Fig. 4: Expression of APOE4 in microglia and its roles in AD pathogenesis.

a, Healthy microglia express low levels of apolipoprotein E (APOE)³⁹. This APOE is involved in immune responses, lipid homeostasis and in clearing amyloid β (Aβ) aggregates and cell debris^23,53,143. b, During stress and aging, microglia increase their APOE expression^138–141. Microglial APOE4 leads to an increase in amyloid plaque-associated reactivity⁵⁴, lipid accumulation^27,148, lysosomal defects^151,152, mitochondrial dysfunction¹⁴¹, disease-associated microglial (DAM) signatures^140,167 and proinflammatory cytokine release¹⁶⁷. c, Microglial APOE4 affects other cells, including neurons and T cells¹⁶⁶, and contributes to AD pathogenesis by reducing Aβ clearance¹⁵⁷ and lysosome function¹⁵¹ and by increasing synaptic engulfment¹⁶¹, p-tau uptake and accumulation^86,151,152, DAM signatures^140,152, lipid-droplet-accumulating microglia LDAM^29,147, and cytokine release¹⁶⁷. Together, these APOE4-induced microglial dysfunctions facilitate tau spreading and seeding^162–164 and, ultimately, synaptic and neuronal degeneration (in conjunction with neuronal APOE4)^140,152. The potential relationships among these microglial APOE4 effects on other cells and AD pathologies is depicted using arrows. Note that non-microglial sources of APOE have been omitted for clarity.