beta-42 ratio showed high diagnostic accuracy among veterans without a history of TBI but had significantly lower accuracy among those with prior head injury.

Among participants without TBI, the assay achieved an accuracy of 90% for identifying amyloid PET positivity. Among participants with TBI involving LOC lasting 0-5 minutes, accuracy declined to 78% (P = .03 vs no TBI) and to 63% among those with LOC lasting longer than 5 minutes (P < .001 vs no TBI).

Reduced accuracy was driven largely by lower sensitivity rather than lower specificity, suggesting the test was more likely to miss amyloid PET-positive cases among veterans with prior TBI.

Sensitivity decreased with greater TBI severity, falling from 53% among veterans without TBI to 38% among those with TBI with LOC lasting 0-5 minutes and 31% among those TBI with LOC lasting longer than 5 minutes. Specificity remained high across groups at 99%, 92%, and 92%, respectively.

When p-tau217 was measured alone, accuracy declined from 87% among participants without TBI to 79% among those with TBI with LOC lasting 0-5 minutes and 62% among those with TBI with LOC lasting longer than 5 minutes.

The FDA-approved dual-cutoff approach for the p-tau217/amyloid-beta-42 ratio also did not improve performance. Among participants, 36% received an indeterminate result, including 35% of those without TBI, 39% with LOC lasting 0-5 minutes, and 33% with LOC lasting longer than 5 minutes.

Investigators also found that greater TBI severity was associated with higher rates of MCI and amyloid positivity. MCI was identified in 8.6% of participants without TBI, 17% of those with TBI with LOC lasting 0-5 minutes, and 24% of those with TBI with LOC exceeding 5 minutes (P = .02).

Similarly, amyloid PET positivity increased from 18% among participants without TBI to 27% and 47% among those with TBI with LOC lasting 0 to 5 minutes and longer than 5 minutes, respectively (P < .001).

Beyond p-Tau217 Testing

The investigators also explored whether TBI altered the relationship between amyloid pathology and other markers of neurodegeneration. Among veterans without TBI, amyloid PET-positive participants had higher median NfL levels (16.9 vs 11.3 pg/mL; P = .03) and glial fibrillary acidic protein (GFAP) levels (182 pg/mL vs 106 pg/mL; P < .001) than amyloid PET-negative participants. These associations were not observed among veterans with prior TBI. 

GFAP and NfL levels may be useful for “the diagnosis and staging of AD vs non-AD pathologies in patients with a TBI history,” the investigators noted.

The study had several limitations, including reliance on self-reported TBI history and its largely homogeneous study population of older male Vietnam War veterans. The investigators also noted that posttraumatic stress disorder was more common among participants with TBI and may have influenced biomarker performance.

“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.

The study was supported by grants from the US Department of Defense Congressionally Directed Medical Research Program Peer-Reviewed Alzheimer’s Research Program and the National Institute on Aging. Disclosure information for study authors is available in the original study publication.