Search

Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer's disease. This study explores a battery of plasma lipids that can differentiate Alzheimer's disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75-97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aβ 42 . This suggests that oligomeric Aβ 42 plays a contributory, if not causal role, in mediating changes in lipid profiles in AD that can be detected in the periphery. In addition, we evaluated the association of plasma lipid profiles with AD-related single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of AD. We found that FERMT2 and MS4A6A showed a significantly differential association with lipids in all lipid classes across disease and control groups. ABCA7 had a differential association with more than half of the DG lipids (52.63%) and PI lipids (57.14%), respectively. Additionally, 43.4% of lipids in the SM class were differentially associated with CLU. More than 30% of lipids in ChE, PE, and TG classes had differential associations with separate genes (ChE-PICALM, SLC24A4, and SORL1; PE-CLU and CR1; TG-BINI) between AD and control group. These data may provide renewed insights into the pathobiology of AD and the feasibility of identifying individuals with greater AD risk.

High protein intake and reduced levels of the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+) have both been independently associated with promotion of the ageing phenotype. However, it has not yet been shown whether these two independent observations are biochemically linked. To investigate this possibility, we used a cross-sectional study design of 100 apparently healthy middle-aged males (n = 48) and females, in which we assessed average dietary intakes of multiple components using a validated questionnaire. We also analysed fasting blood levels of urea, NAD+ and its metabolites, and inflammation-linked biomarkers, including interleukin-6 (IL-6), Kynurenine (Kyn), and Tryptophan (Trp). One-way ANOVA and ANCOVA were then performed for statistical analysis. Our results have shown for the first time that plasma levels of NAD+ and Total NAD(H) were lower with increasing protein intake (F (2, 92) = 4.61, P = 0.012; F (2, 92) = 4.55, P = 0.013, respectively). The associated decrease in NAD+ and NAD(H) levels was even stronger with increasing plasma levels of the protein breakdown product urea (F (2, 93) = 25.11, P≤0.001; F (2, 93) = 21.10, P≤0.001). These associations were all independent of age, gender and energy intake. However, no significant association was observed between protein intake or plasma urea, and plasma levels of NAD+ metabolites. We also observed that plasma levels of the inflammatory cytokine IL-6, and both Kyn, and Trp, but not the Kyn/Trp ratio were higher with increasing plasma urea levels (F (2, 94) = 3.30, P = 0.041; F (2, 95) = 7.41, P≤0.001; F (2, 96) = 4.23, P = 0.017, respectively). These associations were dependent on eGFR and energy intake, except for the urea and Trp association that was independent of all. In conclusion, we report for the first time, a novel association between protein intake, its metabolism, and plasma NAD+ levels with a possible link to inflammation. These findings provide further insight into how protein restriction may contribute to the anti-ageing process observed in several studies., Competing Interests: The authors have declared that no competing interests exist.