Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
Early microglial and astrocyte reactivity in preclinical Alzheimer's disease.
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Fernández-Matarrubia Marta, Valera-Barrero Andrea, Renuncio-García Mónica, Aguilella Marcos, Lage Carmen, López-García Sara, Ocejo-Vinyals J Gonzalo, Martínez-Dubarbie Francisco, Molfetta Guglielmo Di, Pozueta-Cantudo Ana, García-Martínez María, Corrales-Pardo Andrea, Bravo María, López-Hoyos Marcos, Irure-Ventura Juan, Blennow Kaj, Ashton Nicholas J, Zetterberg Henrik, Sánchez-Juan Pascual, Rodríguez-Rodríguez Eloy
Аннотация
INTRODUCTION: The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear.
METHODS: We assessed changes in microglial and astrocytic biomarkers in a well-characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events.
RESULTS: Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau-181 (p-tau181) and neurogranin, and correlated with CSF S100 calcium-binding protein beta (S100β). CSF chitinase-3-like protein 1 (YKL-40) mediated the association between CSF p-tau181 and total tau (t-tau), whereas CSF S100β and neurofilament light showed mutual influence.
DISCUSSION: Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL-40 and S100β contribute to the progression of downstream neurodegenerative changes.
HIGHLIGHTS: Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau-181. Chitinase-3-like protein 1 (YKL-40) mediated tau-induced neurodegeneration. S100 calcium-binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.
METHODS: We assessed changes in microglial and astrocytic biomarkers in a well-characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events.
RESULTS: Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau-181 (p-tau181) and neurogranin, and correlated with CSF S100 calcium-binding protein beta (S100β). CSF chitinase-3-like protein 1 (YKL-40) mediated the association between CSF p-tau181 and total tau (t-tau), whereas CSF S100β and neurofilament light showed mutual influence.
DISCUSSION: Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL-40 and S100β contribute to the progression of downstream neurodegenerative changes.
HIGHLIGHTS: Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau-181. Chitinase-3-like protein 1 (YKL-40) mediated tau-induced neurodegeneration. S100 calcium-binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.