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

Abstract

Background: Although longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light (NfL) correlate with Alzheimers 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 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 amyloid-beta 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 amyloid-beta rather than merely amyloid-beta 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 amyloid-beta constitutes the alternative with the largest effect size for clinical trials quantifying plasma p-tau181 and NfL over 12 and 24 months.

Clinical heterogeneity of neuro-inflammatory PET profiles in early Alzheimer’s disease

“…The cerebellar cortex was validated as a (pseudo)reference region using full quantification and another secondgeneration TSPO tracer ([ 11 C]-PBR-28) (15). The cerebellar cortex was also widely used as a (pseudo)reference region in early AD (2,4,5,18,(20)(21)(22)(23). However, a significant uptake was already observed in the cerebellum (3) and there is now evidence in neuropathology, structural and functional imaging, that this region is involved in AD pathophysiology (24)(25)(26).…”

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer’s disease patients, and associated with amyloid and tau pathologies

“…3c). APOE is a lipid transporter produced predominantly by astrocytes in the brain and plays an important role in modulating microglial immunometabolism (22). APOE ε4 is a genetic risk factor for sporadic AD..…”

Why Therapeutic Trials Fail in Primary Tauopathies

“…33 Surrogate endpoints are less susceptible to placebo effect and allow smaller sample size and shorter duration to observe effects. 34 Although controversial, recent Food and Drug Administration approval of aducanumab for treatment of early AD was based on improvement on amyloid-beta PET, a surrogate endpoint with unknown clinical validity. 35 This points to the importance of clinical validity studies being conducted in parallel with studies to develop biomarkers.…”

“…Such biomarkers, especially if intended as surrogate endpoints, should have acceptable correlation with clinical outcomes and high analytical validity 33 . Surrogate endpoints are less susceptible to placebo effect and allow smaller sample size and shorter duration to observe effects 34 . Although controversial, recent Food and Drug Administration approval of aducanumab for treatment of early AD was based on improvement on amyloid‐beta PET, a surrogate endpoint with unknown clinical validity 35 .…”