We isolated and sequenced a soluble approximately 25 kDa amino-terminal derivative of the beta amyloid protein precursor (beta APP) that is readily detected in human cerebrospinal fluid (CSF). In CSF samples from 24 Alzheimer's disease (AD) patients and 12 controls, we then quantitated this approximately 25 kDa form as well as the approximately 125 and approximately 105 kDa derivatives that we previously identified. Our analysis shows (1) that, in AD, there is a significant decrease in the relative amount of the approximately 105 kDa form and a corresponding significant increase in the relative amount of the approximately 25 kDa form; (2) that these changes correlate with the mental status of the AD patients; and (3) that the same changes occur to a lesser extent in elderly as compared with young control patients. These observations indicate that processing of the beta APP changes in normal individuals as they age and to a greater extent in those who develop AD. The changes in beta APP derivatives that we have observed in CSF could have major implications because they may reflect fundamental mechanisms responsible for amyloid deposition and can be measured in living patients.