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 ADNI database.Results:We included 257 CU individuals [45.5% males; mean age = 73 (6) years; 32% amyloid-beta (Aβ) positive]. Changes in plasma NfL were associated with age, while 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 positron emission tomography (Centiloid 20-40) further reduced the sample size of 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.