Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimer's disease

INTRODUCTION: Although it has become clear that alterations in lipid metabolism are associated with Alzheimer's disease (AD), it is unclear how they contribute to both cognitive decline and the pathophysiology of AD. METHODS: Lipidomics and activity-based protein profiling (ABPP) were performed in the frontal cortex of control, AD and resilient donors, that is, individuals with AD pathology without cognitive decline. RESULTS: The most pronounced alterations in lipids were in ω6-derived oxylipins, which were particularly increased in AD. Triacylglycerols (TAGs) and lipid droplets (LDs) were more abundant in the AD donors compared to the resilient donors. Multi-omics factor analysis (MOFA) showed that increased ω6-derived oxylipins and the loss of inhibitory neurons were associated with amyloid beta (Aβ) plaque load. DISCUSSION: Our multi-omics data show a molecular response associated with Aβ load shared among AD and resilient donors, but reduced LDs in resilient donors compared to AD. HIGHLIGHTS: Comprehensive lipidomics analysis of frontal cortex from controls, Alzheimer's disease (AD) patients and resilient individuals. ω6 Oxylipins, markers of neuroinflammation, are increased in both AD and resilience. Resilient donors have reduced triacylglycerols and lipid droplets compared to AD. Multi-omics integration shows a molecular response to amyloid beta plaques associated with ω6-derived oxylipins and loss of interneurons.