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

Abstract

IMPORTANCEThe 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 MEASURESThe 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). RESULTSAll 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. (continued) Key Points Question Is an amyloid probability score based on a mass spectrometrybased blood test measuring plasma amyloid β 42:40 ratio and apoE proteotype plus age, associated with identifying brain amyloidosis among patients with cognitive impairment? Findings In this cohort study of 686 participants from 2 separate studies, the developed Amyloid Probability Score showed high concordance with amyloid PET status, with an area under the curve of 0.88 and overall accuracy of 81%. The test's findings were significantly associated with the presence or absence of brain amyloidosi...

The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer’s disease: a literature review

“…The weighted average of AUC values for all studies that used an IP-MS assay with a PET reference is 0.834 across twenty-one cohorts [7,17,18,21,22,24,[28][29][30][31][32][33][34]. The weighted average AUC for studies using the WashUdeveloped IP-MS assay with a PET standard is slightly higher, with a value of 0.846 across fourteen cohorts.…”

“…Many studies included in this review utilize high-precision IP-MS techniques in which Aβ species are first purified using antibody beads and then are directly measured in parallel by mass spectrometry so that Aβ42, Aβ40, and other species are measured together [7,17,18,21,22,24,[28][29][30][31][32][33]. A similar technique applied by some studies is known as immunoprecipitation-free liquid chromatography-mass spectrometry (IP-free LC-MS), which measures Aβ species with mass spectrometry, but without antibody purification prior to measurement by LC-MS [22,34].…”

“…Another study combining three plasma biomarkers into a composite biomarker of plasma p-tau217, plasma Aβ42/40, and plasma NfL showed improved performance in predicting amyloidosis over any of the three measures alone [ 67 ]. Many studies have also shown increased performance with the inclusion of APOE genotype in their biomarker [ 18 , 20 , 22 , 25 , 28 – 33 , 39 , 40 ].…”

Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

“…An alternative is to define a high-confidence positive value, a high-confidence negative value, and an intermediate value where further assessment is warranted to interpret the biomarker or come to a clinical conclusion. An example of this strategy is the Amyloid Probability Score (APS) based on the plasma Aß 42/40 ratio, apolipoprotein E (APOE) genotype, and patient age that establishes thresholds for high, intermediate, and low likelihood of a positive amyloid PET scan [ 15 ].…”

“…Each of the members of the AT(N) framework can be measured with brain imaging, CSF biomarkers, and plasma or blood-based biomarkers. Amyloid levels can be measured by amyloid PET [ 74 ], CSF measures of Aβ 42/40, or plasma measures of Aβ 42/40 [ 15 , 25 ]. Tau protein in neurofibrillary tangles is measured with tau PET [ 75 ], and p-tau monomers are measured in CSF and plasma [ 76 ].…”