Senolytic therapy in Alzheimer’s disease: clinical evidence and biomarkers

Abstract

Background: Alzheimer’s disease is a progressive neurodegenerative disorder in which cellular senescence and a pro-inflammatory environment influence its natural course. Senolytic therapy has emerged as a potential strategy by proposing the elimination of these cells, with the potential to modulate disease progression. Early clinical trials, such as SToMP-AD, are investigating its safety, feasibility, and impact on biomarkers. Objective: To analyze the available clinical evidence on senolytic therapy in Alzheimer’s disease, focusing on the observed effects on disease progression. Methods: This systematic review was conducted in accordance with the PRISMA guidelines. Searches were performed in PubMed and ScienceDirect using the descriptors “Senolytic Therapy” and “Alzheimer’s disease.” After applying the filters (publications from the last five years, Portuguese and English languages, full-text articles with free access), 71 articles were identified. After screening and eligibility assessment, five studies were selected to compose the review. Results: Some cells of the central nervous system may become senescent but remain metabolically active and accumulate with aging. For this reason, the use of senolytics—drugs capable of eliminating senescent cells—has been investigated. Studies indicate that the accumulation of tau protein is associated with cognitive decline and that senolytics such as dasatinib and quercetin reduced its presence in experimental models, in addition to decreasing neuroinflammation. The results of the SToMP trial using Dasatinib (D) and Quercetin (Q) in patients with Alzheimer’s disease demonstrated that the therapy is feasible and safe. The study confirmed the penetration of D into the central nervous system in 80% of cases, although Q was not detected. Furthermore, increases in IL-6 and GFAP levels were observed in the cerebrospinal fluid (CSF), along with an elevation of GDF15, indicating glial response and target engagement. A trend toward reduction of SASP cytokines and an increase in Aβ42 levels were also observed. Changes in p-tau rates suggest a potential impact on tauopathy dynamics. Conclusion: Population aging is associated with an increased incidence of neurodegenerative diseases such as Alzheimer’s disease. Therefore, the development of therapeutic approaches capable of reducing the growing burden of these conditions is essential, including senolytic therapy. Thus, the advancement of controlled clinical studies, combined with the use of molecular biomarkers, neuroimaging, and longitudinal cognitive assessment, may clarify the impact of these interventions on disease progression and contribute to the development of more targeted and safer therapies.