Population-based blood screening for pre-clinical Alzheimer’s disease: a British birth cohort at age 70

Abstract

In pre-clinical Alzheimer’s disease, cerebral amyloid-β (Aβ) deposition precedes symptoms; Aβ-targeted therapies may have maximum benefits at this stage. Existing Aβ status measurement techniques, including amyloid PET and CSF testing, are difficult to upscale. We therefore compared the concordance of three different blood-based techniques (liquid chromatography-mass spectrometry (LC¬-MS) measures of plasma Aβ, and single molecule array (Simoa) measures of plasma Aβ and phospho-tau181 (p-tau181)) with amyloid PET-positivity in dementia-free members of Insight 46, a sub-study of the British 1946 birth cohort.Of 441 dementia-free individuals with complete data, 82 (18.6%) were amyloid PET-positive. The area under the receiver operating characteristics 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 best perform- ing Simoa biomarker was p-tau181 (0.707; 0.646–0.768). LC-MS Aβ1–42/1–40 performed significantly better (0.817; 0.770–0.864), with a Youden’s index cut-point of 0.095 detecting amyloid PET-positivity with 86.6% sensitivity and 71.9% specificity. Without screening, 543 individuals would need PET scans, to obtain 100 PET-positive individuals. Screening using the base model would require 940 individuals, with 266 proceeding to scan. Using LC-MS Aβ1–42/1–40 alone would reduce these numbers to 623 and 243 respectively. Across a theoretical range of amyloid PET-positivity prevalence of 10–50%, LC-MS Aβ1–42/1–40 would consistently reduce scan numbers, with greater cost savings at lower prevalence.ashvini.keshavan@nhs.net

The global Alzheimer's Association round robin study on plasma amyloid β methods

“…Furthermore, several studies reported similar findings comparing enzyme-linked immunosorbent assays and Simoa platforms for plasma Aβ40 and Aβ42. 7,14,15 Spearman coefficients were 0.68 and 0.71 for, respectively, Aβ40 and Aβ42, which corroborates the findings in this article for the same assays.…”

Promising Blood Biomarkers for Clinical Use in Alzheimer’s Disease: A Focused Update

“…The accuracy of plasma Aβ42/Aβ40 in IP-MS (AUC=0.817) was higher than that of the pTau181 level (AUC=0.707) on the SIMOA platform in identifying amyloid PET positivity among elderly subjects without dementia. 30 However, its accuracy was higher than that of the Aβ42/Aβ40 ratio (AUC=0.620) when these were both computed using SIMOA. The relative benefits and accuracies of Aβ and tau biomarkers require further investigation, particularly with the inclusion of plasma pTau217 and pTau231.…”

“…However, it should be noted that a biomarker being accepted does not mean that it performs perfectly as an AD biomarker. A large cohort study has started to directly compare the various ultrasensitive techniques to quantify target biomarkers ( Table 1 ) 19 30 A head-to-head comparison was conducted on the efficacy of eight promising measurement tools (two ECL-based immunoassays, two SIMOA methods, one antibody-free liquid chromatography-MS, and three IP-MS techniques) regarding the degree to which the plasma Aβ42/Aβ40 ratio reflects the CSF Aβ42/Aβ40 ratio and positive results in amyloid PET. 19 IP-MS with SISAQ developed at Washington University (St Louis, MO, USA) had the greatest accuracy, with an area under the receiver operating characteristic curve (AUC) of up to 0.872, with low intra- and intertest variabilities.…”

“… 19 IP-MS had an AUC (0.817) superior to that of SIMOA (0.620) for both measuring the Aβ42/Aβ40 ratio and identifying positive amyloid PET findings in subjects without dementia. 30 Accuracy, convenience, and cost will determine which technique and target biomarkers will become the most widely used in clinical applications.…”

Reducing unnecessary tau-PET scans in a memory clinic setting via blood-based biomarker screening

“…The idea of using blood-based biomarkers as a rst-line screening, or risk assessment, tool, to avoid unnecessary use of more invasive or expensive tests is not new in AD. Indeed, algorithms developed to screen for amyloid-PET risk using blood-based biomarkers have shown great promise 20,21 . However, since amyloid-PET has become a de facto requirement for inclusion into clinical trials, trials often aim to recruit a certain number of participants with given characteristics without taking into consideration how many individuals who would meet the inclusion criteria might still get screened out 22 .…”