Abstract
INTRODUCTION: We investigated the usefulness of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) for capturing vascular cognitive impairment (VCI) in the context of amyloidosis. METHODS: Using two independent cohorts (n = 1810), we assessed the relationship of plasma NfL and GFAP with (1) vascular brain indices; (2) diagnostic states using the following definitions: vascular versus not (white matter hyperintensity/total intracranial volume ≥ 1.3%), and cognitively impaired (CI) versus cognitively unimpaired (CU) using Clinical Dementia Rating ([CDR] scale ≥ 0.5); and (3) their upstream predictors using structural equation models (SEMs). RESULTS: Plasma NfL and GFAP were associated with vascular brain damage and differed across states (VCI > vascular CU > non-vascular CI > non-vascular CU). In a population-based sample, these biomarkers distinguished vascular CU and VCI from non-vascular CU groups with greater separation in amyloid negative participants. Pathway analyses showed NfL was primarily influenced by systemic/brain vascular health, whereas amyloid contributed to GFAP variability. DISCUSSION: Plasma biomarkers, particularly NfL, capture vascular brain changes and show promise for VCI identification. HIGHLIGHTS: Plasma NfL and glial fibrillary acidic protein (GFAP) were associated with vascular brain indices. Plasma biomarkers differed across diagnostic states (VCI > vascular CU > non-vascular CI > non-vascular CU). Plasma markers discriminated vascular from non-vascular states with greater separation in Aβ- participants. NfL was linked to vascular health, while amyloid influenced GFAP variability in the population-based sample. Future longitudinal frameworks should consider systemic inflammation markers along with these plasma markers to better understand VCID-related brain changes and cognitive decline.