Plasma p‐tau181 and nfl as surrogates biomarkers in clinical trials targeting preclinical stage of Alzheimer’s disease

Abstract

AbstractBackgroundThe preclinical stage of Alzheimer’s disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) and neurofilament light chain(NfL) correlate with AD progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we aimed to evaluate the utility of using changes in plasma p‐tau181 and NfL as surrogate biomarkers for clinical trials targeting preclinical AD.MethodWe access 257 CU older individuals that had available Aß‐PET at baseline, as well as the baseline, up to 24‐month plasma p‐tau181 and NfL measures from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We calculate the estimated sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers.ResultWe demonstrated that therapeutical clinical trials of 24‐month follow‐up using p‐tau181 and NfL would require 78% and 63% smaller sample sizes compared with a 12‐month follow‐up(Figure 1). The use of intermediate levels of Aß(CL20‐40), rather than merely Aß positivity, as an enrichment strategy reduced the sample size by 73% for p‐tau181 and 59% for NfL over 24 months. As demonstrated in Figure 2A the estimated cost of a clinical trial using only plasma biomarkers is lower than using neuroimaging biomarkers for surrogacy(Figure 2A). However, as showed by Figure 2B a trial including all Aß positive individuals, the total estimated cost when considering surrogate biomarkers plus other related assessments are numerically higher using plasma than neuroimaging biomarkers; while trials including only individuals with intermediate Aß levels, the cost was similar using plasma and neuroimaging biomarkers for surrogacy.ConclusionOur results suggest that to monitor large scale large‐scale population interventions in CU Aß positive individuals’ plasma p‐tau181/ NfL could potentially be used. Furthermore, using a strategy that has been proposed in recent clinical trials, we demonstrated that the use of intermediate levels of Aß is more cost‐effective than trials using Aß‐positive individuals in clinical.