Brain pro-resolving-to-pro-inflammatory lipids and cPLA2 activation associations with late-life cognitive trajectories

Background Lipidome alterations are linked to neurodegenerative disorders, but the association between calcium-dependent phospholipase A2 (cPLA 2 )-related lipid ratios, which reflect pro-resolving and pro-inflammatory lipid biology, and age-related cognitive decline remains unclear. Methods In postmortem dorsolateral prefrontal cortex samples from participants in the Religious Orders Study and the Rush Memory and Aging Project (lipidomics n=191; transcriptomics n=411), we quantified three ratios of cPLA 2 -released fatty acid precursors (primary exposures), three indices of arachidonic acid (AA) metabolism, and two AA transcriptomic activation scores (secondary exposures). Global cognition (primary outcome) and five cognitive domains were derived from annual neuropsychological testing. Findings In mixed-effect change point models (death-age, sex, education, and apolipoprotein E ε4 ( APOEε4 )-adjusted), higher brain eicosapentaenoic acid/AA was associated with better global cognition proximate-to-death (β = 0.254, 95% CI [0.064–0.455]) and a slower rate of cognitive decline (β = 0.045, 95%CI [0.005–0.081]). Separate models including an APOEε4 × cPLA 2 lipid–ratio interaction showed that the association between lipoxin A4/AA and global cognition proximate-to-death differed significantly between APOEε4 carriers and non-carriers (β = 0.396, 95% CI [0.015–0.776]). A secondary analysis, repeating these models with three indices of AA metabolism-to-AA ratios and examining the association between the six cPLA 2 lipid ratios and five cognition domains, yielded similar results. Higher AA transcriptomic activation scores, indicating greater cPLA 2 activation, were associated with lower global cognition at death (β = −0.148, 95% CI [−0.266 to −0.028]) and with multiple cognitive domains. Interpretation Modulation of brain lipid ratios warrants further investigation as a potential target related to cognitive decline. Funding National Institute of Health, the Council for Higher Education-Zuckerman support program for outstanding postdoctoral female researchers.