Accumulating evidence from animal studies indicates that senescent supporting cells in the brain (such as inflammatory microglia and astrocytes) are an important contributing cause of Alzheimer's disease, as well as other forms of neurodegenerative condition characterized by chronic inflammation in brain tissue. There is a good chance that low-cost senolytic therapies capable of crossing the blood-brain barrier to selectively destroy some fraction of the senescent cells present in the aged brain, such as the dasatinib and quercetin combination, will turn out to be the most important Alzheimer's therapy of the next decade or two. Clinical trials are needed to prove or disprove this hypothesis, however, and so far only a couple of projects are underway, such as the ALSENLITE and SToMP-AD trials. I had failed to notice this open access outline paper for SToMP-AD when it was published late last year, but here it is now.
Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to control mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions.
With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease.