CRISPR Gene Editing for Alzheimer’s Disease: Review of Preclinical Evidence and Brain Delivery Challenges
A review of gene editing for Alzheimer’s disease
A review of CRISPR-Cas9 and next-generation gene-editing strategies for modulating Alzheimer’s disease–related genes and molecular pathways was published in Acta neurologica Belgica. The paper examines the potential applications of these technologies, preclinical evidence, and barriers to clinical use; it does not report new treatment effects in patients.
Alzheimer’s disease is a progressive neurodegenerative disorder involving multiple factors and is a leading cause of dementia worldwide. Amyloid-beta accumulation and tau pathology are intertwined with synaptic loss, chronic neuroinflammation, and other changes. The review considers gene-editing strategies targeting these pathways.
Target genes and preclinical evidence
The review examines CRISPR-Cas9, base editing, and prime editing. Targets include APOE4, APP, PSEN1, PSEN2, and MAPT. The strategies assessed include selectively correcting specific alleles, suppressing gene expression, and regulating transcription. CRISPR-based transcriptional repression and activation, as well as epigenome editing, are also covered.
The authors discuss multiplex editing approaches that simultaneously target pathways associated with amyloid-beta accumulation, tau hyperphosphorylation, microglial activation, and synaptic dysfunction. According to the abstract, the preclinical evidence reviewed includes reduced amyloid burden, alleviation of tau pathology, restored synaptic function, and improved cognitive performance. However, the supplied abstract does not specify the models, effect sizes, or observation periods for individual experiments, making it difficult to compare strategies or interpret the findings as evidence of efficacy in patients.
Brain delivery and long-term safety remain challenges
A major focus of the review is delivering editing tools to the central nervous system, particularly across the blood–brain barrier (BBB). It discusses adeno-associated viral vectors, lipid nanoparticles, exosome-based delivery, and BBB modulation using focused ultrasound as candidate approaches. The abstract alone does not provide grounds to conclude that any particular delivery method has overcome the barrier in clinical use.
The authors also identify immunogenicity, long-term genomic stability, and ethical and regulatory issues as challenges to clinical translation. Whether gene editing can prevent or treat Alzheimer’s disease can only be determined after these delivery and safety issues are addressed and the approach is evaluated in patients.
Source: Article abstract indexed in Europe PMC
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. The review examines the integration of bioinformatics, multi-omics profiling, and artificial intelligence-guided design to enhance the efficacy and specificity of gene editing therapies for Alzheimer's disease, as reported in Nature Medicine.
This review brings together evidence to inform the joint assessment of target selection, brain delivery, and safety when developing gene-editing candidates for Alzheimer’s disease. For example, development plans for an editing candidate aimed at a particular genetic background could draw on the review when assessing not only whether it modulates relevant pathology, but also delivery of the editing tool to the central nervous system, immune responses, and long-term genomic stability. This is a potential application scenario for follow-up research drawn from the abstract. The paper itself does not establish treatment effects or the potential for prevention in patients, and the supplied material does not support prioritizing any specific editing method or delivery vehicle.