Table 1.

APOE allele-associated metabolic phenotypes in different cell types and their relationships to neurodegeneration

Cell Type	APOE isoforms examined	Model System	Metabolic Phenotype	Relationship to neurodegeneration	References
Astrocytes	ApoE4, ApoE3	human iPSC-derived astrocytes	ApoE4 leads to decreased cholesterol efflux and increased intracellular cholesterol accumulation compared to ApoE3	Correlates with impaired lysosomal function, increased pro-inflammatory cytokine production, impaired amyloid-beta clearance, actin cytoskeletal defects	[64,66,73]
			ApoE4 leads to increased triglyceride accumulation and lipid droplet formation compared to ApoE3	Increased sensitivity to fatty acid lipotoxicity	[76]
			ApoE4 leads to decreased oxygen consumption and increased glycolysis compared to ApoE3	Correlates with pro-inflammatory astrocyte state	[196]
		primary astrocyte culture from humanized APOE mouse	ApoE4 leads to more lipid droplet accumulation upon lipid challenge compared to ApoE3	Decreased ability to oxidize excess fatty acids, increased sensitivity to lipotoxicity	[75]
	ApoE3, ApoE3-V236E	AAV-ApoE treated amyloid mouse model, primary mouse astrocytes	ApoE3-V236E results in greater cholesterol efflux and better lipidation than ApoE3	Correlates with reduced amyloid plaque load	[36]
Microglia	ApoE4, ApoE3	human iPSC-derived microglia	ApoE4 leads to triglyceride accumulation, lipid droplet formation, and cholesterol accumulation compared to ApoE3	Results in microglial activation, neuroinflammation, decreased neuronal activity	[63,73,76]
		primary microglia from humanized APOE mouse	ApoE4 leads to decreased oxidative phosphorylation, increased glycolysis compared to ApoE3	Associated with increased microglial reactivity and similar transcriptome to disease-associated microglia	[62]
Oligodendrocytes	ApoE4, ApoE3	human iPSC-derived oligodendrocytes	ApoE4 leads to cholesterol, triglyceride, diglyceride accumulation compared to ApoE3	Leads to impaired axon myelination	[20]
		human post-mortem tissue	ApoE4 leads to cholesterol accumulation, lipid droplet accumulation compared to ApoE3	Associated with impaired myelination	[20]