All individuals with Down syndrome (DS) eventually develop the neuropathology of Alzheimer's disease (AD), which is characterized by a premature loss of basal forebrain cholinergic neurons. Similarly, between 4 and 6 months of age, Ts65Dn mice, which model DS, lose cholinergic markers in their medial septal neurons. It is not known whether Ts65Dn mice have age-related learning deficits as well. Control and Ts65Dn mice were tested at several ages in context discrimination. Controls at all ages showed no deficits in learning this task. Ts65Dn mice younger than 3 months demonstrated impaired learning, suggesting a possible developmental delay in Ts65Dn mice. Four-month-old Ts65Dn mice showed no deficits, whereas Ts65Dn mice older than 5 months were impaired in learning the task. Therefore, Ts65Dn mice have an age-related learning impairment that coincides with their age-related neuroanatomical abnormalities and, consequently, may be a useful model of AD.