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

Abstract

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-β (Aβ) 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 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).

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 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.

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Meyer reported having a patent for US20180364260A1 pending to C2N Diagnostics. Dr Rabinovici reported grants from the National Institutes of Health (NIH), American College of Radiology, Alzheimer’s Association, Rainwater Charitable Foundation, Genentech, Avid Radiopharmaceuticals, GE Healthcare, and Life Molecular Imaging; personal fees from El Lilly, Genentech, Eisai, Roche, and Johnson & Johnson outside the submitted work; and serving as Associate Editor of JAMA Neurology. Dr Gatsonis reported receiving grants from American College of Radiology during the conduct of the study. Dr Siegel reported grants and personal fees from the American College of Radiology during the conduct of the study; grants from Blue Earth Diagnostics, Curium Pharma, ImaginAb, and Progenics Pharmaceuticals and personal fees from Curium Pharma, Progenics Pharmaceuticals, American Medical Foundation for Peer Review & Education, Avid Radiopharmaceuticals, BTG Management Services, Capella Imaging, GE Healthcare, Huron Consulting Services, Lantheus Medical Imaging, and Siemens Healthineers outside the submitted work. Dr Bateman reported being a cofounder of C2N Diagnostics, of which Washington University has equity ownership interest, and a coinventor of the stable isotope labeling kinetics and blood plasma assay technology licensed by Washington University to C2N Diagnostics for which he receives royalties, and receiving personal fees from Roche, Genetech, AbbVie, Pfizer, Boehringer-Ingelheim, Merck, and AC Immune and grants from Eisai and Roche outside the submitted work Dr Holtzman reported receiving personal fees from Washington University and C2N Diagnostics during the conduct of the study; serving as a cofounder with equity in C2N Diagnostics; receiving personal fees from Denali, Genentech, Cajal Neurosciences, Eli Lilly, and Casma outside the submitted work; and having a patent for a methods of determining amyloid beta turnover in blood, licensed to C2N Diagnostics. No other disclosures were reported.

Figures

Figure 1.. Diagnostic Performance of Plasma Amyloid-β (Aβ)42:40 Ratio Alone and Combined With Age and apoE Proteotype

A and B, PET positive indicates Centiloid greater than 25 in positron emission tomograph scans; PET negative, Centiloid of 25 or less; dotted blue line, cutoff value defined by the Youden index for each cohort (A); points, individual patient ratios; bold lines, medians; boxes, IQRs; and whiskers, IQR × 1.5. B, Each plot shows the scores that were calculated using the model trained on that cohort. C, Correlation between Aβ42:40 ratio and Centiloid scores for each of the cohorts. vertical dotted line indicates Centiloid of 25; horizontal dotted line, cohort-specific cutoff value for the Aβ42:40 ratio defined by the Youden index for the Aβ42:40 ratio. Patients falling in the top left quadrant are true-negatives, and patients in the bottom right corner are true-positives.

Figure 2.. Density Plot Showing the Distribution of the Amyloid Probability Score Results in the Combined Data Set for Amyloid-Positive and Amyloid-Negative Patients

Vertical lines mark the Amyloid Probability Score cutoffs (35 and 58) for the amyloid-negative (Low APS) and amyloid-positive (High APS) categories based on Centiloid greater than 25.