We have characterized amyloid β peptide (Aβ. concentration, Aβ deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD. patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Aβ deposition, Aβ-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Aβ, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Aβ clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Aβ40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Aβ42. Aβ40 is known to be elevated in cerebrovascular amyloid deposits, and Aβ40 (but not Aβ42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Aβ, particularly soluble Aβ40. Previous experiments attempting to relate Aβ deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.