Clinical utility of plasma Aβ42/40 ratio by LC-MS/MS in Alzheimer's disease assessment

Abstract

Introduction: Plasma Aβ42/40 ratio can be used to help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear.

Methods: Aβ42/40 ratio was measured by LC-MS/MS in 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and 6,192 consecutive clinical specimens submitted for Aβ42/40 testing.

Results: High diagnostic sensitivity and negative predictive value (NPV) for Aβ-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%.

Discussion: Using high-throughput plasma Aβ42/40 LC-MS/MS assays can help reduce PET evaluations in patients with low likelihood of AD pathology, allowing for cost savings.

Keywords: Alzheimer’s disease; LC-MS/MS; PET; amyloid; biomarkers; blood biomarkers; prescreening.

Figure 1:

Correlation and diagnostic performance of the Aβ42/40 ratio and amyloid PET imaging. A) Plasma Aβ42/40 ratio compared with amyloid PET status (Aβ-PET− and Aβ-PET+). Black dashed line denotes optimal Aβ42/40 ratio cutoff of 0.160. Red dashed lines denote Aβ42/40 ratio indeterminant risk cutoffs (0.150 and 0.170); a = significant at P < 0.001; B) ROC-AUC of the plasma Aβ42/40 ratio for prediction of amyloid PET positivity. AUC, area under the curve; ROC, receiver operating characteristic.

Figure 1:

Correlation and diagnostic performance of the Aβ42/40 ratio and amyloid PET imaging. A) Plasma Aβ42/40 ratio compared with amyloid PET status (Aβ-PET− and Aβ-PET+). Black dashed line denotes optimal Aβ42/40 ratio cutoff of 0.160. Red dashed lines denote Aβ42/40 ratio indeterminant risk cutoffs (0.150 and 0.170); a = significant at P < 0.001; B) ROC-AUC of the plasma Aβ42/40 ratio for prediction of amyloid PET positivity. AUC, area under the curve; ROC, receiver operating characteristic.

Figure 2:

Robustness assessment of Aβ42/40 ratio for predicting amyloid PET imaging results. A) Densities of plasma Aβ42/40 ratio by LC-MS/MS in ADRC cohort with and without 10% bias (22% total, upper plot) and 2% measured bias (lower plot) added. B) Scatterplots of Aβ42 and Aβ40 to illustrate proximity to cutoffs defining indeterminate risk and scatterplots of Aβ42/40 ratio with and without 10% CV added noise (upper plot) and 6% added CV (measured) noise (lower plot).

Figure 2:

Robustness assessment of Aβ42/40 ratio for predicting amyloid PET imaging results. A) Densities of plasma Aβ42/40 ratio by LC-MS/MS in ADRC cohort with and without 10% bias (22% total, upper plot) and 2% measured bias (lower plot) added. B) Scatterplots of Aβ42 and Aβ40 to illustrate proximity to cutoffs defining indeterminate risk and scatterplots of Aβ42/40 ratio with and without 10% CV added noise (upper plot) and 6% added CV (measured) noise (lower plot).

Figure 3:

Four-quadrant plot illustrating the relationship between the plasma Aβ42/40 ratio and A) [F¹⁸]-florbetaben SUVR values and, B) [F¹⁸]-florbetapir SUVR values. Horizontal dashed line = optimal plasma Aβ42/40 ratio cutoff (0.160). Vertical dashed lines = optimized SUVR cutoff values for each tracer. Color coding for amyloid positivity and negativity is based SUVR cutoffs or gold-standard visuals reads. SUVR, standardized uptake value ratio.

Figure 3:

Four-quadrant plot illustrating the relationship between the plasma Aβ42/40 ratio and A) [F¹⁸]-florbetaben SUVR values and, B) [F¹⁸]-florbetapir SUVR values. Horizontal dashed line = optimal plasma Aβ42/40 ratio cutoff (0.160). Vertical dashed lines = optimized SUVR cutoff values for each tracer. Color coding for amyloid positivity and negativity is based SUVR cutoffs or gold-standard visuals reads. SUVR, standardized uptake value ratio.

Figure 4:

Distribution (upper) and scatterplots (lower, P <.001 for all) by age of; A) Aβ42/40 ratio, Spearman’s rho = −0.25, 95%CI, −0.27 to −0.22. B) Aβ42 concentrations, Spearman’s rho = 0.22, 95%CI 0.20 to 0.25; and C) Aβ40 concentrations, Spearman’s rho = 0.41, 95%CI 0.39 to 0.43. Black dashed line denotes Aβ42/40 ratio cutoff of 0.160. Red dashed lines denote Aβ42/40 ratio indeterminant risk cutoffs (0.150 and 0.170).

Figure 4:

Distribution (upper) and scatterplots (lower, P <.001 for all) by age of; A) Aβ42/40 ratio, Spearman’s rho = −0.25, 95%CI, −0.27 to −0.22. B) Aβ42 concentrations, Spearman’s rho = 0.22, 95%CI 0.20 to 0.25; and C) Aβ40 concentrations, Spearman’s rho = 0.41, 95%CI 0.39 to 0.43. Black dashed line denotes Aβ42/40 ratio cutoff of 0.160. Red dashed lines denote Aβ42/40 ratio indeterminant risk cutoffs (0.150 and 0.170).

Figure 4:

Distribution (upper) and scatterplots (lower, P <.001 for all) by age of; A) Aβ42/40 ratio, Spearman’s rho = −0.25, 95%CI, −0.27 to −0.22. B) Aβ42 concentrations, Spearman’s rho = 0.22, 95%CI 0.20 to 0.25; and C) Aβ40 concentrations, Spearman’s rho = 0.41, 95%CI 0.39 to 0.43. Black dashed line denotes Aβ42/40 ratio cutoff of 0.160. Red dashed lines denote Aβ42/40 ratio indeterminant risk cutoffs (0.150 and 0.170).