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  • Title: High-Throughput Mass Spectrometry Assay for Quantifying β-Amyloid 40 and 42 in Cerebrospinal Fluid.
    Author: Weber DM, Tran D, Goldman SM, Taylor SW, Ginns EI, Lagier RJ, Rissman RA, Brewer JB, Clarke NJ.
    Journal: Clin Chem; 2019 Dec; 65(12):1572-1580. PubMed ID: 31628138.
    Abstract:
    BACKGROUND: The ratio of β-amyloid 1-42 (Aβ42) to Aβ40 in cerebrospinal fluid (CSF) may be useful for evaluating Alzheimer disease (AD), but quantification is limited by factors including preanalytical analyte loss. We developed an LC-MS/MS assay that limits analyte loss. Here we describe the analytical characteristics of the assay and its performance in differentiating patients with AD from non-AD dementia and healthy controls. METHODS: To measure Aβ42/Aβ40, we used unique proteolytically derived C-terminal peptides as surrogate markers of Aβ40 and Aβ42, which were analyzed and quantified by LC-MS/MS. The assay was analytically validated and applied to specimens from individuals with clinically diagnosed AD (n = 102), mild cognitive impairment (n = 37), and non-AD dementias (n = 22), as well as from healthy controls (n = 130). Aβ42/Aβ40 values were compared with APOE genotype inferred from phenotype, also measured by LC-MS/MS. RESULTS: The assay had a reportable range of 100 to 25000 pg/mL, a limit of quantification of 100 pg/mL, recoveries between 93% and 111%, and intraassay and interassay CV <15% for both peptides. An Aβ42/Aβ40 ratio cutoff of <0.16 had a clinical sensitivity of 78% for distinguishing patients with AD from non-AD dementia (clinical specificity, 91%) and from healthy controls (clinical specificity, 81%). The Aβ42/Aβ40 ratio decreased significantly (P < 0.001) with increasing dose of APOE4 alleles. CONCLUSIONS: This assay can be used to determine Aβ42/Aβ40 ratios, which correlate with the presence of AD.
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