Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care.

Importance: An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD. Objective: To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values. Design, Setting, and Participants: There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n = 307) and a secondary care cohort (n = 300); 1 plasma sample per patient was analyzed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n = 208) and in the secondary care cohort (n = 398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection. Exposure: Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-ß 42 and amyloid-ß 40 (Aß42:Aß40) plasma ratio (the amyloid probability score 2 [APS2]). Main Outcomes and Measures: The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aß42:Aß40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated. Results: The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology. When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%]). Conclusions and Relevance: The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care.

Plasma Aß42/Aß40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.

INTRODUCTION: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aß) into screening algorithms may improve screening efficiency. METHODS: Plasma Aß, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS: The area under the receiver operating curve (AUC) was 0.87 for Aß42/Aß40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aß42/Aß40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p-tau217/np-tau217 along with Aß42/Aß40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer's disease trial.

INTRODUCTION: In trials of amyloid-lowering drugs for Alzheimer's disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P < 0.001). Among plasma eligible participants, PET eligibility did not differ by group. DISCUSSION: These results suggest that prevalence of brain amyloid pathology differed, but that eligibility based on plasma was equally effective across racial and ethnic group members. HIGHLIGHTS: Plasma amyloid eligibility is lower in underrepresented racial and ethnic groups. In plasma eligible adults, positron emission tomography eligibility rates are similar across race and ethnicity. Plasma biomarker tests may be similarly effective across racial and ethnic groups.

Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aß42/40 ratio to identify presence of brain amyloid.

BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease.

Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients.

Considerations for widespread implementation of blood-based biomarkers of Alzheimer's disease.

Diagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders.

Regulatory review of novel therapeutics--comparison of three regulatory agencies.

BACKGROUND: The upcoming reauthorization of the Prescription Drug User Fee Act focuses on improving the review process for new drug applications at the Food and Drug Administration (FDA). METHODS: Using publicly available information from the FDA, the European Medicines Agency (EMA), and Health Canada, we compared the time for completion of the first review and the total review time for all applications involving novel therapeutic agents approved by the three regulatory agencies from 2001 through 2010 and determined the geographic area in which each novel therapeutic agent was first approved for use. RESULTS: There were 510 applications for novel therapeutic agents approved from 2001 through 2010--225 by the FDA, 186 by the EMA, and 99 by Health Canada; among the applications, there were 289 unique agents. The median length of time for completion of the first review was 303 days (interquartile range, 185 to 372) for applications approved by the FDA, 366 days (interquartile range, 310 to 445) for those approved by the EMA, and 352 days (interquartile range, 255 to 420) for those approved by Health Canada (P<0.001 for the comparison across the three agencies). The median total review time was also shorter at the FDA than at the EMA or Health Canada (P=0.002). Among the 289 unique novel therapeutic agents, 190 were approved in both the United States and Europe (either by the EMA or through the mutual recognition process), of which 121 (63.7%) were first approved in the United States; similarly, 154 were approved in both the United States and Canada, of which 132 (85.7%) were first approved in the United States. CONCLUSIONS: For novel therapeutic agents approved between 2001 and 2010, the FDA reviewed applications involving novel therapeutics more quickly, on average, than did the EMA or Health Canada, and the vast majority of these new therapeutic agents were first approved for use in the United States. (Funded by the Pew Charitable Trusts.).

Use of a Blood Biomarker Test Improves Economic Utility in the Evaluation of Older Patients Presenting with Cognitive Impairment.

More than 16 million Americans living with cognitive impairment warrant a diagnostic evaluation to determine the cause of this disorder. The recent availability of disease-modifying therapies for Alzheimer's disease (AD) is expected to significantly drive demand for such diagnostic testing. Accurate, accessible, and affordable methods are needed. Blood biomarkers (BBMs) offer advantages over usual care amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in these regards. This study used a budget impact model to assess the economic utility of the PrecivityAD® blood test, a clinically validated BBM test for the evaluation of brain amyloid, a pathological hallmark of AD. The model compared 2 scenarios: (1) baseline testing involving usual care practice, and (2) early use of a BBM test before usual care CSF and PET biomarker use. At a modest 40% adoption rate, the BBM test scenario had comparable sensitivity and specificity to the usual care scenario and showed net savings in the diagnostic work-up of $3.57 million or $0.30 per member per month in a 1 million member population, translating to over $1B when extrapolated to the US population as a whole and representing a 11.4% cost reduction. Savings were driven by reductions in the frequency and need for CSF and PET testing. Additionally, BBM testing was associated with a cost savings of $643 per AD case identified. Use of the PrecivityAD blood test in the clinical care pathway may prevent unnecessary testing, provide cost savings, and reduce the burden on both patients and health plans.

PrecivityAD2™ Blood Test: Analytical Validation of an LC-MS/MS Assay for Quantifying Plasma Phospho-tau217 and Non-Phospho-tau217 Peptide Concentrations That Are Used with Plasma Amyloid-ß42/40 in a Multianalyte Assay with Algorithmic Analysis for Detecting Brain Amyloid Pathology.

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 (Aß42/40) 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 Aß42/40 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 Aß42/40 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.

Plasma Phosphorylated Tau 217 and Aß42/40 to Predict Early Brain Aß Accumulation in People Without Cognitive Impairment.

Importance: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain ß-amyloid (Aß) levels who are at high risk of accumulating Aß. Objective: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aß pathology in CU individuals with subthreshold brain Aß levels (defined as Aß levels <40 Centiloids) at baseline. Design, Setting, and Participants: This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aß42/40 assessments and Aß assessments with positron emission tomography (Aß-PET) or cerebrospinal fluid (CSF) Aß42/40. Data were analyzed between April 2023 and May 2024. Exposures: Baseline plasma levels of Aß42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Main Outcomes and Measures: Cross-sectional and longitudinal PET and CSF measures of brain Aß pathology. Results: This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aß-status, a combination of plasma %p-tau217 and Aß42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aß-PET, baseline plasma %p-tau217 and Aß42/40 levels were significantly associated with baseline Aß-PET (n = 384) and increases in Aß-PET over time (n = 224). Associations of plasma %p-tau217 and Aß42/40 and their interaction with baseline Aß-PET (%p-tau217: ß = 2.77; 95% CI, 1.84-3.70; Aß42/40: ß = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aß42/40: ß = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aß-PET (%p-tau217: ß = 0.67; 95% CI, 0.48-0.87; Aß42/40: ß = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aß42/40: ß = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aß42/40 were independently associated with longitudinal Aß-PET in Knight ADRC (%p-tau217: ß = 0.71; 95% CI, 0.26-1.16; P = .002; Aß42/40: ß = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aß42/40 in BioFINDER-1 (p-tau217: ß = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aß42/40: ß = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aß levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Conclusions and Relevance: Results of this cohort study suggest that combining plasma p-tau217and Aß42/40 levels could be useful for predicting development of Aß pathology in people with early stages of subthreshold Aß accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

Independent study demonstrates amyloid probability score accurately indicates amyloid pathology.

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 Aß42/40 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.

A blood biomarker test for brain amyloid impacts the clinical evaluation of cognitive impairment.

OBJECTIVE: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. METHODS: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. RESULTS: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). INTERPRETATION: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment.

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-ß (Aß) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. Design, Setting, and Participants: 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. Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging. Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aß42:40 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). Results: 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 Aß42:40 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 Aß42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aß42:40 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. Conclusions and Relevance: 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.

The PrecivityAD™ test: Accurate and reliable LC-MS/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis.

BACKGROUND: There is an unmet need for an accessible, less invasive, cost-effective method to facilitate clinical trial enrollment and aid in clinical Alzheimer's disease (AD) diagnosis. APOE genotype affects the clearance and deposition of amyloid-beta (Aß) with APOE4 carriers having increased risk while APOE2 alleles appear to be protective. Lower plasma Aß42/40 correlates with brain amyloidosis. In response, C2N has developed the PrecivityAD™ test; plasma LC-MS/MS assays for Aß isoform quantitation and qualitative APOE isoform-specific proteotyping. METHODS: In accord with CLIA standards, we developed and validated assay performance: precision, accuracy, linearity, limit of detection (LoD), interferences. RESULTS: Within-day precision varied from 1.5-3.0% (Aß40) and 2.5-8.4% (Aß42). Total (within-lab) variability was 2.7-7.7% (Aß40) and 3.1-9.5% (Aß42). Aß40 quantitation was linear from 10 to 1780 pg/mL; Aß42 was linear from 2 to 254 pg/mL. LoD was 11 and 2 pg/mL for Aß40 and Aß42, respectively. APOE proteotypes were 100% concordant with genotype, while LoD (fM) was much lower than APOE concentrations observed in plasma (mM). CONCLUSIONS: The PrecivityAD™ assays are precise, accurate, sensitive, and linear over a wide analytical range, free from significant interferences, and suitable for use in the clinical laboratory.

A blood-based diagnostic test incorporating plasma Aß42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis.

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 Aß42 and Aß40 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 Aß42/40 ratio. RESULTS: Plasma Aß42/40 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 Aß42/40 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 Aß42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87-0.93) and accuracy (86%) improved further when Aß42/40, 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.

Race, medical researcher distrust, perceived harm, and willingness to participate in cardiovascular prevention trials.

Minority underrepresentation exists in medical research including cardiovascular clinical trials, but the hypothesis that this relates to distrust in medical researchers is unproven. Therefore, we examined whether African American persons differ from white persons in perceptions of the risks/benefits of trial participation and distrust toward medical researchers, and whether these factors influence willingness to participate (WTP) in a clinical drug trial. Participants were self-administered a survey regarding WTP in a cardiovascular drug trial given to 1440 randomly selected patients from 13 Maryland outpatient cardiology and general medicine clinics. Patients reported their WTP, rated their perceived chances of experiencing health benefit and harm, and rated their distrust toward researchers. Of eligible participants, 70% responded, and 717 individuals were included: 36% African American and 64% white. African American participants possessed lower WTP than white participants (27% vs. 39%, p = 0.001) and had higher mean distrust scores than whites (p < 0.0001). African American participants more frequently reported that doctors would less fully explain research participation to them (24% vs. 13%, p < 0.001), use them as guinea pigs without their consent (72% vs. 49%, p < 0.001), prescribe medication as a way of experimenting on people without their knowledge (35% vs. 16%, p < 0.001), and ask them to participate in research even if it could harm them (24% vs. 15%, p = 0.002). African American participants also more often believed they could less freely ask their doctor questions (8% vs. 2%, p < 0.001) and that doctors had previously experimented on them without their consent (58% vs. 25%, p < 0.001). African American participants expressed lesser WTP than white participants after controlling for racial differences in age, sex, socioeconomic status and cardiovascular disease risk profiles (multivariable odds ratio [OR], 0.57; 95% confidence interval [CI], 0.39-0.85). The impact of race was attenuated and nonsignificant after adjustment for potential mediating factors of racial differences in medical researcher distrust and perceived risk of harm (explanatory model OR, 0.84; 95% CI 0.54-1.30). In summary, African American participants expressed markedly greater concerns about experiencing harm from participation in clinical trials and distrust toward medical researchers than white participants. These factors, in turn, appear to explain much of the resistance among African American persons to participate in clinical trials compared to white persons.

Sex differences in perceived risks, distrust, and willingness to participate in clinical trials: a randomized study of cardiovascular prevention trials.

BACKGROUND: Multiple sex differences exist in cardiovascular disease burden and treatment efficacies; adequate participation of both sexes is crucial to clinical research. METHODS: A multicenter, double-blind, randomized study evaluated sex and trial scenarios on willingness to participate (WTP) in cardiovascular prevention trials and examined sex differences in perceived risks and distrust. Hypothetical trial scenarios randomized multifactorial vignettes of adverse effects, trial durations, sponsors, financial incentives, and conflicts of interest. RESULTS: With 783 participants across 13 clinical centers, women showed lower distrust of medical researchers, perceived greater risk of myocardial infarction, and perceived greater risk of harm from trial participation than men. Men had 15% greater WTP than women (33.1% vs 28.7%; relative risk [RR], 1.15; 95% confidence interval [CI], 1.02-1.31); adjusting for explanatory mediators, we found that sex differences in perceived risks and benefits explained the sex gap in WTP. Although greater perceived probability of harm (RR, 0.41; 95% CI, 0.23-0.72), health benefit (RR, 2.99; 95% CI, 1.63-5.46), and quality of care (RR, 1.71; 95% CI, 1.12-2.61) strongly predicted WTP (for perceived probabilities >or=80% vs <20%) similarly in both sexes, and perceptions of distrust and myocardial infarction risk predicted WTP differently between sexes (P

Framingham risk equation underestimates subclinical atherosclerosis risk in asymptomatic women.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of death among American women. Currently, global risk assessment derived by Framingham risk equation (FRE) is used to identify women at increased risk for CHD. Electron-beam computed tomography (EBCT) derived coronary artery calcium (CAC) scores are validated markers for future CHD events among asymptomatic individuals. However, the adequacy of FRE for identifying asymptomatic women with CAC is unknown. METHODS AND RESULTS: We studied 2447 consecutive non-diabetic asymptomatic females (55 +/- 10 years). Based upon FRE, 90% were classified as low-risk (FRE < or = 9% 10-year risk of hard CHD events), 10% intermediate-risk (10-20%), and none were considered as high-risk (> 20%). Coronary artery calcium was present in 33%, whereas CAC > or = 100 and CAC > or = 400 were seen in 10 and 3% of women, respectively. Overall, 20% of women had age-gender derived > or = 75th percentile CAC. According to FRE, the majority (84%) of women with significant CAC > or = 75th percentile were classified as low-risk. Approximately half (45%) of low-risk women with > or = 2 CHD risk factors and a family history of premature CHD had significant CAC. CONCLUSION: Framingham risk equation frequently classifies women as being low-risk, even in the presence of significant CAC. Determination of CAC may provide incremental value to FRE in identifying asymptomatic women who will benefit from targeted preventative measures.

Difference in atherosclerosis burden in different nations and continents assessed by coronary artery calcium.

We utilized coronary artery calcium scores (CACS) to assess differences in atherosclerosis burden between asymptomatic White populations living in continents with different cardiovascular disease rates. The similarities in the genetic pool between Brazilian and Portuguese Caucasian subjects offered an opportunity to assess the influence of environmental factors on the development of atherosclerosis. We reviewed CACS data from 17,563 individuals (12,378 men and 5169 women) collected in the USA (74% of the subjects), Brazil (15% of the subjects) and Portugal (11% of the subjects). CACS was absent in 80 and 88% of Portuguese men and women, compared with 46 and 62% and 33 and 59% of Brazilian and US counterparts (p<0.0001). Although the US subjects showed the lowest prevalence of risk factors they had a higher median (interquartile range) CACS than the Brazilian and the Portuguese cohorts: 4 (0;87), 1 (0;68) and 0 (0;0), respectively (p<0.0001). After adjusting for differences in age and cardiovascular risk factors, US men showed higher relative risk ratios of having any CACS than either Brazilian or Portuguese men. Brazilian and US women did not differ as far as risk of CACS although they demonstrated a greater risk than Portuguese women. In this study, significant differences in CACS were detected among three nations in different continents. The CACS differences paralleled the respective cardiovascular mortality rates.