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.

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Publication Details

Journal
Neurotherapeutics
Published
2025-04-23
DOI
https://doi.org/10.1016/j.neurot.2025.e00591
Citations
9
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
10.48
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article

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

Juan Pablo Palavicini, Mitzi M. Gonzales, James L. Kirkland, Suzanne Hendrix et al.
9 citations
Neurotherapeutics
Alzheimer's disease research and treatments
10.48
article

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

Juan Pablo Palavicini, Mitzi M. Gonzales, James L. Kirkland, Suzanne Hendrix, Samuel Johnson, Jair Machado Espíndola‐Netto, Ailing Xue, Suzanne Craft, Peng Xu, Arash Salardini, Randall John Bateman, Yingxin He, Valentina R. Garbarino, Nagarjunachary Ragi, Nicolas Musi, Tamar Tchkonia, Marisa Lopez‐Cruzan, Ronald Carl Petersen, Tiffany F. Kautz, Miranda E. Orr, Nicolas R. Barthélemy, Justin Melendez, Bin Zhang, Afaf Saliba, Kumar Sharma, D. T. Mason, Julia Mathews
article en
9 citations

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.

NeurotherapeuticsVol. 22(4)
Cedars-Sinai Medical Center (US), The University of Texas at San Antonio Health Science Center (US), Washington University in St. Louis (US), St. Louis VA Medical Center (US), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), TetraLogic Pharmaceuticals (United States) (US), The University of Texas at San Antonio (US), Wake Forest University (US), Saint Louis University (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 2%
Alzheimer's disease research and treatments
10.48
DOIOpen Access PDFOpenAlex
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