One of the characteristic neuropathological features of Alzheimer's disease (AD) is the deposition of amyloid β-protein (Aβ) as senile plaques in the hippocampus, and neucortex, and as congophilic angiopathy in the walls of cerebral and meningeal blood vessels. However, it is still unclear what the relationship is between the composition of soluble Aβ peptides found in cerebrospinal fluid (CSF) and those localized within the insoluble cerebral deposits. To date, no thorough and specific comparative analysis of Aβ peptide composition in CSF specimens from individual patients with AD and controls has been reported. To investigate the production and metabolism of Aβ in AD, we have recently developed an immunoprecipitation/mass spectrometric method for specifically and sensitively measuring Aβ and its variants. Utilizing this methodology, Aβ and its variants were isolated by immunoprecipitation with monoclonal anti-Aβ and its variants were isolated by immunoprecipitation with monoclonal anti-Aβ antibodies. The identity of the isolated Aβ peptides was determined by measuring the molecular masses using mass spectrometry. Using this combined approach, Aβ and several different variants from individual human CSF specimens, including Aβ 1 - 4 0 , Aβ 1 - 4 2 , Aβ 1 - 3 9 , Aβ 1 - 3 8 , and Aβ 1 - 3 7 can be detected. We have analyzed thirty-two CSF specimens from Chromosome 1 (STM2/PS-2), Chromosome 14 (S182/PS-1), Chromosome 21 (APP 7 1 7 I , APP 7 1 7 F , APP 6 7 0 / 6 7 1 N L ) mutation carriers (both clinically affected and unaffected) and their normal siblings. Our preliminary results suggest that subtle but clear differences in CSF Aβ peptide profiles exist between clinically affected and unaffected mutation carriers with the S182/PS-1, STM2/PS-2, APP 7 1 7 I , and APP 7 1 7 F genetic mutations, but not in CSF samples from APP 6 7 0 / 6 7 1 N L double mutation carriers.