The SToMP-AD Trial of Senolytics Dasatinib and Quercetin for Alzheimer's Disease

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.



The brain doesn't just need to remove senescent neuron supporting cells like astrocytes, it needs them rejuvenated and returned to youth. Hence an approach like the Bioviva Trial (DOI:10.37191/Mapsci-2582-385X-3(6)-097) is far preferable to simply removing those cells, which after all will need to be replaced.

Posted by: Mark at April 25th, 2022 5:58 AM

Brains is a complicated matter. The neurons, we would want to rather seno-morph.For the astrocytes and blood blood vessels (all brain vasculature) it would be better to outright kill the senescent cells in those tissues.

Posted by: Cuberat at April 25th, 2022 12:07 PM

Having only 5 adults requires a really large effect to have any confidence for the clinical outcome. Here they will measure proxies like spinal fluid concentration and inflammation markers. Still would be interesting to see the results. Here I am cautiously optimistic but leaning on the pessimistic side

Posted by: Cuberat at April 25th, 2022 7:56 PM

@Cuberat - that is beside the point, of course we don't want to nuke the neurons. What I am saying is we may not want to nuke the astrocytes either, given replacements may or may not be forthcoming.

Posted by: Mark at April 26th, 2022 7:22 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.