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However, growing evidence suggests these may be secondary events arising from earlier disturbances in brain metabolism and lipid homeostasis. The \u03b54 allele of apolipoprotein E (ApoE4) remains the strongest genetic risk factor for LOAD, with carriers exhibiting both increased lifetime risk and earlier age of onset compared to \u03b52 or \u03b53 carriers. ApoE4 disrupts lipid metabolism and is associated with increased lipid droplet accumulation within astrocytes, implicating astrocytic lipidopathy in disease pathogenesis. Here, we propose a self-reinforcing pathogenic feedback loop\u2014driven by dysregulated lipid homeostasis, chronic neuroinflammation, impaired glucose-handling, and cerebrovascular dysfunction\u2014that culminates in astrocytic bioenergetic failure. This framework helps explain why ApoE4 carriers reach a critical bioenergetic threshold earlier in life, triggering the clinical onset of LOAD. Targeting astrocytic lipid homeostasis, through interventions such as blood-brain barrier-permeable statins, choline supplementation, or metabolic therapies, may offer novel strategies to delay disease progression or onset. 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