Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease

Abstract

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.

Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

“…Our strategy to use lipid species as endophenotypes in the search for CVD genes is the 'tip of the iceberg'. We have previously reported phenotypic associations of lipid species with other complex traits, including diabetes 37 , Alzheimer's disease 19 , and atrial fibrillation 38 ; we believe the same integrative genomics approach may now be used to elucidate the mechanistic underpinnings of lipid metabolism in these and other complex diseases. These data now represent a valuable resource for the future exploration of the genetic analysis of the lipidome to identify lipid metabolic pathways and regulatory genes associated with complex disease and identify new therapeutic targets.…”

Challenges in LC–MS-based metabolomics for Alzheimer’s disease early detection: targeted approaches versus untargeted approaches

“…The authors also performed further adjustments for MCI subjects, and in this case only the dehydrocholesteryl ester (DE 18:1) and two plasmalogen species had a significant association. Even though, this study improved the knowledge in the lipidomic area of research validating the results on two large cohorts, a population study will be required to fully assess model performance (Huynh et al, 2020).…”

“…Furthermore, the concentration of some bile acids cannot be explained only by enzymatic synthesis, showing that they may be produced by the gut microbiome and then transported to the brain (Baloni et al, 2020). Another important insight that arose from the reviewed studies, is that alteration of lipids status and related compounds, seem to play a crucial role in AD pathophysiology (Barupal et al, 2019;Casanova et al, 2016;Whiley et al, 2014, Gonzalez-Dominquez et al, 2014Huynh et al, 2020;Klanvis et al, 2015;Liang et al, 2016;Proitsi et al, 2017;Varma et al, 2018;Wood et al, 2016). Blood lipid profiling using both targeted and untargeted lipidomicsbased approaches have been carried out (Astarita et al, 2018;Proitsi et al, 2017;Sandra et al, 2010) and further rigorous studies could actually unlock poor understood biochemical pathway in AD development.…”

“…More recently, Huynh et al ( 2020 ) carried out one of the most comprehensive lipidomic study of AD to date. They used HPLC-QqQ-MS platform to quantify 569 between lipid and lipid-like compounds from 32 classes and subclasses, underling the importance of analyze the whole lipidome at molecular structural detail to identify crucial lipid pathways involved in AD and its future onset.…”

National Pharmacy Associations in the Commonwealth -current scenario and future needs to maximise effective contributions of the pharmacy profession towards Universal health coverage

“…Utilising the pharmacy workforce to cater to health care needs becomes even more meaningful when considering the shortfall of 18 million health workers by 2030 that is projected by WHO and the ampli cation of this problem in LMICs [20]. CPA has currently 54 registered members nations [21] and aims to support member nations through their national pharmacy bodies to achieve the respective national and international UHC goals and to provide equal and effective services for the health care needs of their respective populations.…”