Background

Dasatinib is a cancer drug, sold under the name Sprycel® to treat certain types of leukemia in adults and children. Its side effects include low blood cell counts, anemia, rash, and diarrhea. It may also cause serious side effects such as bleeding, pulmonary edema, heart failure, and prolonged QT syndrome. The therapeutic dose is 100 mg daily. Quercetin is a naturally occurring flavonoid with antioxidant and anti-inflammatory activity. It is sold as a nutritional supplement, purportedly to treat cancer and other diseases, but with no peer-reviewed evidence to back such claims. Doses up to 1 gram daily appear safe.

This drug combination targets and eliminates senescent cells that are linked to multiple age-related chronic diseases. Senescent cells have undergone irreversible cell-cycle arrest in response to damage or stress, but resist apoptotic cell death; they can persist for years. Some produce pro-inflammatory mediators, and studies implicate them in diabetes, osteoporosis, pulmonary fibrosis, and general age-related frailty, as well as in Alzheimer’s and Parkinson's disease brain, and in other conditions (reviewed in Kirkland and Tchkonia, 2020). Dasatinib induces apoptosis in senescent cells by inhibiting the Src tyrosine kinase, while quercetin does so by inhibiting the anti-apoptotic protein Bcl-xL.

The rationale for so-called “senolytic therapy” for AD arises from studies implicating senescent glia, neurons, and endothelial cells in neurodegeneration due to tau or amyloid pathology (Sep 2018 news; Bryant et al., 2020; Gonzales et al., 2021). In one preclinical study, treating rTg4510 human-mutant-tau-expressing mice with D+Q every two weeks for six months resulted in less tau tangle pathology, preservation of neurons and synapses, and better cerebral blood flow compared to untreated mice (Musi et al., 2018). In the APPPS1 mouse model of AD, senescent oligodendrocytes were found surrounding amyloid plaques. D+Q eliminated the senescent cells, reduced amyloid load and inflammation, and improved memory behaviors (see Apr 2019 news on Zhang et al., 2019). The same study identified senescent oligodendrocytes in human postmortem AD brain tissue. In contrast, D+Q did not reduce senescent cell markers in brain, nor did it improve cognitive behaviors in P301S tau-expressing mice (Riordan et al., 2023). D+Q treatment of healthy young female mice reportedly diminished metabolism and cognition; it had no effect on young males (Fang et al., 2023). Quercetin has been reported to also have anti-amyloid and fibril-disaggregating activity (Jiménez-Aliaga et al., 2011).

D+Q is administered in an intermittent-dosing regimen, based on the idea that the combination quickly eliminates senescent cells, and it takes several weeks for the body's tissues to generate new ones. In people with diabetic kidney disease, three days treatment with D+Q reduced senescent cell numbers and inflammation in adipose tissue biopsies taken 11 days later (Hickson et al., 2019; Hickson et al., 2020).

Findings

In February 2020, a Phase 1/2 study at the at University of Texas Health Center in San Antonio began evaluating if D+Q given orally enters the brain (Gonzales et al., 2022). Five people with a clinical diagnosis of AD and using cholinesterase inhibitors received D+Q for six cycles of two days on/14 days off, for CSF levels of both drugs to be determined. According to results presented at December 2022 CTAD conference, dasatinib, but not quercetin, was detected in CSF 60 to 90 minutes after the last dose. The regimen appeared safe and tolerable. No significant changes in biomarkers of Aβ, tau, or senescence, or in cognition occurred over the 12 weeks of treatment. Study results are posted at clinicaltrials.gov, and were published after peer review (Gonzales et al., 2023).

In December 2021, the Phase 2 SToMP-AD study at Wake Forest University began enrolling 48 participants with MCI or early AD and a positive tau-PET scan or CSF tau (Dec 2021 conference news). Participants receive 100 mg D and 1,000 mg Q, or matching placebo, for two consecutive days out of every 15 days, in six cycles lasting 12 weeks. The primary outcome is serious adverse events over 48 weeks, while secondary outcomes are changes in a panel of blood senescence markers over 12 weeks. The study will also measure CDR-SB, ADAS-Cog 14, and tau PET over 48 weeks. It is expected to run until January 2027.

In May 2022, a second open-label pilot study began in Boston to test cyclic administration of 100 mg D and 1,250 mg Q in 12 older adults with mild cognitive impairment and slow walking speed. The study will assess changes in cerebral blood flow during a cognitive test, change in executive functioning, and gait speed after six cycles of treatment. Other outcomes include measures of physical performance, mobility, grip strength, and biomarkers of cell senescence. The trial is anticipated to finish in June 2024.

In July 2022, the Mayo Clinic started ALSENLITE, a third Phase 1/2 open-label pilot. It will enroll 20 people who have a clinical diagnosis of MCI or AD and a positive tau-PET scan. Their treatment will be the same D+Q regimen as in the Wake Forest study, but with no placebo control. The sole listed outcome is safety and tolerability. Primary completion is slated for December 2023.

D+Q is also being tested in biological aging, for frailty in adult survivors of childhood cancer, premature aging after stem cell transplant or due to psychiatric disease, chronic kidney disease, fatty liver disease, obesity and metabolic disorders, and bone health in elderly women. A pilot trial has been completed for idiopathic pulmonary fibrosis; the drug combination was reportedly well-tolerated (Justice et al., 2019).

For details on D+Q trials, see clinicaltrials.gov.