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Protective mutations associated with APOE in Alzheimer’s disease

Molecular Psychiatry (2026)Cite this article

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Abstract

Alzheimer’ s disease (AD) is a progressive neurodegenerative disorder characterized by a spectrum of cognitive impairments, ranging from mild memory loss to severe cognitive decline and, ultimately, death. The global incidence of AD is projected to increase significantly, with late-onset AD being predominantly sporadic in nature. Over the past three decades, the Apolipoprotein E (APOE) gene has been recognized as the most important single genetic determinant of sporadic AD risk. The APOE4 allele is a major risk factor for AD and is known to exacerbate the pathological process for AD. Identifying protective variants that may reduce the risk or delay the onset of AD is of great significance for the development of effective treatments. This review comprehensively examines the protective effects of APOE and its related protective mutations. It also explores the impact of these unique protective variants at the cellular level during the pathological progression of AD. Furthermore, the review compiles new insights for AD treatment offered by these protective mutations, exploring the potential applications of APOE and its related protective variants in advanced therapeutic strategies, including gene editing, RNA editing, and stem cell therapy.

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Fig. 1: Interaction structure prediction and molecular docking of APOE and its structural mutants with LDLR.
Fig. 2: Resistance of APOE3ch to tau-associated pathology.
Fig. 3: Protein structure prediction models of protective variants generated by AlphaFold Server.
Fig. 4: Mechanism of action of LOF of FN1 in APOE4-driven AD.
Fig. 5: Correction of pathological changes induced by APOE4 by protective mutations.

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Data availability

All data analyzed during this study are available from the authors on request.

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Acknowledgements

We acknowledge the participants and investigators for all data sources. Figures in this manuscript were created with FigDraw.com.

Funding

This work was supported by The National Natural Science Foundation of China (82305298), The Fundamental Research Funds for the Central Universities (2025-JYB-XJSJJ037), The Youth Talent Support Program of the China Association of Chinese Medicine (2024-2026) (CACM-2024-QNRC2-B36), The Central High-level Hospital of Traditional Chinese Medicine: Beijing University of Traditional Chinese Medicine Dongzhimen Hospital Talent Training Program-Youth Reserve Talent Project (DZMG-QNHB0010), Beijing University of Chinese Medicine Dongzhimen Hospital Clinical research and achievement transformation ability improvement project-Youth special project (DZMG-QNZX-24003), China Postdoctoral Science Foundation funded project (2022M720521), Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan (No.20250916, No.2025KXQT03).

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Author notes

  1. These authors contributed equally: Yuejia Ma, Yanxi Li, Guangrun Wu.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, China

    Yuejia Ma, Yanxi Li, Guangrun Wu, Lulu Liu, Mengjie Tian, Xinyu Han, Xinyi Chen, Xiuchen Xuan, Tianhu Zheng, Xu Gao & Dayong Wang

  2. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China

    Yuejia Ma & Yanxi Li

  3. State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin, Heilongjiang, 150081, China

    Yuejia Ma & Yanxi Li

  4. The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150028, China

    Guangrun Wu

  5. Key Laboratory of Heilongjiang Province for Genetically Modified Animals, Harbin Medical University, Harbin, Heilongjiang, 150081, China

    Xu Gao & Dayong Wang

  6. Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, Heilongjiang, 150081, China

    Xu Gao & Dayong Wang

  7. Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China

    Qing Xia

  8. Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang, 150081, China

    Fuyuan Li

  9. NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University), Harbin, Heilongjiang, 150081, China

    Fuyuan Li

  10. Joint Key Laboratory of Endemic Diseases (Harbin Medical University, Guizhou Medical University Xi’ an Jiaotong University), Harbin, Heilongjiang, 150081, China

    Fuyuan Li

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  1. Yuejia Ma
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  11. Qing Xia
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  12. Fuyuan Li
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  13. Dayong Wang
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Contributions

Writing – original draft: Yuejia Ma, Yanxi Li and Guangrun Wu. Resources: Lulu Liu, Mengjie Tian, Xinyu Han, Xinyi Chen, Xiuchen Xuan, Tianhu Zheng, Xu Gao. Writing–review & editing: Fuyuan Li. Project administration, Funding acquisition and Writing–review & editing: Qing Xia. Project administration and Writing–review & editing: Dayong Wang. All authors read and approved the final manuscript. All authors read and approved the final manuscript.

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Correspondence to Qing Xia, Fuyuan Li or Dayong Wang.

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Ma, Y., Li, Y., Wu, G. et al. Protective mutations associated with APOE in Alzheimer’s disease. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03496-5

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