Senolytics in Alzheimer's: Phase 1 Trial Insights

The recent Phase 1 trial exploring the efficacy of senolytics in patients suffering from Alzheimer's disease sheds light on potential avenues for future research, particularly in the realm of enhancing cognitive function and understanding disease mechanics. Conducted with a small participant group, this trial examined the impacts of dasatinib and quercetin, two compounds known for their senolytic properties aimed at reducing cellular senescence.

Introduction

This study, published in Neurotherapeutics, aimed to expand upon previous findings regarding the role of senescent cells in the progression of Alzheimer’s, particularly tau aggregation and amyloid plaques associated with the disease. Given the correlation between senescent cells and neurological degeneration, the trial sought to determine if the administration of the senolytics could effectively clear these cells and positively affect cognitive assessments.

Study Design and Methodology

The trial involved a 12-week intervention with just five participants aged between 70 and 82, all diagnosed with early-stage Alzheimer's disease. The subject demographics were as follows:

Participants received a regimen of 100 milligrams of dasatinib and 1 gram of quercetin on an intermittent schedule. The primary objective was to analyze various biomarkers, including tau and amyloid levels, to assess any changes resulting from this senolytic intervention.

Results and Discussion

Despite the hopes surrounding this initial trial, the results were largely disappointing. The administration of dasatinib and quercetin did not produce statistically significant changes in any biomarkers related to Alzheimer’s pathology. Key findings included:

• Fractalkine Levels: An increase was noted in plasma fractalkine levels, but this change did not reach statistical significance.
• Lipid Balance: Notable changes in lipid profiles were observed; however, none of these changes proved to be statistically significant.
• Gene Expression: Of 19 inflammation-related genes examined, 7 showed downregulation, including _IL8_ and _IL1β_.

These outcomes suggest that the current dosage and duration may not be adequate for achieving discernible biochemical changes. According to the researchers, a larger cohort would provide better power to detect significant results, estimating that around 25 participants would be necessary to yield meaningful data concerning senescence-associated secretory phenotype (SASP) factors.

“This trial, while not yielding fruitful outcomes, lays the groundwork for enhancing our understanding and future study designs in combating neurodegenerative diseases." – Research Team

Conclusion and Future Directions

The lack of favorable outcomes in this Phase 1 trial highlights the complexities associated with Alzheimer’s treatment. It prompts further inquiries into the adequacy of focusing exclusively on senolytics as a remedy for cognitive decline in Alzheimer’s. Future studies may benefit from:

• Expanding sample sizes to include a broader demographic for more comprehensive insights.
• Consideration of alternative dosing schedules or combinations of therapies.
• Implementation of longer trial durations to assess potential delayed effects.

Overall, while this study has not proven effective, it has importantly opened avenues for continued research into Alzheimer's disease by demonstrating the need for multifaceted approaches beyond the scope of senolytic therapy.

Literature Cited

[1] Musi, N., et al. (2018). Tau protein aggregation is associated with cellular senescence in the brain. Aging cell, 17(6), e12840.

[2] Bhat, R., et al. (2012). Astrocyte senescence as a component of Alzheimer’s disease.

[3] Zhang, P., et al. (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., et al. (2023). Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nature medicine, 29(10), 2481-2488.

[5] Chang, M. C., et al. (2017). Lysophosphatidylcholine induces cytotoxicity/apoptosis and IL-8 production of human endothelial cells: Related mechanisms. Oncotarget, 8(63), 106177.