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Background The development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. Methods We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. Results Plasma Aβ42/40 ratio was significantly ( p  < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77–0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82–0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87–0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. Conclusions This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer’s disease; and may enhance the efficiency of enrolling participants into Alzheimer’s disease drug trials.

Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder that represents a major global public health concern. Traditionally, AD is diagnosed using cerebrospinal fluid biomarker analysis or brain imaging modalities. Recently, less burdensome, more widely available blood biomarker (BBM) assays for amyloid-beta (Aβ42/40) and phosphorylated-tau concentrations have been found to accurately identify the presence/absence of brain amyloid plaques and tau tangles and have helped to streamline AD diagnosis. However, few BBMs have been rigorously analytically validated. Herein, we report the analytical validation of a novel liquid chromatography–tandem mass spectrometry (LC-MS/MS) multiplex method for quantifying plasma phosphorylated-tau217 (p-tau217) and non-phosphorylated-tau217 (np-tau217) peptide concentrations. We combined the p-tau217/np-tau217 concentrations ratio (%p-tau217) and the previously validated LC-MS/MS multiplex assay for plasma Aβ42/40 into a new multianalyte assay with algorithmic analysis (MAAA; PrecivityAD2™ test) that identifies brain amyloid status based on brain amyloid positron emission tomography. We found (a) the %p-tau217 assay is precise, accurate, sensitive, and linear over a wide analytical measurement range, and free from carryover and interference; (b) the pre-analytical specimen collection, processing, storage, and shipping conditions that maintain plasma tau peptide stability; and (c) using the measured analytical imprecision for plasma Aβ42/40 and p-tau217/np-tau217 levels in a worst-case scenario model, the PrecivityAD2 test algorithm for amyloid pathology classification changed for only 3.5% of participants from brain amyloid positive to negative, or from negative to positive. The plasma sample preparation and LC-MS/MS methods underlying the PrecivityAD2 test are suitable for use in the clinical laboratory and valid for the test’s intended purpose: to aid in the diagnostic evaluation of individuals aged 55 and older with signs or symptoms of mild cognitive impairment or dementia.

Background The amyloid probability score (APS) is the model read‐out of the analytically validated mass spectrometry‐based PrecivityAD® blood test that incorporates the plasma Aβ42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer's disease. Purpose This study aimed to provide additional independent evidence that the pre‐established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals. Methods The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available. Results In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre‐established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9–92.1%) and specificity of 96% (CI: 80.5–99.3%), exclusive of 13 individuals for whom the test was inconclusive. Interpretation The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired.

The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-β (Aβ) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020. Amyloid detected in blood and by positron emission tomography (PET) imaging. The main outcome was the diagnostic performance of plasma Aβ42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aβ42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aβ42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aβ42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology. These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.

Background: Low-density lipoprotein cholesterol (LDL-C) has been the cornerstone measurement for assessing cardiovascular risk for nearly 20 years. Content: Recent data demonstrate that apolipoprotein B (apo B) is a better measure of circulating LDL particle number (LDL-P) concentration and is a more reliable indicator of risk than LDL-C, and there is growing support for the idea that addition of apo B measurement to the routine lipid panel for assessing and monitoring patients at risk for cardiovascular disease (CVD) would enhance patient management. In this report, we review the studies of apo B and LDL-P reported to date, discuss potential advantages of their measurement over that of LDL-C, and present information related to standardization. Conclusions: In line with recently adopted Canadian guidelines, the addition of apo B represents a logical next step to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) and other guidelines in the US. Considering that it has taken years to educate physicians and patients regarding the use of LDL-C, changing perceptions and practices will not be easy. Thus, it appears prudent to consider using apo B along with LDL-C to assess LDL-related risk for an interim period until the superiority of apo B is generally recognized.

The number of circulating LDL particles is a strong indicator of future cardiovascular disease (CVD) events, even superior to the concentration of LDL cholesterol. Atherogenic (primarily LDL) particle number is typically determined either directly by the serum concentration of apolipoprotein B (apo B) or indirectly by nuclear magnetic resonance (NMR) spectroscopy of serum to obtain NMR-derived LDL particle number (LDL-P). To assess the comparability of apo B and LDL-P, we reviewed 25 clinical studies containing 85 outcomes for which both biomarkers were determined. In 21 of 25 (84.0%) studies, both apo B and LDL-P were significant for at least 1 outcome. Neither was significant for any outcome in only 1 study (4.0%). In 50 of 85 comparisons (58.8%), both apo B and LDL-P had statistically significant associations with the clinical outcome, whereas in 17 comparisons (20.0%) neither was significantly associated with the outcome. In 18 comparisons (21.1%) there was discordance between apo B and LDL-P. In most studies, both apo B and LDL-P were comparable in association with clinical outcomes. The biomarkers were nearly equivalent in their ability to assess risk for CVD and both have consistently been shown to be stronger risk factors than LDL-C. We support the adoption of apo B and/or LDL-P as indicators of atherogenic particle numbers into CVD risk screening and treatment guidelines. Currently, in the opinion of this Working Group on Best Practices, apo B appears to be the preferable biomarker for guideline adoption because of its availability, scalability, standardization, and relatively low cost.

Despite the usefulness of standard lipid parameters for cardiovascular disease risk assessment, undiagnosed residual risk remains high. Advanced lipoprotein testing (ALT) was developed to provide physicians with more predictive diagnostic tools. ALT methods separate and/or measure lipoproteins according to different parameters such as size, density, charge, or content, and equivalence of results across methods has not been demonstrated. Through a split-sample study, 25 clinical specimens (CSs) were assayed in 10 laboratories before and after freezing using the major ALT methods for non-HDL particles (non-HDL-P) or apolipoprotein B-100 (apoB-100) measurements with the intent to assess their comparability in the current state of the art. The overall relative standard deviation (CV) of non-HDL-P and apoB-100 concentrations measured by electrospray differential mobility analysis, nuclear magnetic resonance, immunonephelometry, LC-MS/MS, and vertical autoprofile in the 25 frozen CSs was 14.1%. Within-method comparability was heterogeneous, and CV among 4 different LC-MS/MS methods was 11.4% for apoB-100. No significant effect of freezing and thawing was observed. This study demonstrates that ALT methods do not yet provide equivalent results for the measurement of non-HDL-P and apoB-100. The better agreement between methods harmonized to the WHO/IFCC reference material suggests that standardizing ALT methods by use of a common commutable calibrator will improve cross-platform comparability. This study provides further evidence that LC-MS/MS is the most suitable candidate reference measurement procedure to standardize apoB-100 measurement, as it would provide results with SI traceability. The absence of freezing and thawing effect suggests that frozen serum pools could be used as secondary reference materials.

The development of blood-based biomarker tests that are accurate and robust for Alzheimer's disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma A[beta]42 and A[beta]40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF A[beta]42/40 ratio. Plasma A[beta]42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77-0.85) and the percent agreement between plasma A[beta]42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82-0.90) and accuracy (81%) for the plasma A[beta]42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87-0.93) and accuracy (86%) improved further when A[beta]42/40, ApoE4 copy number and participant age were included in the model. This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer's disease; and may enhance the efficiency of enrolling participants into Alzheimer's disease drug trials.

Isolated asymptomatic glycerol kinase deficiency (GKD) or 'pseudohypertriglyceridemia', is an X-linked recessive disorder resulting in hyperglyceroluria and hyperglycerolemia. Patients typically present with hypertriglyceridemia, which is unresponsive to therapy. The falsely elevated triglycerides are a result of clinical laboratories utilizing glycerol levels to report triglyceride concentrations. Glycerol blanking will account for the excess glycerol and provide accurate triglyceride measures. Pseudohypertriglyceridemia is linked to glucose impairment and other forms of GKD involving childhood metabolic crises and developmental limitations. Identifying patients with pseudohypertriglyceridemia prevents overestimation of cardiovascular risk and exposure to unnecessary lipid-altering agents; and heightens the awareness of the potential for symptomatic GKD in male offspring. We urge clinical labs to provide a glycerol-blanked triglyceride measurement for known or suspected pseudohypertriglyceridemia.

Detection of low plasma renin is crucial because it determines the course of treatment of hypertensive patients. Nichols Institute Diagnostics developed an automated chemiluminometric immunoassay for renin (Direct Renin) that is sensitive enough to detect low renin samples, minimizes interference by prorenin, and it can be performed in less than one hour. Two monoclonal antibodies are used: the capture antibody is bound to biotin and recognizes both renin and prorenin. The second antibody is labeled with acridinium-ester and is specific for active renin. The method is automated on the Nichols Advantage® instrument: after a 20 minute 37° C incubation of a 0.2 ml plasma sample with both antibodies, paramagnetic particles coated with streptavidin are added and incubation extended for further 10 minutes. Detection after washing is accomplished by the addition of alkaline peroxide. The ability of this immunoassay to discriminate patients with low renin was assessed by comparing it to the Plasma Renin Activity (PRA) method of Sealey and Laragh. Two separate comparison studies were performed four months apart using different immunoassay reagent lots. The first study of 240 patient specimens included 93 samples with PRA < 0.65 ng/ml/h, 38 samples with PRA 0.65 to 1.0 ng/mg/h, 30 samples from diabetic patients and 28 from pregnant women. Using a 3-h PRA incubation and PRA and Direct Renin cutoffs of 0.65 ng/ml/h and 5 mU/L respectively, classification of low vs. non-low renin agreed in 177 samples (82.3%). Three specimens were classified as low renin by PRA and non-low by Direct Renin. Thirty three specimens were classified as low-renin by Direct Renin and non-low renin by PRA. Since most of these 33 discrepant samples had PRA activities between 0.65 and 1.0 ng/ml/h, in the second 163-sample study, the 43 specimens with PRA values < 1.0 were reanalyzed using an 18-h incubation. Again with 0.65 ng/ml/hr and 5 mU/L as cut-offs, low renin classification agreed in 152 of the 163 samples (93%); 2 samples (1.2 %) had low PRA values and non-low Direct Assay results and 9 samples (5.5 %) low Direct Assay and non-low PRA results. Although prorenin levels are increased in diabetes and pregnancy, samples from diabetic patients behaved like the other specimens in the regression analysis. Direct Renin results in samples from pregnant women were actually lower than the values expected from the regression analysis, most likely because their PRA reflect increased plasma angiotensinogen levels. These results suggest that plasma prorenin does not interfere with the Direct Renin assay. In summary, we report here a simple, fast and reproducible Direct Renin immunoassay with sensitivity and accuracy comparable to those of the classical PRA kinetic assay.