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

Area of Science:

• Neuroscience
• Biochemistry

Background:

• Glial and neuronal changes are implicated in Alzheimer's disease (AD) pathogenesis.
• The direct link between glial markers and synaptic dysfunction in living individuals is not fully understood.

Purpose of the Study:

• To investigate the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF).
• To explore the role of glial markers in cognitively unimpaired (CU) and cognitively impaired (CI) individuals.

Main Methods:

• Analyzed CSF from 478 individuals (CU and CI).
• Measured biomarkers: amyloid-beta (Aβ), phosphorylated tau (pTau181), glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and synaptic markers (GAP43, neurogranin).
• Validated findings in TRIAD and ADNI cohorts.

Main Results:

• CSF GFAP levels correlated with presynaptic and postsynaptic dysfunction, irrespective of cognitive status or Aβ presence.
• CSF sTREM2 levels were associated with synaptic markers, with varying relationships based on cognitive status and Aβ positivity.
• CSF pTau181 mediated the link between GFAP/sTREM2 and synaptic dysfunction.

Conclusions:

• Glial reactivity, particularly astrocyte reactivity (GFAP) and microglial activation (sTREM2), is significantly associated with synaptic dysfunction in Alzheimer's disease.
• Phosphorylated tau plays a mediating role in the relationship between glial markers and synaptic degeneration.
• These findings elucidate specific glial contributions to synaptic pathology in AD, validated across multiple cohorts.