High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis

Abstract

ObjectiveWe examined whether plasma β-amyloid (Aβ)42/Aβ40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/Aβ42 as reference standards.MethodsUsing an immunoprecipitation and liquid chromatography–mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan.ResultsPlasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88, 95% confidence interval [CI] 0.82–0.93) and CSF p-tau181/Aβ42 (AUC 0.85, 95% CI 0.79–0.92). The combination of plasma Aβ42/Aβ40, age, and APOE ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90–0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (p = 0.01).ConclusionsPlasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.Classification of evidenceThis study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg

“…More recently, studies using a more sensitive IP-MSp method detected a decreased Aβ 42 /Aβ 40 ratio in plasma and reported a diagnostic accuracy of almost 90% of plasma Aβ 42 /Aβ 40 ratio in predicting Aβ PET positivity in AD, MCI and cognitively normal states [110]. Similar results have been presented by other groups [111,112].…”

Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls

“…Brain A␤ antemortem is quantifiable via radioactive labelling on positron emission tomography (PET) [6] and can also be estimated from A␤ concentrations in cerebrospinal fluid (CSF) as a molecular biomarker [7]. Amyloid PET and CSF A␤ can be used interchangeably for clinical diagnosis [7,8] and are increasingly relied upon in diagnostic frameworks [9,10]. Both have also been shown to predict future cognitive decline [11][12][13].…”

“…Sophisticated methods for A␤ analysis have been developed in recent years, but results from the first diagnostic and epidemiological applications of these methods have been inconsistent. A number of studies have found an association of lower plasma A␤ concentrations (thought to reflect a greater brain A␤ burden) with more severe neuropsychological deficits [23,24], with an increased risk of developing AD [25,26], and with amyloidpositive PET [8,27,28] or amyloid-abnormal CSF [29,30] as current gold standards for AD diagnosis. Others report results in the opposite direction [31][32][33][34] and null findings, too, are frequent [35][36][37].…”

18F-Flutemetamol PET post-stroke - a seven year follow-up study

“…As far as we know, this is the first study to offer PET examination seven years post-stroke, and by that adding important knowledge to amyloid evaluation post-stroke. Studies have shown that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants (72), and, therefore, might be more feasible in a post-stroke population, both due to antithrombotic medication, CI and low PET attendance in most studies so far.…”