Performance of blood biomarkers in internal jugular vein for Alzheimer's disease pathologies: the Delta Method study

Systemic factors confound blood tests for the diagnosis of Alzheimer's disease (AD). The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alzheimer's pathologies using PET or cerebrospinal fluid (CSF) biomarkers as reference standards in two independent cohorts (n = 463). Blood was collected from the internal jugular vein (IJV) and median cubital vein (MCV), and AD biomarkers were measured with Lumipulse G and Simoa methods. The results showed that the levels of Aβ42, Aβ40, p-tau217, p-tau181, GFAP, and NfL were higher in the IJV than in MCV and were 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%-92.9% vs. 72.4%-88.8%) and a lower percentage of uncertain individuals (17.8%-54.5% vs. 31.3%-70.1%) than MCV-Aβ42/40. Moreover, the diagnostic accuracy of Lumipulse G IJV-Aβ42/40 (88.2%-92.9%) was statistically equivalent to that of MCV-p-tau217 (90.2%-94.3%), although the intermediate percentage of IJV-Aβ42/40 was higher (17.8%-34.0% vs. 0.7%-17.5%). These findings were verified in the validation cohort. This study demonstrated the superior performance of IJV-Aβ42/40 to MCV-Aβ42/40 in detecting cerebral Alzheimer's pathologies, offering a novel perspective to reduce the impacts of systemic factors and comorbidities on blood tests.