Adults with Down's syndrome (DS; n = 44), Fragile X syndrome (FX; n = 20), and normal control (NC) subjects (n = 44) performed eyeblink classical conditioning (EBCC) in a 400-ms delay paradigm. Adults with DS older than 35 (ODS) were significantly impaired relative to younger adults with DS (YDS), adults with FX, and NCs. ODSs conditioned comparably to Alzheimer's disease (AD) patients. The DS mental status examination and the Vineland Adaptive Behavior Scales did not differentiate ODSs from YDSs. YDSs scored higher than ODSs on the Slosson Intelligence Test, but the difference was not clinically significant. Because ODSs had lower blink amplitudes, their poor EBCC could result from peripheral factors. YDSs conditioned similarly to older NCs and worse than their age-matched NCs. Younger and older adults with FX conditioned as well as young NCs. EBCC identified accelerated aging in YDSs and may detect AD neuropathology in ODSs.