To identify changes in brain functions associated with the development of dementia, brain metabolism and cognition were assessed repeatedly in 12 adults with Down syndrome (DS) using positron emission tomography and neuropsychological tests. Ten subjects remained non-demented (ND) and showed no significant changes over time in cognitive measures or in cerebral metabolism. Two subjects developed dementia after 7 years. Brain functions were relatively stable prior to the onset of dementia; after the onset of dementia, both cognitive function and glucose metabolism in parietal and temporal brain regions known to be vulnerable to Alzheimer disease (AD) showed a rapid linear decline. These findings support the concept that brain functions are stable over time in ND individuals with DS and that decline of brain functions in DS subjects with dementia follows two distinct phases that correspond to the clinical progression of AD. This may have implications for timing of new therapeutic strategies.