Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD) Study

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 ofelevated tau from previously available CSF samples will also be allowed foreligibility determination.

6. FDA-approved medications for AD (e.g. donepezil, rivastigmine, galantamine) arepermitted as long as the participant has been maintained on a stable dose for atleast three months prior to study entry.

7. Labs: Normal blood cell counts, normal liver and renal function without clinicallysignificant excursions as determined by coordinating center Medical Monitor. Totalcholesterol <240 mg/dl, HbA1c ≤ 7%.

8. Prothrombin Time (PT)/Partial Thromboplastin Time (PTT)/International NormalizedRatio (INR) within normal limits.

9. Participants must have the ability to provide written consent or be accompanied by aLegally Authorized Representative designated to sign informed consent (if determinednot to have decision capacity).

10. Participants must have a study partner who agrees to participate throughout theduration of the study. The study partner must have frequent and sufficient contact (approximately 10 hours per week) with the participant and be able to provideaccurate information regarding the participant's cognitive and functional abilities.

11. Participants must have no travel plans that would interfere with scheduling visitsfollowing 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 vaccineseries per CDC recommendations, with any dose of the vaccine received at least 30days prior to initiation of the study drug. COVID boosters are allowed during studyintervention period when scheduled at least four days before or after administrationof 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 includingParkinson's disease, Huntington's disease, normal pressure hydrocephalus, braintumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiplesclerosis, or history of significant head trauma followed by persistent neurologicdeficits or known structural brain abnormalities.

6. Current or history of alcohol or substance abuse or dependence within the past 2years 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 ontwo 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 6months.

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 witha narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or stronginhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus, or sirolimus).

16. Participants currently taking drugs that induce cellular senescence: alkylatingagents, anthracyclines, platins, other chemotherapy.

17. Participants on therapeutic doses of anticoagulants (e.g., warfarin, heparin, lowmolecular weight heparin, factor Xa inhibitors, etc.) other than low dose aspirinunless able to be held for 2 days prior to LP and with the documented approval ofthe prescribing clinician.

18. Participants taking H2 antagonists or proton pump inhibitors who are unable orunwilling to reduce or hold therapy for at least 2 days prior to and during each ofthe 2-day courses of Dasatinib plus quercetin dosing. Instead, subjects may useantacids prior to and during each of the 2-day courses of Dasatinib plus quercetindosing.

19. Concomitant use of strong CYP3A4 inhibitors.

20. Co-enrollment in another ADRD research study with a potentially disease-modifyingintervention or study drug that may impact senescent cells. Participants previouslyenrolled in a study meeting these criteria are eligible to screen after a washoutperiod 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 atrisk or would preclude the patient from successfully completing all aspects of thetrial.

22. Use of anti-amyloid therapies (e.g. aducanumab, lecanamab).