Performance of blood biomarkers in internal jugular vein for Alzheimer disease pathologies: the Delta Study

Background: Systemic factors confound blood tests for the diagnosis of Alzheimer disease (AD). The Delta study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral AD pathologies. Methods: Blood was collected from the internal jugular vein (IJV) and median cubital vein (MCV) in the discovery (n=371) and validation (n=92) cohorts. AD biomarkers were measured with Lumipulse G and Simoa methods. Aβ and tau PET imaging and cerebrospinal fluid (CSF) biomarkers were used to evaluate brain pathologies. Results: The levels of Aβ42, Aβ40, p-tau217, p-tau181, GFAP and NfL were higher in the IJV than MCV and highly correlated between the two sites. IJV-Aβ42/40 had stronger correlations with Aβ PET Centiloids and tau PET meta-temporal SUVR than MCV-Aβ42/40. In detecting cerebral Aβ positivity, IJV-Aβ42/40 demonstrated a significantly higher accuracy (79.9% to 92.9% vs. 72.4% to 88.8%) and a lower percentage of uncertain individuals (17.8% to 54.5% vs. 31.3% to 70.1%) than MCV-Aβ42/40. Moreover, the diagnostic accuracy of Lumipulse G IJV-Aβ42/40 (88.2% to 92.9%) was statistically equivalent to that of MCV-p-tau217 (90.2% to 94.3%), although the intermediate percentage of IJV-Aβ42/40 was higher (17.8% to 34.0% vs. 0.7% to 17.5%) than MCV-p-tau217. These findings were verified in the validation cohort. Discussion: IJV-Aβ42/40 performs better than MCV-Aβ42/40 in detecting cerebral AD pathologies, offering a novel perspective to reduce the impacts of systemic factors and comorbidities on blood tests.