Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest

Abstract

Importance: Blood phosphorylated tau (p-tau) and amyloid-β peptides (Aβ) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known.

Objective: To evaluate whether the levels and trajectories of blood p-tau, Aβ42, and Aβ40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest.

Design, setting, and participants: This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aβ42, and Aβ40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest.

Exposures: Serum p-tau, Aβ42, and Aβ40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators.

Main outcomes and measures: Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death).

Results: This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aβ42 and Aβ40 concentrations increased over time in most patients but were only weakly associated with neurological outcome.

Conclusions and relevance: In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aβ peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Figure 1.. Biomarker Discriminative Accuracy Over Time

Receiver operating characteristic curve (ROC) analysis was performed to test the accuracy of serum biomarkers to discriminate between outcome groups at 24 hours, 48 hours, and 72 hours. Aβ40 indicates amyloid-β 40; Aβ42, amyloid-β 42; NfL, neurofilament light; p-tau, phosphorylated tau; t-tau, total tau.

Figure 2.. Biomarker Changes Over Time After 24 Hours in the Validation Cohort

Locally estimated scatterplot smoothing plots showing the mean change in biomarker levels over time: linear mixed-effect models analysis indicated that, except for Aβ42/40, the trajectory of the biomarkers differs between good and poor outcome groups (P < .001). The solid lines indicate the regression line; the shaded area, 95% CIs. Aβ40 indicates amyloid-β 40; Aβ42, amyloid-β 42; NfL, neurofilament light; OHCA, out-of-hospital cardiac arrest; p-tau181, tau phosphorylated at threonine 181; t-tau, total tau.

Figure 3.. Fold Changes of Blood Levels of p-Tau, NfL, t-Tau, Aβ40, Aβ42, and Aβ42/40

Mean biomarker fold changes over time in the poor outcome group plotted using the locally estimated scatterplot smoothing method. Fold changes were calculated based on the mean biomarker levels of the good outcome group at 24 hours. The solid lines indicate the regression line; the shaded area, 95% CIs. Aβ40 indicates amyloid-β 40; Aβ42, amyloid-β 42; NfL, neurofilament light chain; p-tau, phosphorylated tau; t-tau, total tau.