We have previously reported the Ts65Dn (Ts) mouse has impaired intestinal absorptive function and amino acid metabolism. Peptide YY (PYY) has enhanced glucose absorption in mice and turkeys. Other studies have reported that persons with Down syndrome have increased intestinal absorption of aluminum. Alzheimer's-like lesions have been reported in Ts mice. Trial 1 of this study examined brain A1 concentrations, plasma metabolites and intestinal metabolism of 40 control and 40 Ts mice administered 300μg PYY/kg body weight or 0.9% saline for 3d. Trial 2 examined nutrient digestibility of 12 C and 12 Ts given PYY or saline for 14d. In Trial 1, PYY lowered (p<0.05) the brain A1 pool (mg/g FBW) in both C and Ts mice by 80% compared to saline. Ts mice had increased plasma NH3 (329 vs. 269 μM, p<0.05), decreased plasma glucose (7.4 vs. 8.4 mM, p<0.01), elevated apparent energetic efficiency of jejunal glucose uptake (p<0.01) and elevated brain A1 pool (0.41 vs. 0.12μg, p=0.06) compared to C mice. In Trial 2, PYY increased small intestinal density (mg/cm) 12% in both genotypes (p<0.05), but did not alter nutrient digestibility. Brain A1 accretion and hyperammonemia are proposed risk factors for Alzheimer's disease (AD). Ts mice and PYY appear to be suitable models for the study of metabolic and neurological anomalies in Down syndrome and AD.