Arachidic Acid-Carrying Phosphatidylglycerol Lipids Statistically Mediate the Relationship Between Central Adiposity and Cognitive Function in Cognitively Unimpaired Older Adults

<b>Background:</b> Central adiposity is a modifiable risk factor for age-related cognitive decline and has been linked to lipid dysregulation. However, the mechanisms underlying this relationship, particularly the role of plasma lipids at the species level, remain poorly understood. This study investigates whether lipids mediate the relationship between central adiposity and cognition in cognitively unimpaired older adults. <b>Methods:</b> Ninety-four cognitively normal older adults (<i>n</i> = 94, mean age 69.0 ± 5.0 years, 54% female) were included in this study. Cognitive composite scores were derived from z-standardised neuropsychological assessments, and central adiposity was measured using the waist-hip ratio (WHR). Lipidomic profiling identified 918 lipid species, which were clustered into modules of highly correlated lipids using a Weighted Gene Co-Expression Network Analysis (WGCNA). Modules associated with the WHR and cognition were identified via partial Spearman's correlation analysis, followed by a mediation analysis. <b>Results:</b> Of the 39 lipid modules identified, 1 enriched with phosphatidylglycerol (PG) lipids containing an arachidic acid (20:0) sidechain was positively correlated with cognition (ρ = 0.32, FDR <i>p</i> < 0.05) and negatively correlated with the WHR (ρ = -0.43, FDR <i>p</i> < 0.001). Mediation analysis revealed that this arachidic acid-carrying PG lipid-enriched module mediated the WHR-cognition relationship, with individual species PG (20:0_16:1), PG (20:0_18:1), and PG (20:0_18:2) also contributing individually. <b>Conclusions:</b> Arachidic acid-carrying PG lipids statistically mediate the WHR-cognition relationship in cognitively unimpaired older adults. These findings suggest that adiposity-related lipid pathways are detectable in cognitively unimpaired older adults and may represent targets for early intervention to preserve cognitive health.