The purpose of the present study was to longitudinally track changes of metabolite markers detectable by magnetic resonance spectroscopy (MRS) in subjects with mild cognitive impairment (MCI) and to analyze these changes with respect to the rate of cognitive decline and clinical disease progression. Fifteen subjects with MCI and 12 healthy elderly controls were investigated longitudinally (average follow-up period: 3.4 years) using absolute quantification of metabolites within the mid-parietal grey matter and the parietal white matter [N-acetylaspartate (NAA), myo-inositol, choline, creatine, glutamine)] Our main findings include that a longitudinal decline in cognitive function (particularly in memory function) within the MCI group was predicted by a decline in absolute concentrations of the metabolic markers NAA and creatine. This effect was mainly explained by a significant decrease of NAA and creatine in those MCI subjects who converted to Alzheimer's dementia (AD) during the follow-up period. No differences were found at baseline between MCI converters and stable subjects, indicating that at least in the present study MRS did provide a predictive discrimination between converters and stable subjects. Our findings support the use of MRS as a tool for objectively monitoring disease progression even during the earliest stages of AD.