Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study

Abstract

Background: To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer's disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. Methods: We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. Results: Eighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779-0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden's cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913-0.100). Conclusions: Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer's disease.

Performance of Plasma Amyloid β, Total Tau and Neurofilament Light Chain Levels for Alzheimer’s Disease Identification

“…Compared to healthy controls, plasma Aβ42/Aβ40 was signi cantly decreased in AD patients and was in line with most previous studies, which showed a higher degree of consistency than single Aβ peptide even using different detection methods [7,25]. Decreased Aβ42/Aβ40 levels demonstrated value in re ecting pathological changes of AD and predicting cerebral Aβ status, whether regarding amyloid PET or CSF Aβ as a positive reference [26][27][28].…”

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

“…In two of the four studies sensitivity, specificity and AUC of plasma A␤ 42/40 for A␤-positive PET were more promising [28,47] compared with our own analysis comparing AD patients with controls. Yet, in one of these studies, when the full cohort was analyzed rather than a subsample, plasma A␤ 42/40 performed poorly in discriminating MCI from cognitively normal individuals [47], mirroring our own results. A cross-sectional analysis of people with subjective cognitive decline, too, found low AUC and low specificity of the compound alone for A␤-positive PET [48].…”

“…Further, a lower plasma A␤ 42/40 was reported in patients with mild cognitive impairment (MCI) compared with cognitively normal individuals; additionally MCI patients with lower plasma A␤ 42/40 were at increased risk of 2-year conversion to AD [45]. In two of the four studies sensitivity, specificity and AUC of plasma A␤ 42/40 for A␤-positive PET were more promising [28,47] compared with our own analysis comparing AD patients with controls. Yet, in one of these studies, when the full cohort was analyzed rather than a subsample, plasma A␤ 42/40 performed poorly in discriminating MCI from cognitively normal individuals [47], mirroring our own results.…”

“…To our knowledge, we provide the first application of a novel, highthroughput technique for plasma A␤ analysis [43] to a research study that was run independently of the manufacturer. The assay had previously been used in four studies [28,45,47,48] of which one [47] used a subsample of an earlier investigation [45]. In sum, the studies found correlations of plasma A␤ 42/40 with CSF A␤ 42/40 [45], as well as associations of low plasma A␤ with presence of [28,45,47,48] and an increased 3-year accumulation of A␤ burden on PET [28].…”

“…The assay had previously been used in four studies [28,45,47,48] of which one [47] used a subsample of an earlier investigation [45]. In sum, the studies found correlations of plasma A␤ 42/40 with CSF A␤ 42/40 [45], as well as associations of low plasma A␤ with presence of [28,45,47,48] and an increased 3-year accumulation of A␤ burden on PET [28]. Further, a lower plasma A␤ 42/40 was reported in patients with mild cognitive impairment (MCI) compared with cognitively normal individuals; additionally MCI patients with lower plasma A␤ 42/40 were at increased risk of 2-year conversion to AD [45].…”