Complement system and glial activation biomarkers in cerebrospinal fluid: correlation with cognitive decline in Alzheimer’s disease

Abstract

Introduction: Traditionally viewed through a neurocentric lens, Alzheimer's Disease (AD) has been reinterpreted considering the neuroglial unit. Microglial activation and the conversion of astrocytes to the A1 neurotoxic phenotype result in ionic imbalance and neuronal electrical silencing, culminating in synaptic opsonization via the complement system (CS).

Objective: To identify the correlation between the levels of complement system biomarkers (complement component 1q and complement component 3) and glial activation biomarkers in cerebrospinal fluid (glial fibrillary acidic protein, chitinase-3-like protein 1, and soluble triggering receptor expressed on myeloid cells 2) and cognitive performance in Alzheimer’s disease.

Methodology: Integrative literature review with a mechanistic approach of articles published between 2016 and 2026, that related complement system and glial activation biomarkers in the cerebrospinal fluid (CSF) to cognitive decline in AD.

Results: Complement protein levels were associated with impoverished cognitive performance and neurodegeneration markers, while soluble fragment released in triggering receptor expressed on myeloid cells 2 (sTREM2) correlated with tau pathology markers. Glial fibrillary acidic protein (GFAP) and chitinase 3–like protein (YKL-40) showed early elevation in Aβ-positive individuals and were associated with cognitive decline and changes in cortical thickness.

Conclusion: Glial activation and complement system biomarkers may act as potential indicators of the pathophysiological dynamics of Alzheimer's disease across its clinical spectrum, reflecting early changes associated with amyloid deposition and the progression of neurodegeneration.