Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease

We have characterized amyloid beta peptide (A beta) concentration, A beta d eposition, paired helical filament formation, cerebrovascular amyloid angio pathy, 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 los s or overt antemortem symptoms of dementia, The measures of A beta depositi on, A beta-immunoreactive plaques with and without cores, thioflavin histof luorescent plaques, and concentrations of insoluble A beta, failed to disti nguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble A beta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further in vestigation revealed that A beta 40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with A beta 42, A beta 40 is known to be elevated in cerebrovascul ar amyloid deposits, and A beta 40 (but not A beta 42) levels, cerebrovascu lar amyloid angiopathy, and ApoE4 allele frequency were all highly correlat ed with each other. Although paired helical filaments in the form of neurof ibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of syn apse change com pared with soluble A beta, particularly soluble A beta 40. Previous experiments attempting to relate A beta deposition to the neurodeg eneration that underlies AD dementia may have failed because they assayed t he classical, visible forms of the molecule, insoluble neuropil plaques, ra ther than the soluble, unseen forms of the molecule.