Detection of Misfolded Aβ Oligomers for Sensitive Biochemical Diagnosis of Alzheimer’s Disease

•Aβ oligomers can be detected in vitro by cyclic amplification of Aβ misfolding (Aβ-PMCA)•Aβ-PMCA permits detection of as little as 3 fmol of soluble Aβ oligomers•Seeding-competent Aβ oligomers are elevated in CSF samples from AD patients•Aβ-PMCA distinguishes AD CSF from controls with 90% sensitivity and 92% specificity

SummaryAlzheimer's disease (AD) diagnosis is hampered by the lack of early, sensitive, and objective laboratory tests. We describe a sensitive method for biochemical diagnosis of AD based on specific detection of misfolded Aβ oligomers, which play a central role in AD pathogenesis. The protein misfolding cyclic amplification assay (Aβ-PMCA), exploits the functional property of Aβ oligomers to seed the polymerization of monomeric Aβ. Aβ-PMCA allowed detection of as little as 3 fmol of Aβ oligomers. Most importantly, using cerebrospinal fluid, we were able to distinguish AD patients from control individuals affected by a variety of other neurodegenerative disorders or nondegenerative neurological diseases with overall sensitivity of 90% and specificity of 92%. These findings provide the proof-of-principle basis for developing a highly sensitive and specific biochemical test for AD diagnosis.

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