We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer’s disease (AD) stages.
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.
Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ 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 Aβ42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau181, and NfL.
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.

Lower CSF Aβ42/40 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.

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This post is Copyright: Wiesje Pelkmans,
Mahnaz Shekari,
Anna Brugulat‐Serrat,
Gonzalo Sánchez‐Benavides,
Carolina Minguillón,
Karine Fauria,
Jose Luis Molinuevo,
Oriol Grau‐Rivera,
Armand González Escalante,
Gwendlyn Kollmorgen,
Margherita Carboni,
Nicholas J. Ashton,
Henrik Zetterberg,
Kaj Blennow,
Marc Suarez‐Calvet,
Juan Domingo Gispert,
for the ALFA study | September 10, 2023

Wiley: Alzheimer’s & Dementia: Table of Contents