Journal Article

Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease

Bauer-Negrini, Guilherme, Ferreira, Pamela C. L., Bellaver, Bruna, Tissot, Cécile, Rohden, Francieli, Servaes, Stijn, Pascoal, Tharick A., Povala, Guilherme, Ferrari-Souza, João Pedro, Benedet, Andrea L., Therriault, Joseph, Souza, Diogo, Abbas, Sarah, Zimmer, Eduardo R., Zetterberg, Henrik, Soares, Carolina, Zalzale, Hussein, Stevenson, Jenna, Rosa-Neto, Pedro, Leffa, Douglas T., Tudorascu, Dana L., Aguzzoli, Cristiano S., Rahmouni, Nesrine, Blennow, Kaj, Karikari, Thomas K., Lussier, Firoza Z., Ashton, Nicholas J.

2025

Overview

Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic markers (GAP43, neurogranin). CSF GFAP levels were associated with presynaptic and postsynaptic dysfunction, independent of cognitive status or Aβ presence. CSF sTREM2 levels were related to presynaptic markers in cognitively unimpaired and impaired Aβ+ individuals, and to postsynaptic markers in cognitively impaired Aβ+ individuals. Notably, CSF pTau mediated the relationships between GFAP or sTREM2 and synaptic dysfunction. Our findings, validated in two independent cohorts (TRIAD and ADNI), reveal a distinct pattern of glial contribution to synaptic degeneration. This study shows that glial reactivity is linked to synaptic dysfunction in aging and Alzheimer’s disease, with tau pathology mediating these effects–highlighting the potential of synaptic biomarkers track disease progression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/53/2423 / 692/617/375 / Abnormalities / Aged / Aged, 80 and over / Aging / Aging - cerebrospinal fluid / Aging - pathology / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer Disease - physiopathology / Alzheimer's disease / Amyloid beta-Peptides - cerebrospinal fluid / Amyloid beta-Peptides - metabolism / Astrocytes - metabolism / Astrocytes - pathology / Biomarkers / Biomarkers - cerebrospinal fluid / Brain / Brain - metabolism / Brain - pathology / Cerebrospinal fluid / Chi-square test / Cognitive ability / Cognitive Dysfunction - cerebrospinal fluid / Confidence intervals / Degeneration / Female / Glial fibrillary acidic protein / Glial Fibrillary Acidic Protein - cerebrospinal fluid / Humanities and Social Sciences / Humans / Male / Membrane Glycoproteins - cerebrospinal fluid / Microglia - metabolism / Middle Aged / multidisciplinary / Neurodegeneration / Neurodegenerative diseases / Neuroglia - metabolism / Neurogranin / Neurogranin - cerebrospinal fluid / Neuronal-glial interactions / Neurosciences / Neurovetenskaper / Pathology / Phosphorylation / Physiology / Proteins / Receptors, Immunologic / Science / Science (multidisciplinary) / Standard scores / Synapses - metabolism / Synapses - pathology / Tau protein / tau Proteins - cerebrospinal fluid / tau Proteins - metabolism / β-Amyloid