The Role of Nanocarriers in Modulating Cholinergic and Genetic Pathways for Alzheimer’s Disease Management

Alzheimer's disease (AD) remains a formidable neurodegenerative disorder with a complex, multifactorial pathogenesis that is not fully addressed by current monotherapeutic strategies. While the cholinergic hypothesis has provided a foundation for symptomatic treatment using acetylcholinesterase inhibitors (AChEIs) like galantamine, their efficacy is limited by poor bioavailability, short half-life, and systemic side effects. Concurrently, a growing body of evidence underscores the significant role of genetic factors, including mutations in APP, PSEN1/2, and APOE alleles, as well as oxidative stress-induced nucleic acid damage, in driving disease progression. This review explores the transformative potential of nanotechnology in creating a convergent therapeutic platform that simultaneously targets the cholinergic deficit and underlying genetic susceptibilities in AD. We provide a critical analysis of various nanocarriers—including polymeric nanoparticles, lipid-based systems, and chitosan composites—for the enhanced brain delivery of AChEIs, improving their stability, specificity, and therapeutic index. Furthermore, we highlight the promising role of zinc oxide nanomaterials (ZnO-NPs and ZnO-NFs), which exhibit intrinsic anti-acetylcholinesterase, antioxidant, and anti-amyloid properties. By integrating the principles of nanomedicine with the established cholinergic hypothesis and modern genetic insights, this review delineates a path toward multi-targeted, nano-enabled interventions. These advanced strategies hold the promise of not only alleviating cognitive symptoms but also modifying the disease course, offering a novel and more effective paradigm for AD management.