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Early microglial and astrocyte reactivity in preclinical Alzheimer's disease.

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Autores de IDIVAL

Autores ajenos al IDIVAL

  • Valera-Barrero A
  • Renuncio-García M
  • Molfetta GD
  • Blennow K
  • Ashton NJ
  • Zetterberg H
  • Sánchez-Juan P

Unidades

Abstract

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 (Aß)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau-181 (p-tau181) and neurogranin, and correlated with CSF S100 calcium-binding protein beta (S100ß). CSF chitinase-3-like protein 1 (YKL-40) mediated the association between CSF p-tau181 and total tau (t-tau), whereas CSF S100ß 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 S100ß 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 (Aß)42/Aß40. 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 (S100ß) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.

© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Datos de la publicación

ISSN/ISSNe:
1552-5260, 1552-5279

Alzheimers & Dementia  WILEY

Tipo:
Article
Páginas:
70502-70502
PubMed:
40747577
Factor de Impacto:
0,000 SCImago ℠

Citas Recibidas en Web of Science: 11

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Keywords

  • S-100 calcium-binding protein beta (S100ß); astrocyte; biomarkers; chitinase-3-like protein 1 (YKL-40); glial fibrillary acidic protein (GFAP); microglia; preclinical Alzheimer´s disease; soluble triggering receptor expressed on myeloid cells 2 (sTREM2); structural equation modeling

Campos de Estudio

Proyectos asociados

Biomarcadores gliales y otros marcadores neuroinflamatorios en la fase preclínica del continuum de la enfermedad de Alzheimer

Investigador Principal: Marta Fernández Matarrubia

NVAL22/07 . FUNDACION INSTITUTO DE INVESTIGACION MARQUES DE VALDECILLA . 2022

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