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Deficits in the retromer complex are linked to enhanced A\u03b2 production. The levels of the components of the retromer complex are reported to be downregulated in Alzheimer disease (AD). Down syndrome (DS) shares neuropathological features with AD. Recent evidence points to dysregulation of the retromer complex in DS. The mechanisms underlying retromer deficits in DS and AD are poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We measured the levels of retromer components in the frontal cortex of cases of DS\u2010AD (AD in DS) as well as DS; the frontal cortex of a person partially trisomic (PT\u2010DS) for human chromosome 21 (HSA21), whose genome had only the normal 2 copies of the<jats:italic>APP<\/jats:italic>gene, was also examined. We also analyzed these proteins in the Dp16 mouse model of DS. To further explore the molecular mechanism for changes in the retromer complex, we treated Dp16 mice with a \u03b3\u2010secretase modulator (GSM; 776890), a treatment that reduces the levels of A\u03b242 and A\u03b240.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found VPS26A, VPS26B, and VPS29, but not VPS35, were significantly reduced in both DS and DS\u2010AD, but not in PT\u2010DS. Downregulation of VPS26A, VPS26B, and VPS29 was recapitulated in the brains of old Dp16 mice (at 16\u2009months of age) and required increased<jats:italic>App<\/jats:italic>gene dose. Significantly, GSM treatment completely prevented reductions of the retromer complex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our studies point to increased<jats:italic>APP<\/jats:italic>gene dose as a compromising retromer function in DS and suggest a causal role for A\u03b242 and A\u03b240. 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