Multi‐omics approach reveals disturbances in brain phosphatidylcholine metabolism in Alzheimer’s Disease

Abstract

AbstractBackgroundLipid dysregulation is implicated in Alzheimer’s disease (AD) pathology, given its involvement in amyloid β processing, myelination, and cell membrane structure. Studies have demonstrated increased phosphatidylcholine (PC) hydrolysis in the brains of AD individuals, but the connections between AD and PC metabolism are not fully understood.MethodTo investigate the alterations in PC metabolism in AD, we analyzed publicly available transcriptomic, metabolomic, and lipidomic data from the ROSMAP study, which included dorsolateral prefrontal cortex (DLPFC) tissue and serum samples. DLPFC and serum samples were classified based on clinical consensus diagnosis of cognitive status at the time of death and the last valid clinical diagnosis, respectively. Concentration differences were determined with a linear model using the Limma R package.ResultAccording to the lipidomic results, the concentration of total PC‐containing glycerophospholipid was significantly decreased in AD DLPFC samples (P < 0.05). Specifically, diacyl‐PC and acyl‐alkyl‐PC, the two most abundant subclasses, were significantly decreased in the brains of AD patients (P < 0.05). The concentration of the PC breakdown product, glycerophosphocholine (GPC), was increased in AD patient brains (P‐value < 0.05). However, GPC phosphodiesterase 1 (GPCPD1), the enzyme that further hydrolyzes GPC to free choline, was downregulated and choline abundance was reduced in AD DLPFC samples (P < 0.05). The expression of phosphatidylethanolamine N‐methyltransferase (PEMT), which converts PE to PC, was reduced as was the abundance of PEMT products (PC 18:2/20:4 and PC 18:0/20:4, P < 0.05). These alterations in the brain were not observed in the serum.ConclusionThese results indicate that PC metabolism is disturbed in the DLPFC of AD patients, with evidence of increased PC breakdown and reduced GPC hydrolysis as well as reduced conversion of PE to PC in AD brains. However, these changes in the brain are not reflected in serum. Further studies are needed to better understand changes in phospholipid metabolism in the brains of AD patients.