Astrocyte biomarkers GFAP and YKL‐40 mediate early Alzheimer's disease progression

Abstract

Abstract INTRODUCTION We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. METHODS We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. RESULTS Cerebrospinal fluid (CSF) amyloid beta (Aβ) 42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p‐tau 181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ 42/40 and Aβ‐PET, and CSF YKL‐40 partly explained the association between Aβ‐PET, p‐tau 181 , and NfL. DISCUSSION Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL‐40 mediates the latter association between Aβ and downstream Aβ‐induced tau pathology and tau‐induced neuronal injury. Highlights Lower CSF Aβ 42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL‐40 mediated Aβ‐induced tau phosphorylation and tau‐induced neuronal injury.