Background: We investigated the relationship between the cerebrospinal fluid (CSF) proteome in Alzheimer's disease (AD) and the clinical and biomarker-assisted diagnoses.
Methods: CSF was collected in 500 individuals of non-Hispanic white, African Americans, and Caribbean Hispanic individuals from Dominican Republic and New York City. CSF biomarkers of AD were measured including P-tau181, Aβ40, Aβ42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co-abundant modules of proteins were tested with the clinical diagnosis of AD, as well as biologically defined AD pathological process based on CSF P-tau181 and other biomarker levels.
Results: We detected 1030 protein groups (with at least one peptide per protein), yielding an overall data completeness value of 97%. CSF levels of 41 proteins were significantly associated with P-tau181 levels after multiple testing correction. Notably, phospholipase D3 (PLD3, p=2.41E-09), APOE (p=4.25e-08) and osteopontin (OSTP, p=1.4E-16) were increased and ceruloplasmin (CERU, p=2.72E-07) decreased among individuals with high P-tau181 levels. These proteins were also associated with CSF Aβ42/Aβ40 ratio and total Tau levels but not with NfL. OSTP was also associated with CSF levels of GFAP (p=1.32e-05). We did not identify any protein association with clinical AD. Among proteins associated with P-tau181 levels, pathways related to axon development (p=2.4E-12), axonogenesis (p=1.45E-11) and regulation of axonogenesis (p=5.1E-09) were enriched.
Conclusion: Unbiased profiling of circulating CSF proteins identified key proteins associated with β-amyloid and phosphorylated tau pathology. Biologically based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.
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