Natural variation in the human plasma lipidome signature using mass spectrometry: relevance to healthy ageing

Population ageing and the associated increase in neurodegenerative diseases has made brain health an important research priority. Lipidomics, a subfield of omics, involves characterisation and quantification of total lipids in biological systems. Since brain lipids influence protein function and synaptic throughput in neurons, lipidomics may help to uncover dysregulated metabolic pathways in ageing and disease, and serves as a potential diagnostic tool for the identification of biomarkers for ageing and dementia. This thesis investigated: (1) the optimal approach for lipid extraction and analysis, to minimize volume required of valuable cohort plasma, while maximising lipid recoveries and identification; (2) identified cross-sectional associations of the human plasma lipidome with ageing (56-100 years), sex and BMI, using plasma (n=100) from three population ageing studies - the Sydney Memory and Ageing Study (MAS), the Hunter Community Study (HCS) and the Sydney Centenarian Study (SCS); (3) examined the influence of APOE genotype on the plasma lipidome (n=152); and (4) evaluated the relative contribution of genetic and environmental influences on variation in plasma lipids from the Older Australian Twin Study (OATS), using n=75 pairs of monozygotic twins and n=55 pairs of dizygotic twins. Lipidomics was conducted using liquid chromatography - mass spectrometry (LC-MS). Major findings include a global reduction in lipid abundance in the oldest subjects (>95 years), which was steeper among males. Females also had increases in particular sphingomyelins (SM) and phospholipids. The APOE ԑ2 allele was associated with higher levels of phosphatidylethanolamines (PE), and subjects with the highest baseline tertile of these lipids had lower odds of developing Alzheimers disease. A small proportion of lipids showed significant heritability, with highest heritability among triglycerides and ceramides (h2 up to 0.59). These results confirm and extend previous findings, suggestive of age and sex as important factors which influence the human lipidome, especially in the oldest old. The association of APOE2 with increased phosphatidylethanolamines could imply a protective role of these lipids against cognitive decline and warrants further investigation. Finally, the dominance of environmental influences on lipid variance suggests that the aged lipidome is modifiable by lifestyle factors, with potential implications for treatment of disease