Work

CRISPR Gene Editing in Alzheimer’s Disease: From APP/PSEN1/PSEN2 Proof-of-Concept to APOE4 Translational Challenges

Year: 2026

Type: article

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia worldwide and remains without disease-modifying therapies. (1) Background: Genetically, AD comprises rare monogenic forms associated with pathogenic variants in the APP, PSEN1, and PSEN2 genes, as well as the much more prevalent sporadic form, in which the APOE ε4 allele constitutes the major genetic risk factor. Advances in CRISPR-based genome-editing technologies have generated increasing interest in their potential application to AD. (2) Methods: This is a narrative clinical-translational review of preclinical evidence on CRISPR-mediated genome editing in monogenic AD and of the limitations to its application in sporadic AD associated with APOE ε4. (3) Results: Preclinical studies demonstrate robust proof of concept for genome editing of APP and PSEN1/PSEN2, indicating the feasibility of upstream interventions in the pathogenic cascade of monogenic AD. In contrast, the application of these strategies to sporadic AD faces substantial challenges, including the pleiotropic effects of APOE ε4, unresolved safety concerns, and complex ethical and regulatory implications related to irreversible genomic interventions in the central nervous system. (4) Conclusions: A framework for prioritizing genetic targets based on clinical and ethical criteria may guide responsible translational research and clinical decision-making in genome-editing approaches for Alzheimer’s disease.

Source: International Health Sciences Review

DOI: 10.70164/ihsr.v2i1.108