First Senolytic Trial in Alzheimer's Patients Reveals Promising Biomarker Shifts

Cellular senescence — a state in which damaged cells stop dividing but remain metabolically active and secrete pro-inflammatory factors — is increasingly recognized as a driver of Alzheimer's disease (AD) pathology. Senescent cells accumulate in aging brains and promote amyloid-β and tau pathologies through their senescence-associated secretory phenotype (SASP). Dasatinib plus quercetin (D+Q), a well-studied senolytic combination, has shown efficacy in preclinical AD models, motivating the first human trial of senolytics specifically in AD patients.

The SToMP-AD phase 1 open-label pilot trial enrolled five older adults with early symptomatic AD. Participants received oral dasatinib (100 mg) and quercetin (1000 mg) on an intermittent schedule for 12 weeks. Biospecimens — plasma, CSF, and urine — were collected at baseline and post-treatment under fasting conditions. Peripheral blood mononuclear cells (PBMCs) were also isolated for transcriptomic analysis. The current paper reports exploratory biomarker analyses from these banked samples, using immunoassay multiplexing, targeted mass spectrometry for amyloid and tau peptides, shotgun lipidomics, urinary metabolomics, and a custom CTRA transcriptomics panel focused on chronic stress and inflammation.

Several notable biomarker signals emerged. In plasma, fractalkine (CX3CL1) and MMP-7 increased significantly from baseline to post-treatment — both are implicated in immune surveillance and tissue remodeling relevant to senescence clearance. CSF IL-6, a canonical SASP cytokine, also increased post-treatment, which the authors interpret cautiously as potentially reflecting transient inflammatory signaling during senescent cell clearance rather than worsening inflammation. Critically, CSF amyloid-β and tau/phospho-tau peptide levels remained stable across 27 measured analytes, suggesting no acute adverse effect on AD pathology markers over the 12-week window. Lipidomic analysis of plasma and CSF revealed modest but detectable treatment-associated changes in lipid profiles, consistent with known links between lipid dysregulation and AD. Urinary metabolites were largely unchanged. Transcriptomic profiling of PBMCs revealed downregulation of key inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, and PTGS2 — a pattern consistent with reduced inflammatory signaling following senolytic treatment.

The authors emphasize that this study was not powered to detect disease modification and lacked a placebo control. The primary value lies in establishing baseline levels, variance estimates, and directional treatment responses across a broad analyte panel. These data can now inform sample size calculations, biomarker panel selection, and outcome measure design for larger phase 2 trials. The team also used the same laboratory and methods as prior D+Q trials in idiopathic pulmonary fibrosis and diabetic kidney disease to facilitate cross-study harmonization — an important step toward standardizing senolytic trial readouts.

Overall, this exploratory analysis supports the biological plausibility of senolytic therapy in AD and identifies several candidate biomarkers — particularly fractalkine, MMP-7, CSF IL-6, and PBMC inflammatory gene expression — that warrant validation in larger, controlled studies.