Phase II Evaluation of Dasatinib and Quercetin Senolytic Therapy in Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease

The primary objective of this Phase II clinical trial is to assess the **safety** and feasibility of a 12-week treatment regimen with senolytics, specifically dasatinib plus quercetin, compared to placebo in adults diagnosed with amnestic mild cognitive impairment (aMCI) or early-stage Alzheimer's Disease (AD) with elevated tau levels in cerebrospinal fluid (CSF). This evaluation is clinically relevant as it aims to determine the potential of senolytic therapy to modulate disease progression by targeting cellular senescence, which is implicated in the pathophysiology of Alzheimer's Disease.

Secondary objectives include:

• Testing the hypothesis that 12 weeks of senolytic treatment will improve functional performance, as measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), compared to placebo in adults with aMCI or early AD.
• Evaluating whether the same treatment duration will enhance cognitive performance, assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14), compared to placebo.

The clinical trial involves a total of **24 participants** diagnosed with **amnestic mild cognitive impairment** (aMCI) or early-stage **Alzheimer's Disease**. The study population includes both male and female subjects aged 60 years and older. Participants are required to have a study partner who can provide accurate information regarding their cognitive and functional abilities. All participants must be fully vaccinated against COVID-19 and must speak Spanish fluently with at least six years of formal education. The trial population was selected based on specific criteria, including elevated tau protein levels as determined by cerebrospinal fluid analysis. Participants are expected to maintain normal blood cell counts, liver and renal function, and have total cholesterol levels below 240 mg/dl and HbA1c levels of 7% or less. The study does not involve a vulnerable population, and all ethnicities are included. Approved medications for Alzheimer's Disease are permitted if the participant has been on a stable dose for at least three months prior to the baseline visit.

The clinical trial is designed to evaluate the **safety** and feasibility of a 12-week treatment regimen using **senolytics** (dasatinib plus quercetin) compared to a placebo in adults diagnosed with amnestic mild cognitive impairment (aMCI) or early-stage Alzheimer's Disease (AD). This study is structured as a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or placebo, thus minimizing bias. The trial is expected to span approximately 18 months, with participant involvement lasting up to 12 months from the initial screening to the end-of-study visit.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, cognitive status, and elevated tau protein levels in cerebrospinal fluid (CSF). Following successful screening, participants will be randomized to receive either the active treatment or placebo. The primary endpoint is the safety of the treatment, assessed by the incidence of adverse events (AEs) and serious adverse events (SAEs) from baseline to week 48. Secondary endpoints include changes in blood senescence markers and cognitive assessments over the study period.

Study visits will occur at baseline, after 12 weeks of treatment, and every 12 weeks during follow-up, with blood samples collected under fasted conditions to evaluate biomarkers. The end-of-study visit will occur at week 48, marking the conclusion of participant involvement. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the study is terminated for any reason. The trial aims to provide valuable insights into the potential of senolytic therapy to modulate disease progression in aMCI and early-stage AD.

The clinical trial involves the administration of **quercetin**, an experimental medication, in the form of a **film-coated tablet**. Quercetin is administered orally with a maximum daily dose of 1000 mg and a total maximum dose of 12000 mg over the course of the study. The treatment period is set for 12 weeks. Quercetin is not a paediatric formulation and is not classified as an orphan drug. The administration of quercetin is monitored to ensure compliance with the dosing schedule.

In addition to quercetin, the trial also includes the administration of **Dasatinib Teva 100 mg**, another experimental medication, also in the form of a film-coated tablet. Dasatinib is administered orally with a maximum daily dose of 100 mg and a total maximum dose of 1200 mg over the 12-week treatment period. Similar to quercetin, dasatinib is not a paediatric formulation and is not classified as an orphan drug. Participant compliance with dasatinib administration is closely monitored throughout the trial.

The study also includes a **placebo** group to serve as a comparator treatment. The placebo is administered in a manner identical to the experimental medications, ensuring blinding and maintaining the integrity of the trial. The placebo is also provided in the form of a film-coated tablet and is administered orally. Compliance with placebo administration is monitored to ensure adherence to the study protocol.

The efficacy of the clinical trial titled "Phase II Clinical Trial to Evaluate the Safety and Feasibility of Senolytic Therapy in Alzheimer's Disease: 'Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD)'" will be assessed through several primary and secondary endpoints. The primary endpoint focuses on the safety of 12 weeks of treatment with dasatinib and **quercetin** compared to placebo, measured by the incidence of adverse events (AEs) and serious adverse events (SAEs) from baseline to week 48. AEs and SAEs will be collected at each in-person visit and during scheduled telephone visits.

Secondary endpoints include changes in blood senescence marker SASP composite score from baseline to week 12, with biomarker analysis involving a composite score generated from ten core SASP factors. Blood collections for this analysis will occur at baseline, after 12 weeks of treatment, and every 12 weeks during follow-up visits under fasted conditions. Additionally, changes in p16INK4a+/CD3+ T cells in blood from baseline to week 12 will be assessed, with similar blood collection schedules. Cognitive assessments will include changes in the CDR Sum of Boxes (CDR-SB) slope from screening to week 48, with evaluations at screening, week 12, and the end of the study at week 48. The ADAS-Cog slope will also be measured from baseline to week 48 to evaluate cognitive function over time.