Abstract
Alzheimer’s disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques—liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181—to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden’s index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548–0.691) and phospho-tau181 (0.707; 0.646–0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770–0.864 and amyloid-β composite: 0.820; 0.775–0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10–50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.
Highlights
A core early feature of Alzheimer’s disease is brain deposition of amyloid-b, which is detectable in vivo using amyloid PET ligands binding fibrillar amyloid-b (Klunk et al, 2004; Morris et al, 2016), and by CSF testing showing reduced concentrations of amyloid-b42 (Motter et al, 1995; Olsson et al, 2016) or amyloid-b42/amyloid-b40 (Slaets et al, 2013; Toledo et al, 2013; Pannee et al, 2016)
All study assessments were designed to be completed in a single day, 59 individuals (13.4% of those included in the analysis) had their PET scans on a different day to blood sampling due to PET tracer availability or scanner maintenance issues; the median delay between the blood test and the scan in these individuals was 0.131 years [interquartile range (IQR): 0.060–0.211 years]
Weak positive correlations were observed between single molecule array (Simoa) ln amyloid-b42 and LC-MS ln amyloid-b1-42 (r = 0.207, P = 0.001), Simoa ln amyloid-b40 and LC-MS ln amyloid-b1-40 (r = 0.406, P 5 0.0001), and Simoa ln amyloid-b42/amyloid-b40 and LC-MS ln amyloid-b1-42/ amyloid-b1-40 (r = 0.189, P = 0.003)
Summary
A core early feature of Alzheimer’s disease is brain deposition of amyloid-b, which is detectable in vivo using amyloid PET ligands binding fibrillar amyloid-b (Klunk et al, 2004; Morris et al, 2016), and by CSF testing showing reduced concentrations of amyloid-b42 (Motter et al, 1995; Olsson et al, 2016) or amyloid-b42/amyloid-b40 (Slaets et al, 2013; Toledo et al, 2013; Pannee et al, 2016). A meta-analysis of studies published until 2015 (Olsson et al, 2016) yielded conflicting results on the ability of plasma amyloid-b to distinguish Alzheimer’s disease dementia from controls, or mild cognitive impairment (MCI) progressing to Alzheimer’s disease dementia from stable MCI. These mixed findings were related to heterogeneity of comparisons; older studies compared clinically diagnosed Alzheimer’s disease cases with various nonpathologically defined control groups, while newer studies compared amyloid-positive and -negative groups as defined by PET or CSF. Plasma amyloid-b42/amyloid-b40 measured by an immunoprecipitation–mass spectrometry (IP-MS) method was able to predict conversion from PET-negative to PET-positive status more than 1.5 years later, with individuals who had plasma amyloid-b42/amyloid-b40 5 0.1218 being 15 times more likely to convert from PET-negative to PETpositive than those above this cut-off point (Schindler et al, 2019)
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