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

Nature communications 2025

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.

5 Figures Extracted

Fig. 1 PMC

CSF GFAP is associated with synaptic dysfunction biomarkers independently of amyloid-β (Aβ) status or cognitive impairment. Scatter plots illustrate s...

Fig. 2 PMC

CSF sTREM2 is associated with synaptic dysfunction biomarkers only in the presence of amyloid-β (Aβ) pathology. The scatter plots revealed that the as...

Fig. 3 PMC

CSF synaptic biomarker levels increased as a function of CSF GFAP and CSF sTREM2. CSF GAP43 and CSF Ng as a function of CSF GFAP ( a ) and CSF sTREM2 ...

Fig. 4 PMC

CSF pTau mediated the association of glial reactivity with synaptic dysfunction. CSF pTau181 levels fully mediated the association between CSF GFAP an...

Fig. 5 PMC

Schematic representation of the association between astrocytic and microglial abnormalities with synaptic dysfunction. Our study revealed that astrocy...