Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related β-Amyloid Status

Abstract

Importance: Accurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials.

Objective: To examine the accuracy of plasma β-amyloid (Aβ) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral Aβ.

Design, setting, and participants: Two prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study.

Main outcome and measures: The cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio was used as the reference standard for brain Aβ status. Plasma Aβ42, Aβ40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of Aβ status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1.

Results: The mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma Aβ42 and Aβ40 predicted Aβ status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to Aβ42, Aβ40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma Aβ42 and Aβ40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma Aβ42, Aβ40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff.

Conclusions and relevance: Plasma Aβ42 and Aβ40 measured using Elecsys immunoassays predict Aβ status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of Aβ positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.

Figure 1.. Levels of Plasma β-Amyloid (Aβ) Biomarkers

Plasma Aβ42 (A), Aβ40 (C), and the plasma Aβ42/Aβ40 ratio (E) in the Aβ-positive (Aβ+) (CSF Aβ42/Aβ40 ≤ 0.059) and Aβ-negative (Aβ−) (CSF Aβ42/Aβ40 > 0.059) groups. Plasma Aβ42 (B), Aβ40 (D), and the plasma Aβ42/Aβ40 ratio (F) in the CU, MCI, and AD participant groups stratified by Aβ status. The dotted lines indicate median levels in the CU Aβ-negative group. P values are calculated from t test (A, C, E) or 1-way analysis of variance and post hoc tests with the statistical significance set to P < .005 (.05/10.00) to account for the Bonferroni correction (B, D, F). The significant findings were similar when adjusting for age and sex (data not shown). Group comparisons of plasma tau, NFH, and NFL are shown in eFigure 2 in the Supplement. AD, Alzheimer disease; CSF, cerebrospinal fluid; CU, cognitively unimpaired; MCI, mild cognitive impairment; NFH, neurofilament heavy chain; and NFL, neurofilament light chain.

Figure 2.. Receiver Operating Characteristic (ROC) Analysis of Plasma Biomarkers in the BioFINDER and Validation Cohorts

Optimized ROC curves and corresponding areas under the curve (AUCs) for plasma Aβ together with the additional predictors, APOE, plasma tau, and neurofilament light chain (NFL) to assess accuracy when predicting Aβ positivity (crebrospinal fluid Aβ42/Aβ40 ≤ 0.059) in the BioFINDER (A and B, n = 842); and the replication of these models (C and D, n = 237) in the validation cohort using the estimates and intercepts established in BioFINDER. APOE genotype and NFL were not available in the validation cohort. Error bars indicate 95% CIs. ROC analyses in subpopulations can be found in Figure 3 and eTable 4 and 6 in the Supplement. Sensitivities and specificities are shown in Table 2. ROC analyses using the alternative reference standard for Aβ positivity (CSF P-tau/Aβ42 ≥ 0.022) are shown in eFigures 3 and 4 in the Supplement.

Figure 3.. Receiver Operating Characteristic (ROC) Analysis of Plasma Biomarkers in Subpopulations in BioFINDER

ROC curves and corresponding areas under the curve (AUCs) from logistic regression models for plasma Aβ together with the additional predictors APOE, plasma tau, and neurofilament light chain (NFL), to assess accuracy when detecting Aβ positivity (cerebrospinal fluid Aβ42/Aβ40 ≤ 0.059) in cognitively unimpaired participants (A and B, n = 513), cognitively impaired participants (C and D, n = 329), the younger half of the cohort (E and F, n = 428; 60-72 y), and the older half of the cohort (G and H, n = 414; 73-88 y). Cognitively unimpaired comprised of cognitively healthy controls and participants with subjective cognitive decline. Cognitively impaired comprised of participants with mild cognitive impairment and Alzheimer disease dementia. AUC indicates area under the curve; and NFL, neurofilament light chain.