Shutting off the ApoE ε4 allele to combat Alzheimer's disease. The ApoE ε4 allele is considered the most significant genetic risk factor for late-onset Alzheimer’s disease, playing a complex role in modulating microglial responses within the brain. Microglia exhibit what is termed an “MGnD response” under neurodegenerative conditions, a critical yet intricate process that the ApoE ε4 allele appears to suppress. New findings in mice indicate that eliminating microglial ApoE ε4 can restore the MGnD response, providing a potential pathway for neuroprotection in the context of neurodegenerative diseases like Alzheimer's disease. In experiments, the ApoE ε4 allele demonstrated the ability to modify the behavior of astrocytes via microglial cells, including the clearance of β-amyloid, protein aggregates recognized as a key hallmark of Alzheimer's disease. Further exploration revealed the prospect of targeting the ITGB8-TGFβ signaling pathway, a significant process in the pathogenesis of Alzheimer's disease. Pharmacological intervention within this pathway enhanced the MGnD response and increased plaque clearance. While current research continues to uncover the molecular complexities of Alzheimer’s disease, these findings hint at potential therapeutic interventions and new ways of managing this devastating disease.