Different astrocyte phenotypes mediate the pathological cascade early in the Alzheimer’s disease continuum

Abstract

AbstractBackgroundGlial fibrillary acidic protein (GFAP) and chitinase‐3‐like protein 1 (YKL‐40) are biomarkers of different astrocyte phenotypes, both of which are elevated in the dementia phase of Alzheimer’s disease (AD). However, the specific contribution of these astrocyte phenotypes early in the AD continuum is not fully understood. Here, we studied how these two astrocyte phenotypes mediate the early pathogenic cascade in the preclinical stage of AD.MethodWe assessed 384 cognitively unimpaired individuals from the ALFA+ study with amyloid‐β (Aβ)42/40, phosphorylated tau (p‐tau181), neurofilament light (NfL) and YKL‐40 measured in cerebrospinal fluid (CSF) and GFAP measured in plasma, as well as [18F]flutemetamol positron emission tomography (PET) and neuropsychological testing (Annual change in the Preclinical Alzheimer’s Cognitive Composite [PACC]). Path analysis using structural equation modelling was used to quantify the relationships between biomarkers of reactive astrogliosis and Amyloid‐Tau‐Neurodegeneration biomarkers, while incorporating age, sex, and apolipoprotein E (APOE) ε4 effects. Direct effects with FDR‐corrected p‐values below .05 were considered significant.ResultCSF Aβ42/40 was associated with Aβ aggregation as measured by PET and with CSF p‐tau181, respectively. The latter was associated with CSF NfL, but no associations were found between any biomarkers and PACC changes in this early sample (Figure 1; Table 1). Plasma GFAP mediated the association between CSF Aβ42/40 and Aβ‐PET. Additionally, CSF YKL‐40 mediated the association between Aβ‐PET and p‐tau181 and between p‐tau181 and NfL. APOE ε4 had a direct association with CSF Aβ42/40 only, whereas age had independent associations with CSF Aβ42/40, NfL, GFAP and YKL‐40. Male sex was associated with higher CSF NfL levels, independently of other variables tested.ConclusionOur results suggest that astrocyte phenotypes that release GFAP into the blood influence the aggregation of soluble Aβ into fibrillary plaques. On the other hand, those releasing YKL‐40 into the CSF appear to play a role later in the pathological cascade, mediating downstream tau pathology and neuronal damage. These results indicate that different astrocyte phenotypes are specifically involved in distinct stages of the early pathological cascade in preclinical AD. Interventions targeting astrocyte dysfunction in preclinical stages may prevent or delay the onset of AD dementia.