Gene therapy and RNA-directed medicines in Alzheimer’s disease: toward a precision framework for clinical translation

Background Gene transfer and RNA-directed medicines offer distinct approaches to modifying disease-relevant biology in Alzheimer’s disease (AD). Existing precision drug-development frameworks require adaptation to account for persistent expression, anatomical distribution, and platform-specific limits on dose adjustment. Objective To propose a modality-specific framework organized around molecular target, biological subgroup, anatomical and cellular delivery, and disease stage, with common requirements for target engagement, clinically meaningful outcomes, and long-term safety. Methods A targeted appraisal of selected clinical, translational, and registry sources was used to develop and illustrate the framework, without a systematic review or quantitative synthesis. Results The retrieved clinical programs illustrate core domains of the suggested framework: nerve growth factor (NGF) studies showed persistent expression, but postmortem findings in three phase I participants revealed limitations in anatomical delivery; apolipoprotein E ( APOE ) ε2 gene addition in APOE ε4 homozygotes represents a genotype-directed intervention, whereas brain-derived neurotrophic factor delivery targets vulnerable memory circuits; tau-directed antisense oligonucleotides and RNA-interference approaches targeting tau or amyloid precursor protein expand the range of molecular targets and platforms. The conference-reported phase II CELIA trial findings, consisting of a missed primary dose–response endpoint despite biomarker reductions and exploratory secondary clinical findings, highlight why target engagement and efficacy require separate evaluation. When designing trials in this field, there must be explicitly defined relationships among mechanism, population, exposure, timing, and outcomes before interpreting results. Conclusion The proposed framework is in its early developmental phase, and its value depends on prospective evaluation, platform-appropriate measures of biological activity, as well as on reassessment of delivery assumptions and therapeutic mechanisms following negative findings.