CSF turnover reshapes biomarker interpretation in neurodegeneration studies

Area of Science:

• Neuroscience
• Biomarker Discovery
• Proteomics

Background:

• Cerebrospinal fluid (CSF) biomarkers are crucial for Alzheimer's disease (AD) diagnosis and research.
• However, CSF composition is influenced by factors beyond neurodegeneration, such as physiological processes affecting CSF turnover and blood-brain barrier (BBB) integrity.
• These confounding factors complicate the interpretation of AD biomarkers.

Purpose of the Study:

• To investigate the impact of CSF dynamics (turnover and BBB integrity) on multi-omics data.
• To identify how CSF dynamics affect core AD biomarker levels and classification.
• To establish a robust AD proteomic signature independent of confounding factors.

Main Methods:

• Integration of multi-omics CSF data from the ACE CSF cohort and Global Neurodegeneration Proteomics Consortium.
• Analysis of quantitative trait loci data.
• Utilized OPCML as a reference marker to adjust biomarker levels.
• Validated a curated AD signature in independent cohorts (ACE CSF and Knight ADRC).

Main Results:

• Two primary factors, CSF turnover rate and BBB integrity, explain 73.2-85.9% of molecular variance in CSF omics data.
• CSF turnover influences brain-derived molecules, while BBB damage increases blood-derived proteins.
• Adjusting for CSF dynamics and using OPCML improved AD progression prediction and revealed a consistent AD proteomic signature.
• A curated AD signature of 446 proteins was identified and validated.

Conclusions:

• CSF dynamics are a major determinant of molecular variance in CSF, significantly impacting AD biomarker interpretation.
• Accounting for CSF turnover and BBB integrity is essential for accurate AD diagnosis and research.
• The identified 446-protein AD signature offers a more reliable basis for understanding AD pathology.