Prognostic value of plasma biomarkers in a clinical trial of mild‐to‐moderate Alzheimer’s Disease

Abstract

AbstractBackgroundInformative, readily accessible plasma biomarkers of pathology, neuroinflammation, and neurodegeneration in Alzheimer’s disease (AD) could enhance targeted approaches to AD trial design and treatment. In post‐hoc analyses, we examined whether plasma biomarkers (Aβ1‐40, Aβ1‐42, total tau, p‐tau‐181, NfL, and GFAP) predicted 48‐week change in cognitive (ADAS‐Cog11), global function (CDR‐SB), and volumetric MRI (6 cortical regions and 2 whole brain measures) outcomes in T2 Protect AD, a phase‐2 placebo‐controlled RCT of troriluzole in mild‐to‐moderate AD (NCT03605667).MethodAt least one baseline biomarker measurement was available for 319 of 350 trial participants, forming the analytic sample. No significant treatment effects were found in T2 Protect AD (Feldman 2021, JPAD 8(4):s46); thus, treatment arms were pooled for this analysis. Baseline levels of, and 48‐week changes in, plasma biomarkers were assessed for association with 48‐week change in outcomes using linear regression adjusted for relevant covariates. Combinations of baseline plasma biomarkers that best predicted 48‐week decline on the ADAS‐Cog11 and CDR‐SB were identified using LASSO regression. Statistical significance level was 5%; p‐values were Bonferroni corrected for multiple comparisons.ResultParticipant characteristics are presented in Table 1. Higher baseline plasma NfL predicted greater 48‐week decline on ADAS‐Cog11 (p = 0.026) and CDR‐SB (p = 0.048; Fig. 1A). LASSO revealed that the combination of baseline plasma NfL, total tau, and Aβ42/40 ratio best predicted 48‐week decline on ADAS‐Cog11, whereas baseline NfL alone best predicted 48‐week decline on CDR‐SB. Regarding MRI outcomes, baseline NfL predicted increase in ventricular volume (p = 0.018; Fig 1A). Baseline NfL, GFAP, and p‐tau‐181 each predicted 48‐week decline in mid‐temporal cortical volume (all p<0.02; Fig.1B); LASSO results were similar. The only significant association between 48‐week biomarker change and clinical outcomes was between increased plasma NfL and worsening CDR‐SB.ConclusionElevated baseline plasma NfL predicted greater 48‐week decline on cognitive, global function, and MRI measures in a clinical trial of mild‐to‐moderate AD. Furthermore, greater increase in plasma NfL over time was associated with greater clinical decline. Plasma NfL is an easily accessible biomarker that may enhance AD clinical trial design and treatment strategies.Acknowledgement: Trial funding by Biohaven Pharmaceuticals; data and trial coordination by the Alzheimer’s Disease Cooperative Study (ADCS).