Biomarkers

Abstract

Background: Recent results from clinical trials in Alzheimer's disease (AD) emphasize the importance of treating early-stage disease. However, recruitment of preclinical AD participants is difficult due to the lack of symptoms, and the costs and/or invasiveness of established CSF and PET tests. We aimed to investigate whether plasma p-tau217 could be used to pre-screen cognitively unimpaired (CU) potential participants for amyloid-β (Aβ) pathology to improve the efficiency of clinical trial recruitment.

Method: We included 1,471 CU participants from eight cohorts (Table 1) with available plasma p-tau217, Aβ CSF biomarkers and Aβ-PET status (served as standard-of-truth). Plasma p-tau217 concentrations were z-scored based on Aβ-negative participants and harmonized across cohorts using neuroCombat. Cut-offs for plasma p-tau217 were derived in the BioFINDER-1 cohort (n=104) based on different specificity levels (90%, 95% and 97.5%) to maximize positive predictive values (PPV). These cut-offs were used in the other cohorts to assess the accuracy of plasma p-tau217 for detecting Aβ-PET positivity. Next, within plasma positive participants only, we evaluated the value of dichotomized Aβ CSF (based on established clinical thresholds) on assessing Aβ-PET positivity. All models included age and APOE-ε4 carriership as covariates.

Result: 334 (24.4%) of participants were Aβ-PET positive. Using the a priori defined cutoffs, plasma p-tau217 categorization resulted in high PPVs (72.9%-81.2%), negative predictive values (NPVs, 82.5%-86.2%), and accuracy (82.4%-83.8%), with an overall rate of positivity between 10.9%-18.1% (Figure 1). When applying CSF biomarkers to the plasma positive participants in a second step, the PPVs increased up to 90.8%-95.3%, with NPVs ranging between 82.8%-86.7% and accuracies between 84.0%-87.3%, with a slight decrease in the proportion of overall positive cases (9.3%-14.3% from the original sample) given that the CSF positivity in the plasma positive participants ranged between 79.4%-85.2% (Figure 2).

Conclusion: Plasma p-tau217 can identify Aβ-PET positive CU individuals with PPVs reaching 81%, which can be further improved to PPVs of up to 95% with a subsequent CSF measurement. Plasma p-tau217 could be used, either as stand-alone biomarker, or as an initial step before CSF biomarkers (reducing their need by ∼80-90%), for pre-screening in clinical trials of preclinical AD depending on the certainty needed for Aβ-PET positivity.