Exploring inflammation-related protein expression and its relationship with TSPO PET in Alzheimer's disease.

INTRODUCTION

To understand the role of neuroinflammation in Alzheimer's disease (AD), we characterized immune-related proteins in central and peripheral biofluids.

METHODS

Selection of participants from the Translational Biomarker of Aging and Dementia (TRIAD) cohort with available translocator protein (TSPO) positron emission tomography (PET), cerebrospinal fluid (CSF) (n = 97), and plasma (n = 165). Biofluid samples analyzed with Olink technology (368 inflammation proteins).

RESULTS

Elevated proteins levels in CSF of TSPO-positive individuals were identified. Functional enrichment analysis of CSF proteins revealed processes implicated in AD (MAPK, ERK cascades, cytokine, and leukocyte signaling). Selected candidates (CXCL1 and TNFRSF11B) showed high correlation with each other in CSF and with TSPO PET signal, but weaker associations with amyloid and tau PET. No significantly changed proteins in plasma between TSPO groups were found.

DISCUSSION

This explorative study identified two potential targets in CSF showing correlations with TSPO, amyloid and tau PET, suggesting a direct link between neuroinflammation, expression of these proteins and their potential implication in AD.

HIGHLIGHTS

Several proteins are elevated in CSF of TSPO PET-positive individuals, linking them to neuroinflammation. Elevated CSF proteins were enriched in pathways such as MAPK, ERK, and cytokine signaling, linking them to the AD pathophysiology. Candidate proteins (CXCL1 and TNFRSF11B) correlated strongly with TSPO PET, particularly in brain regions known to be affected in AD. Although none of the plasma proteins remained significant after multiple comparisons correction when comparing their expression between TSPO groups, as done for CSF, candidate CSF proteins were found to correlate with plasmatic proteins, highlighting the complexity of the immune system.