An Association Between Saturated Fatty Acid-Containing Phosphatidylcholine in Cerebrospinal Fluid with Tau Phosphorylation

Background: Mechanistic studies in animal models implicate a role for saturated fatty acids in neurodegeneration, but validation of this finding in human studies is still lacking. Objective: We investigated how cerebrospinal levels of sphingomyelins (SM) and phosphatidylcholine (PC)-containing saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids associate with total tau and phosphorylated tau (p-tau). Methods: Cerebrospinal fluid (CSF) lipids were measured in two cohorts, a discovery and a confirmation cohort of older non-demented individuals from the University of Southern California and Huntington Medical Research Institutes cohorts. Lipid analysis was performed using hydrophilic interaction liquid chromatography, and individual PC and SM lipid species were measured using tandem mass spectrometry. In addition, CSF levels of A beta(42), total tau, and p-tau-181 were measured using an MSD multiplex assay. Results: The discovery cohort (n = 47) consisted of older individuals and more females compared to the confirmation cohort (n = 46). Notwithstanding the age and gender differences, and a higher p-tau, A beta(42), and LDL-cholesterol in the discovery cohort, CSF concentrations of dipalmitoyl-PC (PC32a:0) were significantly associated with p-tau in both cohorts. Similarly, total saturated PC but not mono or polyunsaturated PCs correlated with p-tau concentrations in both cohorts. Conclusion: Saturated PC species in CSF associate with early markers of neurodegeneration and are potential early disease progression biomarkers. We propose mechanisms by which saturated PC may promote tau hyperphosphorylation.