Plasma platelet-derived growth factor receptor-β decrease correlates with blood-brain barrier damage in Alzheimer's disease

BACKGROUND: The blood-brain barrier (BBB) damage is frequently observed in Alzheimer’s disease (AD). However, it remains unclear whether plasma platelet-derived growth factor receptor-β (PDGFRβ) level is related to BBB damage and how it correlates with AD core pathologies, neurodegeneration, and cognitive decline. METHODS: In this study, we measured cerebrospinal fluid (CSF) albumin, plasma albumin, and plasma PDGFRβ concentrations for 93 participants with paired CSF and plasma samples. We investigated the association between CSF/Plasma albumin ratio (Qalb) and plasma PDGFRβ. Subsequently, plasma PDGFRβ, phosphorylated tau (p-Tau) 217 (p-Tau217), p-Tau231, and N-terminal tau (NT1-tau) concentrations were measured in 592 participants. Of them, 519, 278, 152, 470, and 586 participants underwent testing for plasma p-Tau181, Amyloid-β (Aβ) positron emission tomography (PET), tau PET, structural magnetic resonance imaging (MRI), and MoCA, respectively. Additionally, 154 and 210 had longitudinal MRI and cognition data. We investigated the association between plasma PDGFRβ and baseline Aβ and tau PET, as well as the baseline and slope of temporal-MetaROI cortical thickness and MoCA. We did these analyses separately for the whole cohort, females, and males. RESULTS: Plasma PDGFRβ was associated with Qalb in the whole cohort (standardized β = − 0.218 [95% confidence interval: − 0.412, − 0.024], p = 0.028). Mild cognitive impairment and dementia patients showed lower plasma PDGFRβ than cognitively unimpaired individuals. Lower plasma PDGFRβ levels were associated with higher Aβ and tau PET burden, thinner cortical thickness, worse MoCA scores, and a more rapid decline in cortical thickness and MoCA scores, which were particularly significant in males. Furthermore, the relationships of plasma p-Tau181, p-Tau217, p-Tau231, and NT1-tau with baseline Aβ and tau PET, as well as baseline and slopes of cortical thickness and MoCA, were much stronger in males with low (< median) plasma PDGFRβ levels compared to males with high (> median) plasma PDGFRβ levels. DISCUSSION: This study demonstrated that decreased plasma PDGFRβ levels are associated with BBB damage, Aβ plaques, tau tangles, neurodegeneration, and cognitive decline in AD, and modulate the relationship between plasma tau biomarkers and both longitudinal neurodegeneration and cognitive decline. These findings suggest a potential plasma biomarker for detecting and monitoring BBB leakage in AD.