Proteomic Profiling of CSF Reveals Inflammatory Pathways Associated with Tau Neuropathology in Alzheimer's Disease

Abstract Background Aggregation of amyloid beta (Aβ) and tau proteins is a hallmark of Alzheimer's disease (AD) and tauopathies. In AD, extracellular deposition of Aβ peptide precedes tau aggregation and the onset of neuroinflammatory processes. Both neuroinflammation and tau deposition are associated with synaptic loss, neurodegeneration, and cognitive decline. However, the precise sequence of events from amyloid deposition to tau aggregation, neuroinflammation, and neurodegeneration remains unclear. A cross‐sectional analysis of tau and other proteins in the cerebrospinal fluid (CSF) of AD patients can provide insight into the inflammatory and degenerative processes. Tau levels may be used as a proxy for disease progression, and we hypothesize that the expression of neuroinflammatory markers will be modulated in response to increasing tau aggregation. Method To investigate this, we collaborated with the EPND‐biomarker consortium to analyze over 150 human CSF samples from AD and control patients. We measured levels of Aβ1‐40, Aβ1‐42, pTau181, and total tau, and conducted proteomic profiling using the O‐link and SomaScan platforms. Next, AD patients were stratified into Aβ+Tau+ and Aβ+Tau‐ groups to identify biomarkers associated with Aβ and/or tau aggregation. Result As expected, inflammation markers were elevated in AD CSF samples compared to controls. Interestingly, we observed distinct correlations between these markers and amyloid versus tau pathology biomarkers. Approximately 10% of the measured CSF proteins (∼250 proteins) showed significant differences ( p < 0.05) between AD and control samples. CSF samples with elevated tau levels exhibited altered levels of proteins involved in the complement cascade, cytokine‐cytokine receptor interactions, cell adhesion, and vesicular transport. Conclusion Increased inflammation markers were observed in AD. Proteins linked to innate immune response and synaptic loss were significantly altered in relation to tau aggregation. These findings are crucial for guiding therapeutic strategies for neurodegenerative diseases and assessing their efficacy.