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. 2024 Aug;20(8):5132-5142.
doi: 10.1002/alz.13909. Epub 2024 Jun 28.

Plasma amyloid beta X-42/X-40 ratio and cognitive decline in suspected early and preclinical Alzheimer's disease

Jonathan Vogelgsang  1 , Niels Hansen  2 , Melina Stark  3   4 , Michael Wagner  3   4 , Hans Klafki  2 , Barbara Marcos Morgado  2 , Anke Jahn-Brodmann  2 , Björn Schott  2 , Hermann Esselmann  2 , Chris Bauer  5 , Johannes Schuchhardt  5 , Luca Kleineidam  3   4 , Steffen Wolfsgruber  3   4 , Oliver Peters  6   7 , Luisa-Sophie Schneider  7 , Xiao Wang  7 , Felix Menne  6   8 , Josef Priller  6   7   9   10 , Eike Spruth  6   7 , Slawek Altenstein  6   7 , Andrea Lohse  7 , Anja Schneider  3   4 , Klaus Fliessbach  3   4 , Ina Vogt  3 , Claudia Bartels  2 , Frank Jessen  3   11   12 , Ayda Rostamzadeh  11 , Emrah Duezel  13   14 , Wenzel Glanz  13 , Enise Incesoy  13   14   15 , Michaela Butryn  13 , Katharina Buerger  16   17 , Daniel Janowitz  17 , Michael Ewers  16   17 , Robert Perneczky  16   18   19   20 , Boris Rauchmann  18   21   22 , Selim Guersel  18 , Stefan Teipel  23   24 , Ingo Kilimann  23   24 , Doreen Goerss  23   24 , Christoph Laske  25   26 , Matthias Munk  25   27 , Carolin Sanzenbacher  25 , Annika Spottke  3   28 , Nina Roy-Kluth  3 , Michael Heneka  29 , Frederic Brosseron  3 , Alfredo Ramierez  3   4   30   31   32 , Matthias Schmid  3   33 , Jens Wiltfang  2   34   35
Affiliations

Plasma amyloid beta X-42/X-40 ratio and cognitive decline in suspected early and preclinical Alzheimer's disease

Jonathan Vogelgsang et al. Alzheimers Dement. 2024 Aug.

Abstract

Introduction: Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation-immunoassay (IP-IA) as a test for predicting cognitive decline.

Methods: We measured levels of amyloid beta (Aβ)X-40 and AβX-42 in immunoprecipitated eluates from the DELCODE cohort. Receiver-operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aβ42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia.

Results: We detected a significant correlation between AßX-42/X-40 in plasma and CSF (r = 0.473). Mixed-modeling analysis revealed a substantial prediction of AßX-42/X-40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AβX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline.

Discussion: Our results suggest that assessing the plasma AβX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD.

Highlights: New plasma Aβ42/Aβ40 measurement using immunoprecipitation-immunoassay Plasma Aβ42/Aβ40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity.

Keywords: Alzheimer's disease; MCI; amyloid beta; biomarker; dementia; plasma.

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Conflict of interest statement

J.V.: DFG/Clinician Scientist Kolleg (#413501650) and McLean Eric Dorris Memorial Fellowship. N.H.: DFG (530229798), Lilly AG travel support. S.T.: Advisory Board Memberships for Biogen, Eisai, Lilly; Member of the Independent Data Safety and Monitoring Board for ENVISION (Biogen). E.D.: Paid consultancy work and talks for Roche, Lilly, Eisai, Biogen, neotiv, and UCLC; Holds shares of neotiv. C.B.: Employee of MicroDiscovery GmbH. MicroDiscovery was paid by University Goettingen for supporting the statistical analysis. J.S.: Employee of MicroDiscovery GmbH. MicroDiscovery was paid by University Goettingen for supporting the statistical analysis. C.l.B.: received honoraria as a diagnostic consultant for Boehringer Ingelheim (last time: 10/2019); received honoraria for lectures from Roche (06/2021); received funding from the German Alzheimer Association (DAlzG; 2021‐2023). O.P.: Paid consultancy work and talks for Biogen, Eisai, Grifols, Lilly, Noselab, Prinnovation, Schwabe, and Roche. F.M.: Employee of ki:elements GmbH. J.W.: Paid consultancy and talks for Abbott, Actelion, Amgen, Beeijing Yibai Science and Technology Ltd., Biogen, Boehringer Ingelheim, Gloryren, Immungenetics, Janssen‐Cilag, Lilly, medUpdate GmbH, MSD Sharp & Dohme, Noselab, Pfizer, Roche, and Roboscreen; holds patents PCT/EP2011 001724 and PCT/EP 2015 052945. M.S., M.W., H.K., B.M., A.J.B., B.S., H.E., L.K., S.W., L.S.S., X.W., J.P., E.S., S.A., A.L., A.S., K.F., I.V., F.J., A.R., W.G., E.I., M.B., K.B., D.J., E.W., R.P., B.R., S.G., I.K., D.G., C.L., M.M., C.S., A.Sp., N.R.K., M.H., F.B., A.R., and M.S. did not report any disclosures. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Correlation between plasma and CSF Aβ40, Aβ42, Aβ42/Aβ40. No correlation was detected between Aβ IP eluates from plasma and CSF. Note the weak correlation (r = 0.169, p = 0.000988) between IP eluates and CSF Aβ42, and a stronger correlation (r = 0.47, p = 2.76e‐22) between plasma and CSF Aβ42/Aβ40. Aβ40, amyloid beta X‐40; Aβ42, amyloid beta X‐42; Aβ42/Aβ40, amyloid beta X‐42/amyloid beta X‐40 ratio; CSF, cerebrospinal fluid; IP, immunoprecipitation. The Pearson´s correlation coefficient (r) and the corresponding p‐values are indicated in each figure part. In addition, a Deming regression is shown in each figure part.
FIGURE 2
FIGURE 2
Mixture modeling analysis of the Aβ42/Aβ40 ratio in plasma and CSF. Mixture modeling analysis revealed a typical bimodal distribution for CSF (A) but not Aβ42/Aβ40 in IP eluates from plasma (B). To determine the Aβ42/Aβ40 cutoff value in plasma, Aβ42/Aβ40 values in CSF were correlated with the corresponding Aβ42/Aβ40 values in plasma via a linear regression model (C). The intersection of the dashed blue lines indicates the 0.106 cutoff value for plasma Aβ42/Aβ40. In (D), the receiver‐operating characteristic (ROC) curve was plotted with an area under the curve (AUC) of 0.81 for Aβ42/Aβ40 to predict amyloid positivity based on Aβ42/Aβ 40 classification in CSF. Aβ42/Aβ40, amyloid beta X‐42/amyloid beta X‐40; CSF, cerebrospinal fluid.
FIGURE 3
FIGURE 3
Receiver‐operating characteristic curves for the Aβ40 and Aβ42, Aβ42/Aβ40 ratio, and Aβ42/Aβ40 ratio + APOE ε4 carriage. For the plasma Aβ42/Aβ40 ratio, we calculated a receiver‐operating characteristic (ROC) curve comparing amyloid‐positive against amyloid‐negative cases with an area under the curve (AUC) of 0.81. However, when stratified by APOE ε4 positivity, the AUC rose as high as 0.87, with a 0.73 corresponding specificity and 0.87 sensitivity. Significantly lower AUCs were found for Aβ40 at 0.56 and for Aβ42 plasma at 0.59. Aβ40, amyloid beta X‐40; Aβ42, amyloid beta X‐42; Aβ42/Aβ40, amyloid beta X‐42/amyloid beta X‐40 ratio; APOE ε4, apolipoprotein E ε4.
FIGURE 4
FIGURE 4
PACC5 slopes for patient groups with low and high amyloid beta peptide 42/40 ratios. (A) shows PACC5 slopes for all patients over time [visit 1 (V1)‐visit 4 (V4)]. In (B–E), box plots of low and high IP eluate Aβ42/Aβ40 ratios are shown for different patients regarding their PACC5 slope depicted as yearly change. Of interest, lower Aβ42/Aβ40 ratios in all patients in B and subjective cognitive decline (SCD) in D were associated with negative PACC5 slopes, suggesting cognitive decline. However, this association did not appear in controls in C and MCI patients in E. Aβ42/Aβ40, amyloid beta X‐42/amyloid beta X‐40; MCI, mild cognitive impairment; SCD, subjective cognitive decline.
FIGURE 5
FIGURE 5
COX regression modeling conversion to MCI or dementia over time. Kaplan–Meier survival curve estimates and 95% confidence intervals displaying the risk of progression to dementia (A: whole sample, B: MCI group) or MCI (C: control group, D: SCD group). MCI, mild cognitive impairment; SCD, subjective cognitive decline.
See this image and copyright information in PMC

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