Altered L‐carnitine and acylcarnitine profiles in APOE e4 carriers with Alzheimer’s disease reflect impaired fatty acid oxidation.

Abstract

AbstractBackgroundAbnormal lipid metabolism is now considered one of the key biological features of Alzheimer’s disease (AD). The L‐carnitine system plays an important role in lipid metabolism, particularly fatty acid (FA) transport and metabolism in mitochondria. Blood and tissue acylcarnitine accumulation reflects incomplete fatty acid beta‐oxidation (FAO), corresponding with insulin resistance, oxidative stress and inflammation. We hypothesized that changes in blood and brain markers of the L‐carnitine system would indicate dysfunctional FAO in aging e4 carriers, thereby influencing AD pathogenesis.MethodPlasma and brain L‐carnitine, L‐carnitine metabolites and acylcarnitine were analyzed in controls and patients with early or moderate AD stratified by APOE genotypes. The L‐carnitine system was examined over a range of ages (10 to 50 weeks) in plasma and brains from transgenic mice expressing different human APOE isoforms and EFAD mice with human APOE and 5 x AD mutations.ResultAmong e4 carriers, plasma L‐carnitine decreased, but its metabolite, Trimethylamine N‐oxide, increased in patients with early or moderate AD. Among non‐e4 carriers these changes are detected only in moderate AD patients. Among e4 carriers, plasma long chain acylcarnitines (LCA) and very‐LCA (VLCA) were lowest in moderate AD patients. In e4 carriers, plasma acylcarnitines correlated with cerebrovascular, amyloid and tau pathologies. Whereas in e2 carriers, both brain and plasma acylcarnitines were correlated with amyloid, tau and cerebrovascular pathologies. In APOE4‐TR mice, medium chain acylcarnitines (MCA) and LCA decreased with age within the cerebrovasculature. Parenchymal acylcarnitines increased at an earlier age (25 weeks) among APOE4‐TR mice compared to mice with other APOE genotypes (50 weeks).ConclusionThese data suggest that among e4 carriers, the L‐carnitine system‐mediated FAO is dysregulated early in the disease process of AD. Age‐dependent decreases in MCA and LCA in the cerebrovasculature in APOE4‐TR compared to APOE3‐TR mice indicate FAO deficits at an earlier age in APOE4‐TR. Understanding the role of APOE4 in impaired FAO with age in relation to the L‐carnitine system is required for developing novel preventative/therapeutic strategies for AD.