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INTRODUCTION Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS‐AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS‐AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11. METHODS We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS‐AD mouse model was treated with a mouse App‐specific antisense oligonucleotide (App‐ASO) and Rab5‐specific ASOs targeting Rab5a and Rab5b. RESULTS App‐ASO treatment normalized full‐length APP (fl‐APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5‐ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS‐AD‐linked pathologies. DISCUSSION These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO‐based strategies targeting APP or Rab5 to counteract DS‐AD features. Highlights App‐ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5‐ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP‐linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App‐ASO or Rab5‐ASOs reversed established pathological phenotypes in Dp16 mice.