Potential utility of plasma p-tau and NfL as surrogate biomarkers for preventive clinical trials

Background Although longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light (NfL) correlate with Alzheimer’s disease (AD) progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we tested the utility of changes in plasma p-tau181 and NfL as surrogate biomarkers for clinical trials focusing on cognitively unimpaired (CU) individuals. Methods We evaluated 257 CU older individuals with amyloid-beta (Aβ) positron emission tomography (PET) at baseline, as well as the baseline, up to 24-month plasma p-tau181 and NfL measures. Linear regressions and Cox-proportional hazards tested the associations of change in markers with age and clinical progression, respectively. 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. Results Longitudinal changes in plasma NfL were associated with age, while changes in plasma p-tau181 with progression to amnestic MCI. Clinical trial using p-tau181 and NfL would require 78% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. The use of Aβ positivity for enrichment had a larger impact on reducing the sample size required for trials using p-tau181 (43% reduction) than NfL (17%) as surrogate. Notably, population enrichment with intermediate levels of Aβ, rather than merely Aβ positivity, reduced the sample size by 88% for p-tau181 and 64% for NfL over 12 months, and by 73% for p-tau181 and 59% for NfL over 24 months. Conclusion Our results highlighted that changes in plasma NfL could be used as a surrogate for age-related degeneration, while longitudinal changes in plasma p-tau181 were associated with parallel clinical progression. A follow-up duration of 24 months was associated with more stable changes in plasma measures and, consequently, a greater effect size than a follow-up period of 12 months. The enrollment of CU subjects with intermediate levels of Aβ constitutes the alternative with the largest effect size for clinical trials quantifying plasma p-tau181 and NfL over 12 and 24 months.