The present article mainly discusses how lipid metabolic disorders in the brain microenvironment are involved in regulating the progression of cognitive impairment, and it explores the regulatory effects of targeting the key lipid transport protein APOE in the context of the role of lipid metabolism in the common pathogenesis of three diseases—Aβ deposition, tau hyperphosphorylation, and insulin resistance—which will help elucidate the potential of targeting lipid metabolism for the treatment of cognitive impairment. Here, APOE is linked to Disorder of lipid metabolism.