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PROTEOMIC ANALYSIS OF CEREBROSPINAL FLUID TO IDENTIFY BIOMARKERS ASSOCIATED WITH AMYLOID AND TAU IN ALZHEIMER’S DISEASE
Abstract
Aims
To quantify proteome-wide changes in CSF across normal controls and individuals diagnosed with AD.
Methods
Using quantitative liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and multiplex tandem mass tags (TMT) we comparatively analyzed the CSF proteomes from 300 samples collected fom participants in the Emory Goizueta ADRC and affiliated cohorts, including 150 cognitively normal individuals (avg. MoCA=26.5) and 150 subjects with clinical diagnoses of AD (avg. MoCA=14.8). Samples across these two diagnostic groups were matched for age and sex. AD cases demonstrated low Aβ1–42 (299.8 pg/mL) and high tau (114.8 pg/mL) levels compared to controls (546.8 pg/mL and 54.5 pg/mL, respectively) as measured by ELISA. Following regression for age and sex, both differential expression and co-expression analysis were used to identify CSF proteins related to Aβ1–42 and tau concentration and clinical phenotypes.
Results
A total of approximately 1,800 proteins were quantified across all 300 samples. Synaptic proteins (GAP43, YWHAZ) and proteins involved in energy metabolism (PKM, PGAM1) were increased in AD and correlated strongly with Aβ1–42 and tau levels by ELISA. Proteins with links to microglia and neuroinflammation (SPP1, MIF) were also increased in AD and correlated to total tau levels. Tau levels were also identified and quantified by mass spectrometry and correlated to tau ELISA measurements. Co-expression network analyses revealed modules of CSF proteins that strongly overlap with protein networks in AD postmortem brain tissue.
Conclusions
These results reveal robust CSF protein biomarkers highly reflective of underlying disease pathology in brain with potential to assess disease progression and therapeutic target engagement.