The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer's disease: a literature review

Abstract

The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer's disease (AD). Detection of Aβ pathology is essential for AD diagnosis and for identifying and recruiting research participants for clinical trials evaluating disease-modifying therapies. Currently, AD diagnoses are usually made by clinical assessments, although detection of AD pathology with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used by specialty clinics. These measures of Aβ aggregation, e.g. plaques, protofibrils, and oligomers, are medically invasive and often only available at specialized medical centers or not covered by medical insurance, and PET scans are costly. Therefore, a major goal in recent years has been to identify blood-based biomarkers that can accurately detect AD pathology with cost-effective, minimally invasive procedures.To assess the performance of plasma Aβ assays in predicting amyloid burden in the central nervous system (CNS), this review compares twenty-one different manuscripts that used measurements of 42 and 40 amino acid-long Aβ (Aβ42 and Aβ40) in plasma to predict CNS amyloid status. Methodologies that quantitate Aβ42 and 40 peptides in blood via immunoassay or immunoprecipitation-mass spectrometry (IP-MS) were considered, and their ability to distinguish participants with amyloidosis compared to amyloid PET and CSF Aβ measures as reference standards was evaluated. Recent studies indicate that some IP-MS assays perform well in accurately and precisely measuring Aβ and detecting brain amyloid aggregates.

Keywords: Alzheimer’s disease; Amyloid beta; Amyloidosis; Biomarker; Blood; Plasma.

Fig. 1

Timeline of Aβ studies [, –25]. Timeline denoting significant events surrounding plasma Aβ use as a biomarker in AD diagnosis, color-coded by assay type. Results were conflicting for many years, but recent IP-MS studies provide promising AUC values for plasma Aβ42/40 measures. The diagnostic reference standard used in each study is listed in parentheses. For studies that used PET as a reference, the tracers include Pittsburg Compound B [, –21, 25], flutemetamol [17, 20, 22, 23], florbetapir [17, 18, 20, 22, 24], and florbetaben [20]. Abbreviations: Disc., Discovery; Val., Validation. Figure created with BioRender.com

Fig. 2

Contrasting methods to measure plasma Aβ. Two common methods to measure plasma Aβ are IP-MS assays (left) and immunoassays (right). In IP-MS assays, the detector measures Aβ species directly and quantitation is performed with an internal standard of stable isotope-labeled Aβ. In immunoassays, Aβ species are measured indirectly with antibody binding, and a different detection antibody must be used for each Aβ isoform. Immunoassays perform quantitation with an external standard. The immunoassay depicted in this figure is a plate-based sandwich immunoassay; bead-based immunoassays are also common, using fluorescently barcoded beads bound to an antibody for indirect measuring of a target. Figure created with BioRender.com

Fig. 3

Forest plots of all AUC values with PET and CSF references. The points are categorized and color-coded by assay type, and the horizontal bars represent a 95% confidence interval. Blue is IP-MS assay, yellow is ECL, orange is an antibody-free LC-MS assay, green is ELISA, and red is SIMOA. The black diamond symbols represent the weighted average of the assays for each category, and within categories, the assay name is listed on the y-axis. The size of each point corresponds to the sample size of the cohort and the diagnostic accuracy of AUC values is depicted on a scale below the x-axis [27]. Abbreviations: WashU, Washington University; Univ. Got., University of Gothenburg