APOE e4 and Alzheimer?s disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain.

Background: The apolipoprotein E (APOE) e4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influ-ence on the clinical and pathological outcomes of AD. Methods: L-carnitine, its metabolites g-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individu-als (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatogra-phy tandem mass spectrometry (LC-MS/MS). Findings: Relative to total blood acylcarnitines, levels of short chain acylcarnitines (SCAs) were higher whereas long chain acylcarnitines (LCAs) were lower in AD, which was observed pre-clinically in APOE e4s. Plasma medium chain acylcarnitines (MCAs) were higher amongst cognitively healthy APOE e2 carriers rela-tive to other genotypes. Compared to their respective controls, elevated TMAO and lower L-carnitine and GBB were associated with AD clinical diagnosis and these differences were detected preclinically among APOE e4 carriers. Plasma and brain GBB, TMAO, and acylcarnitines were also associated with post-mortem brain amyloid, tau, and cerebrovascular pathologies. Interpretation: Alterations in blood L-carnitine, GBB, TMAO, and acylcarnitines occur early in clinical AD pro-gression and are influenced by APOE genotype. These changes correlate with post-mortem brain AD and cere-brovascular pathologies. Additional studies are required to better understand the role of the FAO disturbances in AD. (c) 2022 Elsevier Masson SAS. All rights reserved.