Investigating Alzheimer’s disease risk and protective genetic factors in iPSC-microglia

O'Donoghue, Rachel 2026. Investigating Alzheimer’s disease risk and protective genetic factors in iPSC-microglia. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Sporadic Alzheimer’s Disease (AD) is a polygenic disorder, with several genes identified to modify the risk or protection conferred to an individual. Apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic AD, where the ε4 allele confers high risk, the ε3 allele is neutral, and the ε2 allele is protective. A novel protective variant, R251G, is coinherited with APOEε4 to recover its conferred risk to AD pathogenesis. This variant, or the effect of a combination of smaller AD risk genes, which can be represented in a polygenic risk score (PRS), have not yet been investigated in iPSC models of microglia, a cell type considered to be critical in AD pathogenesis. This thesis sought to better understand AD risk and protective genetic factors on microglial function, specifically in endocytic and lipid biology. iPSC were harnessed as a human model that can be genetically modified to incorporate specific mutations, such as R251G, or that can be generated from selected patients who carry extremes of AD PRS. CRISPR-Cas9 editing of an isogenic APOE iPSC series to incorporate R251G generated a novel resource. iPSC were differentiated into iPSC-derived microglia and their endocytic and lipid biology scrutinised. 51 patient iPSC lines with high and low AD PRS were differentiated into iPSC-derived microglia, and their endocytic biology interrogated. This thesis showed that APOE genotype affects microglial endocytic function, but that this may depend on APOE haplotype or high AD genetic risk background. Microglial responsiveness to amyloid-β appears to be driven by genetic risk factors, both high AD PRS and APOE, implying that this pathway may be an important therapeutic target. There were no significant phenotypes observed in iPSC-microglia harbouring the R251G variant, although several aspects of their endocytic and lipid biology should be probed further, an recommendations are made regarding avenues to be explored.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Funders:	UK Dementia Research Institute
Date of First Compliant Deposit:	29 October 2026
Last Modified:	29 Oct 2026 15:18
URI:	https://orca.cardiff.ac.uk/id/eprint/190522

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