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

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 (A ss) 42/40 was associated with A ss aggregation on positron emission tomography (PET) and with CSF p-tau181, which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF A ss(42/ 40) and A ss-PET, and CSF YKL-40 partly explained the association between A ss- PET, p-tau181, andNfL. 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 A ss, CSF YKL-40 mediates the latter association between A ss and downstream A ss-induced tau pathology and tau-induced neuronal injury.

Automated summary

We studied the role of biomarkers of reactive astrogliosis in the pathogenic cascade of Alzheimer's disease. Various fluid biomarkers were found to influence the progression of the disease, with GFAP mediating the association between soluble and insoluble Aβ, and YKL-40 partly explaining the association between Aβ and downstream tau pathology and neuronal injury.