Investigating APOE Genotype, Sex, and Age on Flavonoid Metabolism

Hunt, Thomas James (2025) Investigating APOE Genotype, Sex, and Age on Flavonoid Metabolism. Doctoral thesis, University of East Anglia.

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Abstract

Alzheimer’s disease (AD) is influenced by several non-modifiable risk factors, notably age, APOE genotype, and sex, with risk increasing with advancing age, the presence of APOE ε4 alleles, and in females. These factors also shape gut microbiota composition. Dietary flavonoids, plant-based bioactives known to support cognitive health, require microbial metabolism in the colon, as humans lack the necessary enzymes for their breakdown. Although substantial interindividual variation in flavonoid metabolism has been documented, the specific effects of APOE genotype, sex, and age remain unexplored.

This thesis employed targeted metabolomics to investigate the metabolism of epicatechin (EC), both as a pure compound and within meals, using a human colon model, APOE-targeted replacement (TR) mouse models, and reanalysis of clinical data. 16S rRNA sequencing and untargeted metabolomics were applied to link microbial community patterns with metabolic outcomes, while EC supplementation studies in APOE-TR mice assessed physiological impacts.

Results revealed that APOE genotype significantly modulated EC metabolism, influencing concentrations of both microbially derived valerolactones and valeric acids, as well as non-microbially derived EC metabolites. These effects were context-dependent, varying with age, sex, and food matrix. In APOE-TR mice, sex and genotype shaped gut microbiota composition, while dietary effects were observed only with flavan-3-ol-rich cocoa powder, not purified EC. Human data showed greater intragroup variability. Cognitive improvements in spatial working memory were limited to APOE4/4-TR males, underscoring genotype- and sex-dependent effects. APOE genotype and sex were also associated with hepatic inflammation and sulfotransferase pathway activity.

Collectively, these findings demonstrate that APOE genotype, sex, and age critically influence EC metabolism, gut microbiota structure and physiological responses, emphasising the necessity of considering genetic and biological context when evaluating flavonoid-related metabolism and health outcomes.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	17 Mar 2026 10:54
Last Modified:	17 Mar 2026 10:54
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102360
DOI:

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