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Down syndrome and control brain tissues were evaluated for phosphorylated tau, tau modulators, and cathepsin\u2010D activity. Several kinases and phosphatase PP2A were unchanged, but tau phosphorylation was elevated, and cathepsin\u2010D activity decreased in aged patients with Down syndrome. Retromer proteins positively associated with soluble tau, whereas pathogenic tau negatively correlated with retromer proteins and cathepsin\u2010D activity. Retromer deficiency and consequent reduction of cathepsin\u2010D activity may contribute to pathogenic tau accumulation, thus, retromer represents a viable therapeutic target against tau pathology in Down syndrome. 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