Integrative Lipidomic Analyses of Metabolic and Cognitive Health: From Obesity to Exercise in Ageing Adults

Maria Kadyrov

doi:10.60867/00000142

Ageing is the greatest risk factor for declining brain health and cognitive function, and growing evidence suggests that these processes may be closely intertwined with changes in lipid metabolism. Lipids have critical structural and functional roles in maintaining neurological health, and disruptions to lipid homeostasis are increasingly recognised as early contributors to cognitive impairment and dementia risk. Importantly, lipids are highly sensitive to lifestyle factors such as adiposity and physical activity, which can profoundly alter lipid composition and function. However, the mechanisms linking systemic lipid metabolism with cognitive ageing, and how these relationships are influenced by adiposity, exercise, and genetic factors such as apolipoprotein E (APOE), remain poorly understood. This thesis aimed to elucidate how lipidomic signatures relate to ageing, adiposity, and cognitive function, using systems-level and targeted lipidomic approaches across population and intervention cohorts. Chapter One provides a general overview of the topic and leads into Chapter Two, which provides a narrative review of age-related changes in key lipid classes, including fatty acyls, glycerolipids, phospholipids, sphingolipids, and sterol lipids, and explores associations of age-related pathological cognitive decline with these lipid classes. Additionally, evidence for the beneficial effects of exercise in modulating lipid metabolism is also summarised to highlight the therapeutic potential of lifestyle modification strategies to counteract age-related lipid perturbations and mitigate cognitive decline. Chapter Three applied Weighted Gene Co-expression Network Analysis (WGCNA) to plasma lipidomic data from “Baby Boomers” (n = 1000) enrolled in the Busselton Healthy Ageing Study (BHAS) to uncover co-regulated lipid modules linked to adiposity and lipoprotein subfractions. Twenty-four lipid modules were identified, several of which were strongly preserved across follow-up data obtained after a gap of several years. Modules enriched in triacylglycerol (TG) lipid species were positively associated with adiposity and exhibited a “pro-atherogenic” lipoprotein profile. This was characterised by strong positive associations with Apolipoprotein B100, very-low-density lipoprotein (VLDL), intermediate-density (IDL), and lowdensity lipoprotein (LDL) particles – particularly the smaller, more dense subfractions (LDL-5 and LDL- 6) – and inverse associations with high-density lipoproteins (HDL) and larger LDL subfractions (LDL-2 and LDL-3). In contrast, modules enriched in hexosylceramides (HexCer), lactosylceramides (LacCer) and phospholipid containing a 22:6 fatty acyl chain displayed “anti-atherogenic” lipoprotein and adiposity associations. These findings established distinct lipid-lipoprotein interaction patterns that differentiated metabolically healthy and adverse obesity phenotypes. Chapter Four extended this systems-level approach to investigate whether specific lipid modules statistically mediated the relationship between central adiposity and cognition. This was performed using data from cognitively unimpaired older adults (n = 94) enrolled in the Intense Physical Activity and Cognition (IPAC) study, which was a 6-month aerobic exercise intervention aimed to improve cognition. For the purposes of this chapter, only the pre-intervention data were used to explore the relationships between lipids, central adiposity, and cognition independently of the exercise intervention. A module enriched in arachidic acid (20:0)-containing phosphatidylglycerol (PG) species was positively associated with cognition and inversely associated with waist-hip ratio. Mediation analysis confirmed that this module statistically mediated the adiposity-cognition relationship, suggesting that 20:0-PG lipids may represent early biomarkers of metabolic resilience relevant to brain health. Chapter Five examined whether APOE ε4 carrier status modulates the relationships between changes in plasma lipid subclasses, fat-mass, and cognition in cognitively unimpaired older adults (n = 86). APOE ε4 carriers exhibited lower ceramide (Cer) and dihydroceramide (DhCer) levels and reduced body fat at baseline. While no associations were detected in the whole cohort across changes in plasma lipid subclasses, fat mass, and cognitive performance, stratified analyses revealed distinct genotype-dependent patterns. In APOE ε4 carriers, increases in sphingolipid and phospholipid subclasses were associated with a decline in attention and working memory, and reduced android and total fat mass. Contrary to expectations, gains in android and total fat-mass were correlated with cognitive improvement in APOE ε4 carriers only. Investigation of lipid-lipid covariance matrices also indicated tighter correlations among sphingolipid and phospholipid subclasses and disrupted associations with glycerolipids in APOE ε4 carriers than APOE ε4 noncarriers, suggesting reduced metabolic flexibility and altered lipid coordination. Together, these studies demonstrate that lipid metabolism is a critical interface linking interactions between adiposity, exercise, and cognitive function in ageing. The findings reveal that distinct lipidomic profiles, shaped by genetic background and adiposity, may underlie variability in cognitive ageing trajectories. Understanding these lipid signatures provides novel insight into the metabolic pathways that support brain health and offers potential targets for personalised interventions to preserve cognitive function across the lifespan.

Integrative Lipidomic Analyses of Metabolic and Cognitive Health: From Obesity to Exercise in Ageing Adults

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