Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease
Year: 2025
Type: article
Abstract: 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.
Source: Neurotherapeutics
Authors: Valentina R. Garbarino, Juan Pablo Palavicini, Justin Melendez, Nicolas R. Barthelemy, Yingxin He, Tiffany F. Kautz, Marisa Lopez-Cruzan, Julia J. Mathews, Peng Xu, Bin Zhang, Afaf Saliba, Nagarjunachary Ragi, Kumar Sharma, Dallin Mason, Samuel Johnson, Suzanne Hendrix, Suzanne Craft, Ronald C. Petersen, Jair Machado Espindola-Netto, Ailing Xue, Tamara Tchkonia, James L. Kirkland, Arash Salardini, Nicolas Musi, Randall J. Bateman, Mitzi M. Gonzales, Miranda E. Orr
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
Funders: Hevolution Foundation, U.S. Department of Veterans Affairs, Mayo Clinic, Alzheimer's Association, American Federation for Aging Research, Alzheimer's Drug Discovery Foundation, Cure Alzheimer's Fund, GHR Foundation, Noaber Foundation, National Institutes of Health, University of Texas Health Science Center at San Antonio, Claude Pepper Older Americans Independence Center, Wake Forest School of Medicine, Washington University School of Medicine in St. Louis, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Institute for Integration of Medicine and Science, Duke Claude D. Pepper Older Americans Independence Center, Duke Aging Center, Duke University, Robert and Arlene Kogod Center on Aging
Awards: G1253501386, Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease, G3142071638, Alzheimers Disease Patient Registry, G4152094827, G4489142451, G4766824899, Novel Network Biology Approaches to Reposition FDA-approved Drugs for Alzheimer's Disease, G5385426983, NRSA Training Core (TL1), G7673054179, ALSENLITE: An Open-Label Pilot Study Of Senolytics For Alzheimer Disease, G8238560729, MarkVCID Validation in the General Community, Training Grant on the Biology of Aging, Effect of Aging on Preadipocyte Differentiation, Characterizing Older Mexican (American) Participation in Activity Digitally, Reliably, and Ecologically with the CART Platform (COMPADRE CART): Implications for Cognition and ADRD, Alzheimer's Clinical Trials Consortium (ACTC), Alzheimer's Disease Neuroimaging Initiative (ADNI4), Targeting Cellular Senescence to Extend Healthspan, Mayo Alzheimer's Disease Research Center, Precursors of Stroke Incidence and Prognosis, Spatial Multi-Omics to Profile Metabolic Pathways for Kidney Disease, San Antonio Claude D. Pepper Older Americans Independence Center, Alzheimer's Disease Research Center, South Texas Alzheimer's Disease Center
OpenAlex ID: W4409701152