CRISPR-Cas9 and next-generation gene editing strategies for therapeutic intervention of neurodegenerative pathways in Alzheimer's disease: a state-of-the-art review.

Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder and the leading cause of dementia worldwide, characterized by extracellular amyloid-β (Aβ) plaque deposition, intracellular neurofibrillary tangles composed of hyperphosphorylated tau, synaptic loss, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. Despite major advances in understanding its molecular basis, currently approved therapies remain largely symptomatic and fail to halt or reverse neurodegeneration, emphasizing the urgent need for disease-modifying strategies. In this comprehensive state-of-the-art review, we examine the rapidly evolving landscape of CRISPR-Cas9 and next-generation gene-editing technologies, including base editors and prime editors, as innovative therapeutic platforms for precisely modulating AD-associated genetic and molecular pathways. We discuss targeting of critical genes such as APOE4, APP, PSEN1, PSEN2, and MAPT, which play central roles in amyloid processing, tau pathology, lipid metabolism, and neuroinflammatory cascades, and evaluate strategies for allele-specific correction, gene silencing, and transcriptional regulation using CRISPR interference/activation and epigenome editing tools. The review further explores multiplex editing approaches that simultaneously target interconnected pathogenic networks underlying Aβ accumulation, tau hyperphosphorylation, microglial activation, and synaptic dysfunction. A central focus is placed on overcoming delivery barriers to the central nervous system, particularly the blood-brain barrier (BBB), highlighting advances in engineered adeno-associated viral vectors, lentiviral systems, lipid nanoparticles, polymeric nanocarriers, exosome-based delivery, receptor-mediated transcytosis, immune-evasive vector design, and focused ultrasound-mediated BBB modulation. Review examines the integration of bioinformatics, multi-omics profiling, and artificial intelligence-guided design to enhance editing specificity, efficiency, and safety while minimizing off-target effects. Preclinical evidence demonstrating reductions in amyloid burden, attenuation of tau pathology, restoration of synaptic function, and improvement in cognitive performance is critically evaluated. This review discusses translational challenges, including immunogenicity, long-term genomic stability, ethical considerations, and regulatory frameworks. It outlines future directions, emphasizing personalized, precision-based, and durable gene-editing strategies that may redefine therapeutic intervention for AD.