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<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by significant cognitive decline. Glycogen synthase kinase-3β (GSK3β), a key regulator in the pathological process of AD, exacerbates neuronal damage by phosphorylating tau proteins and promoting Aβ production. The activity of GSK3β is modulated by multiple signaling cascades, including the PI3K/AKT and Wnt/β-catenin transduction pathways. Furthermore, Apolipoprotein E ε4 (<i>ApoE4</i>) has been identified as a major genetic risk factor for increased susceptibility to AD. ApoE4 aggravates lipid metabolism disorders by interfering with LRP1 receptor function, inhibiting insulin signaling, and promoting the release of inflammatory factors (IL-6, TNF-α) and GSK3β. Specifically, ApoE4 may intensify the pathological process of AD by interacting with GSK3β, altering the balance of lipid metabolism in the body, regulating GSK3β activity, and modulating neuroinflammatory responses. This article systematically reviews the synergistic mechanisms of ApoE4 and GSK3β in AD and provides a new theoretical basis and potential intervention strategies for early diagnosis and targeted therapy of AD.</p>

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The Synergistic Role of ApoE4 and GSK3β in Alzheimer’s Disease: Pathological Mechanisms and Therapeutic Implications

  • 期刊论文

  • 发表日期：

    2025年11月12日

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  • Qianwei Li,
  • Yinghui Shang,
  • Han-Chang Huang,
  • Xueling Dai,
  • Fengxue Lao

摘要

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by significant cognitive decline. Glycogen synthase kinase-3β (GSK3β), a key regulator in the pathological process of AD, exacerbates neuronal damage by phosphorylating tau proteins and promoting Aβ production. The activity of GSK3β is modulated by multiple signaling cascades, including the PI3K/AKT and Wnt/β-catenin transduction pathways. Furthermore, Apolipoprotein E ε4 (ApoE4) has been identified as a major genetic risk factor for increased susceptibility to AD. ApoE4 aggravates lipid metabolism disorders by interfering with LRP1 receptor function, inhibiting insulin signaling, and promoting the release of inflammatory factors (IL-6, TNF-α) and GSK3β. Specifically, ApoE4 may intensify the pathological process of AD by interacting with GSK3β, altering the balance of lipid metabolism in the body, regulating GSK3β activity, and modulating neuroinflammatory responses. This article systematically reviews the synergistic mechanisms of ApoE4 and GSK3β in AD and provides a new theoretical basis and potential intervention strategies for early diagnosis and targeted therapy of AD.