Title: "When Memory Unravels: How the Alzheimer's disease risk gene APOE4 impacts oligodendrocyte metabolism and myelination"

Abstract: The APOE gene is a keystone in the genetic architecture of late-onset Alzheimer's disease, but the cellular mechanisms mediating its contribution to disease risk remain unclear. In Part I of this thesis, we address this question by performing single-nuclear RNA-sequencing on human post-mortem brain from individuals carrying 0, 1, and 2 copies of APOE4. We find that APOE4 expression leads to cholesterol accumulation and impaired myelination in oligodendrocytes (Blanchard, Akay, Davila-Velderrain, & von Maydell et al., Nature 2022). In Part II of this thesis, we use a genome-wide CRISPR screen to identify regulators of APOE4's effects on lipid metabolism in oligodendrocytes. This functional genomics approach unexpectedly reveals signaling pathways and a class of lipid-modifying enzymes as regulators of lipid accumulation. We show that modifying these signaling pathways restores lipid homeostasis across model systems. Finally, in Part III of this thesis, we leverage single-nuclear RNA sequencing across six distinct regions of the human brain. We find evidence of glial lipid modifying enzymes as participatory in cognitive resilience to disease pathology. Together, our work provides evidence for glial lipid metabolism underlying both genetic mechanisms of risk, and cognitive resiliency to Alzheimer's disease.