Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials
Pâmela C.L. Ferreira, João Pedro Ferrari‐Souza, Cécile Tissot, Bruna Bellaver, Douglas Teixeira Leffa, Firoza Z Lussier, Guilherme Povala, Joseph Therriault, Andréa Lessa Benedet, Nicholas J. Ashton, Ann D. Cohen, Oscar L. López, Dana Tudorascu, William E. Klunk, Jean‐Paul Soucy, Serge Gauthier, Victor L. Villemagne, Henrik Zetterberg, Kaj Blennow, Pedro Rosa‐Neto, Eduardo R. Zimmer, Thomas K. Karikari, Tharick A. Pascoal, for the Alzheimer's Disease Neuroimaging Initiative
Abstract
OBJECTIVE: To test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations. METHODS: We estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers in CU participants from Alzheimer's Disease Neuroimaging Initiative database. RESULTS: We included 257 CU individuals (45.5% males; mean age = 73 [6] years; 32% β-amyloid [Aβ] positive). Changes in plasma NfL were associated with age, whereas changes in plasma p-tau181 with progression to amnestic mild cognitive impairment. Clinical trials using p-tau181 and NfL would require 85% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. A population enrichment strategy using intermediate levels of Aβ PET (Centiloid 20-40) further reduced the sample size of the 24-month clinical trial using p-tau181 (73%) and NfL (59%) as a surrogate. DISCUSSION: Plasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate Aβ levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL.