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From genetic roots to recent advancements in gene therapy targeting amyloid beta in Alzheimer’s disease

  • Pinar Peyvand ORCID logo , Pantea Allami ORCID logo and Nima Rezaei EMAIL logo
Published/Copyright: May 30, 2025
Become an author with De Gruyter Brill

Abstract

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders. The pathological hallmarks of AD are amyloid-beta (Aβ) plaques and tau protein tangles, which cause neurodegeneration and lead to cognitive decline. The distinguished role of Aβ plaques in the onset of the disease, especially in familial AD, alongside the genetic complexity of AD, underscores the need for precise and targeted genetic interventions targeting Aβ. This review first highlights the amyloidogenic and non-amyloidogenic pathways and inflammatory mechanisms contributing to Aβ accumulation. It also introduces the role of genetic variants such as amyloid precursor protein (APP), presenilin (PSEN1), PSEN2, and Apolipoprotein E (APOE) alongside the molecular and cellular mechanisms involved in Aβ pathology. Then, gene therapy techniques are discussed for their potential to target Aβ either directly by inhibiting its production or enhancing its degradation or indirectly by targeting APOE, inflammatory pathways, and neurotrophic factors. While these approaches show significant preclinical promise, challenges such as timing, safety, and delivery across the blood–brain barrier persist and need further investigation.


Corresponding author: Nima Rezaei, Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Children’s Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran; Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran; and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran, E-mail:

Acknowledgments

The figures in this article were prepared with the help of Servier Medical Art https://smart.servier.com/ under CC BY 4.0 license https://creativecommons.org/licenses/by/4.0.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: P.P. conceptualized the review, drafted the initial manuscript, and contributed to the initial title proposal. P.A. revised and finalized the title, thoroughly edited the manuscript, and provided structural and linguistic improvements to refine the content. N.R. supervised the project, provided critical feedback, and guided the overall development and direction of the review. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: Grammarly and Quill bot were adopted minorly in some parts to improve the language.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: None declared.

  7. Data availability: Not applicable.

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Received: 2025-02-15
Accepted: 2025-05-10
Published Online: 2025-05-30

© 2025 Walter de Gruyter GmbH, Berlin/Boston

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