The objective of the study is to determine the safety, feasibility, and efficacy of senolytics in older adults with amnestic mild cognitive impairment (MCI) or early-stage AD (Clinical Dementia Rating (CDR)=0.5 or 1) who are tau PET positive

This study is a Phase II multi-site, randomized, double-blind placebo controlled trial to determine safety, feasibility, and efficacy of senolytics in older adults with amnestic mild cognitive impairment (MCI) or early-stage AD (Clinical Dementia Rating (CDR)=0.5 or 1) who are tau PET positive.

Inclusion Criteria:

1. Ages 60 years and older at study entry
2. Both sexes
3. All ethnicities
4. Diagnosis of amnestic mild cognitive impairment (aMCI) or early Alzheimer's disease (AD)
5. Elevated tau protein as determined by CSF performed during screening. Evidence of elevated tau from previously available CSF samples will also be allowed for eligibility determination.
6. FDA-approved medications for AD (e.g. donepezil, rivastigmine, galantamine) are permitted as long as the participant has been maintained on a stable dose for at least three months prior to study entry.
7. Labs: Normal blood cell counts, normal liver and renal function without clinically significant excursions as determined by coordinating center Medical Monitor. Total cholesterol <240 mg/dl, HbA1c ≤ 7%.
8. Prothrombin Time (PT)/Partial Thromboplastin Time (PTT)/International Normalized Ratio (INR) within normal limits.
9. Participants must have the ability to provide written consent or be accompanied by a Legally Authorized Representative designated to sign informed consent (if determined not to have decision capacity).
10. Participants must have a study partner who agrees to participate throughout the duration of the study. The study partner must have frequent and sufficient contact (approximately 10 hours per week) with the participant and be able to provide accurate information regarding the participant's cognitive and functional abilities.
11. Participants must have no travel plans that would interfere with scheduling visits following consent over the 12 months of study duration.
12. Must speak English fluently and have at least six years of formal education.
13. Participants must be fully vaccinated against COVID-19 with the primary vaccine series per CDC recommendations, with any dose of the vaccine received at least 30 days prior to initiation of the study drug. COVID boosters are allowed during study intervention period when scheduled at least four days before or after administration of the investigational product.

Exclusion Criteria:

1. Body mass index (BMI)>40 kg/m2.
2. Average QTcF (from 3 ECGs obtained at least one minute apart) at screening of ≥450msec in males and ≥460msec in females.
3. MRI contraindications including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.
4. Pregnancy or possible pregnancy.
5. Any significant neurologic disease other than prodromal or early AD including Parkinson's disease, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.
6. Current or history of alcohol or substance abuse or dependence within the past 2 years per Diagnostic and Statistical Manual of Mental Disorders (DSM V criteria).
7. Endorsement of current suicidality or suicidal ideation on the screening C-SSRS.
8. Uncontrolled diabetes (HbA1c > 7% or the current use of insulin or sulfonylureas).
9. Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg) based on two or more readings and as determined by the PI/study clinician.
10. eGFR < 10 ml/ min/ 1.73 m2.
11. Myocardial infarction, angina, stroke, or transient ischemic attack in the past 6 months.
12. Chronic heart failure.
13. Presence of significant liver disease with total bilirubin >2X upper limit.
14. Inability to tolerate oral medication.
15. Participants taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus, or sirolimus).
16. Participants currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy.
17. Participants on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.) other than low dose aspirin unless able to be held for 2 days prior to LP and with the documented approval of the prescribing clinician.
18. Participants taking H2 antagonists or proton pump inhibitors who are unable or unwilling to reduce or hold therapy for at least 2 days prior to and during each of the 2-day courses of Dasatinib plus quercetin dosing. Instead, subjects may use antacids prior to and during each of the 2-day courses of Dasatinib plus quercetin dosing.
19. Concomitant use of strong CYP3A4 inhibitors.
20. Co-enrollment in another ADRD research study with a potentially disease-modifying intervention or study drug that may impact senescent cells. Participants previously enrolled in a study meeting these criteria are eligible to screen after a washout period of ≥6 months from date of last dose to date of screening.
21. Presence of any condition that the Investigator believes would put the subject at risk or would preclude the patient from successfully completing all aspects of the trial.
22. Use of anti-amyloid therapies (e.g. aducanumab, lecanamab).