The results of a Phase 1 trial of the well-known senolytic combination of dasatinib and quercetin (D+Q) in patients with Alzheimer’s disease have been published in Neurotherapeutics.
Building on substantial previous work
The researchers introduce this study by discussing the relationship of senescent cells to Alzheimer’s and its related pathologies; for example, senescent cells in the brain are associated with tau aggregation [1], and senescent astrocytes have been linked to Alzheimer’s [2]. Dasatinib and quercetin are very well-known to reduce cellular senescence, and they have been reported to reduce both tau [1] and amyloid beta plaques [3] in mouse models. However, mice don’t naturally get Alzheimer’s, and without human testing, it’s not clear how much good senolytics could do against this disease in people.
This group has previously conducted a feasibility trial using D+Q in people with Alzheimer’s, finding that the dasatinib had successfully infiltrated the brain and that it was well-tolerated [4]. Here, they build on that trial with more work, aiming to develop a standardized system of biomarker analysis in order to determine if senescent cells are actually being effectively cleared in this population, thus paving the way for Phase 2 studies.
Largely negative results
This trial utilized only five people, who were between the ages of 70 and 82, were in the early stage of clinical Alzheimer’s disease, and received 100 milligrams of dasatinib and 1 gram of quercetin on an intermittent schedule for three months.
Fractalkine, an inflammatory chemokine, appeared to be increased in plasma by the D+Q treatment, although this result was not considered statistically significant after multiple comparisons correction, nor were any others. Urinary analysis of metabolites also showed no statistically significant changes. This was likely due to the low number of participants involved in this study. The researchers estimated that, if only one SASP factor (such as the inflammatory biomarker IL-6) were considered, only 25 participants would need to be included in a future study in order to gain statistically significant results.
Unfortunately, this lack of statistical significance also applied to markers of AD pathology. The researchers examined a great many biomarkers relating to tau and amyloids, finding statistically significant changes to none of them. One person with more substantial neurodegeneration than the other four had more dasatinib uptaken into the brain, which may be due to reduced function of the blood-brain barrier.
The fat balance (lipidome) of the blood was somewhat affected by D+Q. Phosphatidylcholine, which makes up lipoprotein membranes and is usually tightly controlled, decreased by a sixth after treatment. Lysophosphatidylcholine, which is associated with inflammation and cellular death [5], decreased by 24%; this result was close to statistical significance. However, none of the lipid classes were significantly affected.
Overall cellular stress, as measured by transcriptomic analysis, was also somewhat affected. Of 19 inflammation-related genes in peripheral blood mononuclear cells (PBMCs), 7 of them were downregulated, including the SASP-related IL8 and IL1β.
This small study was meant to test safety and was never meant to show efficacy. It only lasted for 12 weeks, which is unlikely to be long enough for disease modification; however, the lack of any discernible signal in amyloid or tau biomarkers may suggest that this particular combination of senolytics, if not senolytics as a whole, may be the wrong approach in dealing with Alzheimer’s despite a documented link in mouse studies.
With some promising study results, a larger and longer study may be useful in verifying efficacy; here, with this lack of effect on crucial neurological amyloids, the opposite is likely to be true, and a Phase 2 study would probably yield the same largely negative results. Ultimately, the evidence suggests that Alzheimer’s is not a disease that relies on senescence to propagate, and entirely different methods are likely to be necessary for dealing with this proteostasis disorder.
Literature
[1] Musi, N., Valentine, J. M., Sickora, K. R., Baeuerle, E., Thompson, C. S., Shen, Q., & Orr, M. E. (2018). Tau protein aggregation is associated with cellular senescence in the brain. Aging cell, 17(6), e12840.
[2] Bhat, R., Crowe, E. P., Bitto, A., Moh, M., Katsetos, C. D., Garcia, F. U., … & Torres, C. (2012). Astrocyte senescence as a component of Alzheimer’s disease.
[3] Zhang, P., Kishimoto, Y., Grammatikakis, I., Gottimukkala, K., Cutler, R. G., Zhang, S., … & Mattson, M. P. (2019). Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nature neuroscience, 22(5), 719-728.
[4] Gonzales, M. M., Garbarino, V. R., Kautz, T. F., Palavicini, J. P., Lopez-Cruzan, M., Dehkordi, S. K., … & Orr, M. E. (2023). Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nature medicine, 29(10), 2481-2488.
[5] Chang, M. C., Lee, J. J., Chen, Y. J., Lin, S. I., Lin, L. D., Liou, E. J. W., … & Jeng, J. H. (2017). Lysophosphatidylcholine induces cytotoxicity/apoptosis and IL-8 production of human endothelial cells: Related mechanisms. Oncotarget, 8(63), 106177.
