Total Aβ
            <sub>42</sub>
            /Aβ
            <sub>40</sub>
            ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis

Doecke, James D.; Pérez‐Grijalba, Virginia; Fandos, Noelia; Fowler, Christopher; Villemagne, Victor L.; Masters, Colin L.; Pesini, Pedro; Sarasa, Manuel

doi:10.1212/wnl.0000000000009240

Cited by 120 publications

(122 citation statements)

References 38 publications

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“…In comparison, prescreening of CN participants solely based on age and APOE-ε4 genotype would reduce the number of necessary PET scans by only 40%. Previous studies using IP-MS [36] or ABtest ELISAs [14,15] to quantify the plasma amyloid ratio reported higher PPVs than the ones observed here, which might give the impression that these methods are superior to the SIMOA or conventional ELISA technology. However, the prevalence of amyloid-PET positivity was also higher in these other studies (≈ 30%), which directly influences the reported PPV.…”

Section: Discussioncontrasting

confidence: 64%

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis

et al. 2020

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Background Blood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages. Methods In this prospective cross-sectional study, we quantified plasma Aβ1–42/Aβ1–40 ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ1–42/Aβ1–40 to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer’s disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms. Results ELISA and SIMOA plasma Aβ1–42/Aβ1–40 detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72–0.84; SIMOA: AUC 0.79, 95% CI 0.73–0.85), and both increased the performance of a basic demographic model including only age and APOE-ε4 genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ1–42/Aβ1–40 correlated similarly with amyloid-PET for both platforms (Spearman ρ = − 0.32, p < 0.0001), yet correlations with CSF Aβ1–42/t-tau were stronger for ELISA (ρ = 0.41, p = 0.002) than for SIMOA (ρ = 0.29, p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ1–42 and Aβ1–40 measured by SIMOA consistently underestimating those measured by ELISA. Conclusions ELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ1–42/Aβ1–40, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment. Trial registration EudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE).

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Section: Discussioncontrasting

confidence: 64%

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis

et al. 2020

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“…As A self-assembly strongly depends on the context of its release, we sought to determine whether the assembly of interest was produced particularly by CHO cells or commonly across other models. This reduction correlated with the severity of AD symptoms exerted by the patients (see raw values in Table1), concordantly with previous reports [51]. On the contrary, relative quantification of hexameric A levels detected by Western blotting, using soluble APP as an intrasubject control, revealed an increase in hexameric levels with the progression of AD (Table1).…”

Section: Formation Of Hexameric A Across a Wide Range Of Modelssupporting

confidence: 91%

Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies

Vrancx

Vadukul

Contino

et al. 2020

Preprint

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BackgroundThe β-amyloid peptide (Aβ) plays a key role in Alzheimer’s disease. After its production by catabolism of the amyloid precursor protein (APP) through the action of presenilin 1 (PS1)- or presenilin 2 (PS2)-dependent γ-secretases, monomeric Aβ can assemble in oligomers. In a pathological context, this eventually leads to the formation of fibrils, which deposit in senile plaques. Many studies suggest that Aβ toxicity is related to its soluble oligomeric intermediates. Among these, our interest focuses on hexameric Aβ, which acts as a nucleus for Aβ self-assembly.MethodsBiochemical analyses were used to identify hexameric Aβ in a wide range of models; cell lines, cerebrospinal fluid from cognitively impaired patients and transgenic mice exhibiting human Aβ pathology (5xFAD). We isolated this assembly and assessed both its effect on primary neuron viability in vitro, and its contribution to amyloid deposition in vivo following intracerebral injection. In both cases, we used wild-type mice (C57BL/6) to mimic an environment where hexameric Aβ is present alone and 5xFAD mice to incubate hexameric Aβ in a context where human Aβ species are pre-existing. Using CRISPR-Cas9, we produced stable knockdown human cell lines for either PS1 or PS2 to elucidate their contribution to the formation of hexameric Aβ.ResultsIn WT mice, we found that neither in vitro or in vivo exposure to hexameric Aβ was sufficient to induce cytotoxic effects or amyloid deposition. In 5xFAD mice, we observed a significant increase in neuronal death in vitro following exposure to 5μM hexameric Aβ, as well as a 1.47-fold aggravation of amyloid deposition in vivo. At the cellular level, we found hexameric Aβ in extracellular vesicles and observed a strong decrease in its excretion when PS2 was knocked down by 60%.ConclusionsOur results indicate the absence of cytotoxic effects of cell-derived hexameric Aβ by itself, but its capacity to aggravate amyloid deposition by seeding other Aβ species. We propose an important role for PS2 in the formation of this particular assembly in vesicular entities, in line with previous reports linking the restricted location of PS2 in acidic compartments to the production of more aggregation-prone Aβ.

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“…The abnormal threshold for the ratio of plasma Aβ in AIBL participants was set as ˂0.085. This threshold was based upon receiver operating characteristics using the Youden index for plasma Aβ against brain Aβ positives and negatives ( Doecke et al , 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Longitudinal evaluation of the natural history of amyloid-β in plasma and brain

Burnham

Fandos

Fowler

et al. 2020

Brain Communications

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Plasma amyloid-β peptide concentration has recently been shown to have high accuracy to predict amyloid-β plaque burden in the brain. These amyloid-β plasma markers will allow wider screening of the population and simplify and reduce screening costs for therapeutic trials in Alzheimer’s disease. The aim of this study was to determine how longitudinal changes in blood amyloid-β track with changes in brain amyloid-β. Australian Imaging, Biomarker and Lifestyle study participants with a minimum of two assessments were evaluated (111 cognitively normal, 7 mild cognitively impaired, 15 participants with Alzheimer’s disease). Amyloid-β burden in the brain was evaluated through PET and was expressed in Centiloids. Total protein amyloid-β 42/40 plasma ratios were determined using ABtest® assays. We applied our method for obtaining natural history trajectories from short term data to measures of total protein amyloid-β 42/40 plasma ratios and PET amyloid-β. The natural history trajectory of total protein amyloid-β 42/40 plasma ratios appears to approximately mirror that of PET amyloid-β, with both spanning decades. Rates of change of 7.9% and 8.8%, were observed for total protein amyloid-β 42/40 plasma ratios and PET amyloid-β, respectively. The trajectory of plasma amyloid-β preceded that of brain amyloid-β by a median value of 6 years (significant at 88% confidence interval). These findings, showing the tight association between changes in plasma and brain amyloid-β, support the use of plasma total protein amyloid-β 42/40 plasma ratios as a surrogate marker of brain amyloid-β. Also, that plasma total protein amyloid-β 42/40 plasma ratios has potential utility in monitoring trial participants, and as an outcome measure.

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Total Aβ ₄₂ /Aβ ₄₀ ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis

Abstract: ObjectiveTo explore whether the plasma total β-amyloid (Aβ) Aβ 42 /Aβ 40 ratio is a reliable predictor of the amyloid-PET status by exploring the association between these 2 variables in a subset of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging cohort.

Cited by 120 publications

References 38 publications

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis

Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies

Longitudinal evaluation of the natural history of amyloid-β in plasma and brain

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Total Aβ 42 /Aβ 40 ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis

Abstract: ObjectiveTo explore whether the plasma total β-amyloid (Aβ) Aβ 42 /Aβ 40 ratio is a reliable predictor of the amyloid-PET status by exploring the association between these 2 variables in a subset of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging cohort.

Cited by 120 publications

References 38 publications

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis

Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies

Longitudinal evaluation of the natural history of amyloid-β in plasma and brain

Contact Info

Product

Resources

About

Total Aβ ₄₂ /Aβ ₄₀ ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis