Clearing Senescent Cells in Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia that affects more than 6.5 million Americans, according to the Alzheimer’s Association. To find effective treatments and slow the progression of this debilitating disease, researchers have made much progress in developing new drugs that target beta-amyloid plaques, one of the hallmarks of Alzheimer’s disease.

Beta-amyloid plaques are accumulations of brain protein fragments, which can impact cognition. However, these recent drugs have only yielded modest results.

Now, scientists are reporting results from a Phase I trial in another area of promising research — cellular senescence.

Senescent cells are old, sick cells that cannot properly repair themselves and don’t die off when they should. Over time, they continue to build up in tissues throughout the body contributing to the aging process, neurocognitive decline and cancer.

Researchers repurposed a U.S. Food and Drug Administration-approved drug designed to clear cancer cells (dasatinib) in combination with a flavonoid, a plant-derived antioxidant (quercetin).

For the current study, the research team enrolled five participants aged 65 and older with symptoms of early-stage Alzheimer’s disease. Participants received oral dasatinib plus quercetin over two consecutive days, followed by two weeks of no drugs. The cycle repeated six times for a total of 12 weeks.

“Our primary goal was to determine whether the medicines penetrated the central nervous system,” Orr said. “We collected samples of patients’ cerebrospinal fluid (CSF) before the first dose of medicine was given and after the last dose of medicine was given.”

They found that both dasatinib and quercetin levels increased in the blood, and dasatinib was detected in the CSF in four subjects. Quercetin was not detected in the CSF of any participants.

“We also determined that the treatment was safe, feasible and well-tolerated,” Orr said. “There were no significant changes in brain function as determined by assessing memory and brain imaging to provide additional evidence that it is a safe therapy to evaluate further.”

Researchers also saw evidence to suggest that the combination therapy cleared amyloid from the brain and lowered inflammation in the blood.

“However, we shouldn’t over-interpret these results,” Orr said. “There was a small number of people enrolled, there was no placebo arm to compare results.”

“We can confidently move forward with a larger study population and placebo arm knowing that the treatment is safe,” Orr said. “We will also look forward to learning more about how the treatment may impact Alzheimer’s disease biomarkers.”

Sources:

Mitzi M. Gonzales, Valentina R. Garbarino, Tiffany F. Kautz, Juan Pablo Palavicini, Marisa Lopez-Cruzan, Shiva Kazempour Dehkordi, Julia J. Mathews, Habil Zare, Peng Xu, Bin Zhang, Crystal Franklin, Mohamad Habes, Suzanne Craft, Ronald C. Petersen, Tamara Tchkonia, James L. Kirkland, Arash Salardini, Sudha Seshadri, Nicolas Musi, Miranda E. Orr. Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nature Medicine, 2023; DOI: 10.1038/s41591-023-02543-w

Atrium Health Wake Forest Baptist. “Phase I clinical trial shows treatment designed to clear senescent cells in Alzheimer’s disease is safe.” ScienceDaily. ScienceDaily, 7 September 2023. <www.sciencedaily.com/releases/2023/09/230907130337.htm>.

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