Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease.

Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures reflecting senescent cell burden or response to senolytics, therapeutics that clear senescent cells. Results from the first open-label trial of senolytics, dasatinib plus quercetin (D ​+ ​Q), in older adults (N ​= ​5) with early AD demonstrated central nervous system penetration of dasatinib and favorable safety and tolerability. Herein, we present exploratory analyses of senescence and AD-associated analytes in blood, cerebrospinal fluid (CSF) and urine from this study in effort to guide biomarker development for future senolytic trials. Immunoassays, mass spectrometry and transcriptomics were performed and changes in analyte levels were assessed from baseline to post-treatment using paired t-tests. Targeted cytokine and chemokine analyses revealed increases in plasma fractalkine and MMP-7 and CSF IL-6 from baseline to post-treatment. Mass spectrometry indicated stable levels of amyloid β and tau proteins in CSF, unchanged urinary metabolites, and modest treatment-associated lipid profile changes. Targeted transcriptomic analysis of peripheral blood mononuclear cells indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. The levels and treatment responses of the analytes identified here may help inform trial design and outcomes for senolytic studies. Independent validation will be necessary to develop standardized biomarker panels across senolytic trials for AD. ClinicalTrials.gov: NCT04063124.