Crispr Gene Therapy for Alzheimer’s Disease: A Systematic Review of Advances and Challenges

A BSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that worsens with time and is typified by tau hyperphosphorylation, amyloid-beta (Aβ) buildup, and synaptic dysfunction. Despite advances in symptomatic treatments, effective disease-modifying therapies remain elusive. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based gene editing offers a novel approach for precisely targeting AD-associated genetic risk factors, including APOE4, microtubule-associated protein tau (MAPT), BACE1, and TREM2. A PRISMA-compliant systematic review was carried out. Studies published between 2017 and 2025 were retrieved from PubMed, Google Scholar, Europe PMC, DOAJ, Semantic Scholar, and ResearchGate. Quality assessment was performed using the Newcastle-Ottawa Scale and SYRCLE’s Risk of Bias Tool. Studies involving CRISPR interventions targeting AD-related genes were included. Fifteen studies met the inclusion criteria. CRISPR-based editing resulted in significant reductions in Aβ deposition (45-60%), decreased tau phosphorylation (~40%), and improved neuronal survival (~30%) in preclinical models. Recent advances, including base editing, prime editing, and epigenetic CRISPR, have improved editing precision and reduced off-target effects. However, challenges such as effective blood-brain barrier (BBB) penetration, immune responses, and long-term genomic stability persist. Non-viral delivery systems, including nanoparticles and exosomes, demonstrated improved safety profiles compared to viral vectors. Human-derived iPSC platforms enhanced the understanding of CRISPR-mediated therapeutic strategies. CRISPR technology holds transformative potential for AD therapy. Nevertheless, clinical translation requires further optimization of delivery systems, safety validation, and regulatory oversight. Integration of precision gene-editing platforms with advanced delivery technologies may accelerate the development of personalized CRISPR-based treatments for Alzheimer’s disease.