title: Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls.
abstract: OBJECTIVE
  Although amyloid-beta (Aβ) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer disease; soluble oligomeric Aβ has been hypothesized to more directly underlie impaired learning and memory in dementia of the Alzheimer type. However, the lack of a sensitive, specific, and quantitative assay for Aβ oligomers has hampered rigorous tests of this hypothesis.
  
  
  METHODS
  We developed a plate-based single molecule counting fluorescence immunoassay for oligomeric Aβ sensitive to low pg/ml concentrations of synthetic Aβ dimers using the same Aβ-specific monoclonal antibody to both capture and detect Aβ. The Aβ oligomer assay does not recognize monomeric Aβ, amyloid precursor protein, or other non-Aβ peptide oligomers.
  
  
  RESULTS
  Aβ oligomers were detected in aqueous cortical lysates from patients with dementia of the Alzheimer type and nondemented patients with Aβ plaque pathology. However, Aβ oligomer concentrations in demented patients' lysates were tightly correlated with Aβ plaque coverage (r = 0.88), but this relationship was weaker in those from nondemented patients (r = 0.30) despite equivalent Aβ plaque pathology. The ratio of Aβ oligomer levels to plaque density fully distinguished demented from nondemented patients, with no overlap between groups in this derived variable. Other Aβ and plaque measures did not distinguish demented from nondemented patients. Aβ oligomers were not detected in cerebrospinal fluid with this assay.
  
  
  CONCLUSIONS
  The results raise the intriguing hypothesis that the linkage between plaques and oligomers may be a key pathophysiological event underlying dementia of the Alzheimer type. This Aβ oligomer assay may be useful for many tests of the oligomer hypothesis.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Esparza
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Zhao
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: David L
authors.initials: DL
authors.lastname: Brody
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D055503:Protein Multimerization / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides