Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF...

Area of Science:

• Neuroscience
• Neuroimmunology
• Biomarker Research

Background:

• Synaptic homeostasis is crucial for brain function and is disrupted in aging and neurodegenerative diseases.
• Microglia and astroglia play key roles in maintaining synaptic health.
• Alzheimer's disease (AD) core biomarkers are associated with neuroinflammation and synaptic dysfunction.

Purpose of the Study:

• To investigate the relationship between TREM2-dependent microglial reactivity, astroglial response, and synaptic dysfunction.
• To determine if this relationship is influenced by AD core biomarkers in cognitively healthy individuals.
• To examine longitudinal changes in these markers over time.

Main Methods:

• Analysis of cerebrospinal fluid (CSF) biomarkers including soluble TREM2 (sTREM2), GFAP, S100B, neurogranin, and α-synuclein.
• Utilized two longitudinal cohorts: Wisconsin Registry for Alzheimer's Prevention (WRAP) and Alzheimer's and Families (ALFA+).
• Employed linear regression and mixed-effects models, adjusting for AD biomarkers (Aβ42, p-tau) and performing subgroup analyses.

Main Results:

• Cross-sectional associations found between sTREM2 and α-synuclein/S100B in subgroups with AD-related profiles.
• Longitudinally, lower neurogranin and α-synuclein, and higher S100B predicted increased sTREM2 over time, independent of AD markers.
• Higher baseline sTREM2 was associated with more stable neurogranin levels over time in both cohorts.

Conclusions:

• Synaptic dysfunction markers influence the longitudinal dynamics of CSF sTREM2 independently of AD biomarkers.
• TREM2-dependent microglial activation interacts with synaptic dysfunction in aging and early neurodegeneration.
• These findings suggest a TREM2-mediated pathway distinct from established AD pathology.