We have sought for disease-related proteins that could predict the onset of Alzheimer's disease (AD) in a study population derived from the Rotterdam Scan Study, a population-based prospective cohort study designed to investigate the etiology and natural history of age-related brain changes in the elderly. The serum proteome of 43 persons who developed AD, after an average of 4.2 years (±2.6 years SD) after blood sampling, and 43 gender- and age-matched controls who remained dementia-free during follow-up was investigated by liquid chromatography mass spectrometry. We identified 61 differentially expressed peptides between presymptomatic AD and controls, 9 of which were derived from pregnancy zone protein (PZP). Quantitative measurements using a multiple reaction monitoring assay showed a significant increase in concentration of PZP in presymptomatic AD (34.3 ± 20.6 mg/L) compared with controls (23.6 ± 13.6 mg/L) (p = 0.006). The difference in PZP was significant in women. Immunohistochemical validation of the findings on brain tissue sections showed strong PZP expression in senile plaques and in microglial and glial cells in AD with only low expression in some scattered glial cells in controls.