Safety and Feasibility of Dasatinib and Quercetin in Adults at Risk for Alzheimer's Disease

Phase 1

Completed

Brief Summary: The purpose of this pilot study is to demonstrate the safety and feasibility of administering intermittent doses of Dasatinib and Quercetin (D+Q) in older adults at risk of Alzheimer's disease (AD). The study will evaluate whether giving D+Q may improve cerebral blood flow regulation, mobility, and cognition in older adults, and thus may prevent progression to Alzheimer's disease.

Detailed Description: The investigators will conduct a 12-week single arm, open label, pre-post pilot study in 12 adults aged 65 or older with slow gait speed (\<1.0 m/sec) and Mild Cognitive Impairment (MCI, defined as a Telephone Montreal Cognitive Assessment Score (MoCA) \<19). Participants will be asked to take 100mg of Dasatinib and 1,250mg of Quercetin for 2 consecutive days, every two weeks over a period of 12 weeks (12 doses in total, given over 6 cycles).

At baseline, enrolled participants will undergo gait speed and neurocognitive testing, and provide blood and urine to evaluate biomarkers of senescence. At visits 3,4, 6, and 7, participants will have safety labs drawn, and the study team will assess medication adherence and adverse events. At visits 2, 5, and 8, participants will undergo cognitive assessments, gait speed testing, cerebral blood flow and neurovascular coupling testing. At the final study visit, participants will again provide blood and urine to assess biomarkers of senescence.

Recruitment & Eligibility

Inclusion Criteria

Men and women >/= 65 years
Ambulatory,
Community dwelling,
Slow gait speed (<1 m/second),
Mild Cognitive Impairment (Telephone MoCA score <21, which is indicative of cognitive impairment)

Exclusion Criteria, or as per clinical judgment:

Telephone MoCA score <10 points
Unwilling to take study medications or follow study protocol
Inability to independently perform Katz Activities of Daily Living (ADLs),
Allergies to Dasatinib or Quercetin,
Hospitalization within 6 months,
Unstable coronary artery disease (myocardial infarction within 6 months or angina),
Stroke or transient ischemic attack in the past 6 months,
Chronic heart failure,
Current or chronic history of liver disease,
Neurodegenerative disease including Parkinson's disease,
Anemia,
Chronic renal disease,
Drug or alcohol abuse in the last 5 years,
QTc prolongation,
Thrombocytopenia,
Neutropenia,
Prolonged prothrombin time or INR,
Indications of current fluid retention,
History or current diagnosis of pulmonary hypertension,
Inability to insonate the middle cerebral artery through a temporal bone window on at least one side using transcranial Doppler ultrasound, or
Chronic use of any of the following medications: anti-arrhythmic medications, antipsychotics, anxiolytics, anti-platelet or anti-coagulant medications other than aspirin, quinolone antibiotics, or drugs metabolized by the same liver enzymes as Quercetin or Dasatinib.

Exclusion Criteria

Not provided

Arm && Interventions

Group	Intervention	Description
Arm 1	Dasatinib	Dasatinib and Quercetin
Arm 1	Quercetin	Dasatinib and Quercetin

Primary Outcome Measures

Name	Time	Method
Neurovascular Coupling	Screening, 8, and 14 weeks	Change in cerebral blood flow during an N-back cognitive task using transcranial doppler ultrasound.
Executive Function	Baseline, 8, and 14 weeks	Assess change in executive cognitive function using TRAILS test, corrected for response time. Higher scores indicate worse executive functioning.
Gait Speed	Baseline, 8, and 14 weeks	Assess change in gait speed. Performed without a distracting cognitive task.
Montreal Cognitive Assessment (MoCA) Score	Baseline, 8, and 14 weeks	The Montreal Cognitive Assessment evaluates global cognition. Scores range from 0-30 points, with higher scores indicating better cognition

Secondary Outcome Measures

Name	Time	Method
Physical Performance	Baseline, 8, and 14 weeks	Assessment of overall physical function using the short physical performance battery (SPPB) scored from 0-12, based on a composite of balance, strength, and walking speed. Higher scores indicate better mobility.
Mobility	Baseline, 8, and 14 weeks	Test of mobility using timed up and go test, including standing from a chair, walking, and turning.
Grip Strength	Baseline, 8, and 14 weeks	Measure of grip strength using a hand dynamometer.
Gait Speed During Cognitive Task	Baseline, 8, and 14 weeks	Measure of gait speed during a cognitive task.
P16 ink4a Expression in CD3 Positive Cells	Screening and 14 weeks	Measure of P16 ink4a expression in senescent CD3 lymphocytes in the blood.
SASP Factors in Blood and Urine	Screening and 14 weeks	Measure of the senescence-associated biomarkers MMP-9 nanograms/mL and MMP-12 nanograms/mL.