Alzheimer's disease (AD) is characterized by overlapping pathological processes, including amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, mitochondrial dysfunction, and neuroinflammation. Monogenic therapies have shown limited benefits, and only in a subset of patients, as other pathological processes continue to drive disease progression. Given the multifactorial and heterogeneous nature of AD, therapeutics targeting more than one gene simultaneously represent a promising strategy to achieve broader therapeutic outcomes. This study highlights the advantages of multigene RNA-based therapeutics, which may overcome compensatory mechanisms and patient heterogeneity. Here, we report the design and functional validation of antisense oligonucleotides (ASOs) specifically engineered for simultaneous silencing of more than one AD-related gene. Using algorithm-assisted sequence design, we generated 11 bispecific gapmer ASOs from 20 candidate genes. In human and mouse cellular models, these ASOs achieved potent and sustained knockdown with picomolar to low-nanomolar IC50 values. Functionally, treatment led to significant reductions in Aβ42 production, up to 70%, while maintaining favorable safety and specificity profiles. Collectively, our findings establish a proof of concept for multigene silencing in AD, demonstrating that rationally designed ASOs can provide robust target suppression across key pathological pathways. This strategy introduces a new paradigm in oligonucleotide design, with the potential to deliver disease-modifying benefits for patients with AD.