X11α is a neuronal-specific adaptor protein that binds to the amyloid-β protein precursor (AβPP). Overexpression of X11α reduces Aβ production but whether X11α also protects against Aβ-related memory dysfunction is not known. To test this possibility, we crossed X11α transgenic mice with AβPP-Tg2576 mice. AβPP-Tg2576 mice produce high levels of brain Aβ and develop age-related defects in memory function that correlate with increasing Aβ load. Overexpression of X11α alone had no detectable adverse effect upon behavior. However, X11α reduced brain Aβ levels and corrected spatial reference memory defects in aged X11α/AβPP double transgenics. Thus, X11α may be a therapeutic target for Alzheimer's disease.