Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial
Abstract
The first feasibility study of orally delivered senolytic therapy in Alzheimer’s disease reports favorable safety data and penetrance of dasatinib into the brain with a modest impact on Alzheimer’s and aging biomarkers. Cellular senescence contributes to Alzheimer’s disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. Five participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study. D and Q levels in blood increased in all participants (12.7–73.5 ng ml^−1 for D and 3.29–26.3 ng ml^−1 for Q). In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) ranging from 0.281 to 0.536 ml^−1 with a CSF to plasma ratio of 0.422–0.919%; Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile. CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased ( t (4) = 3.913, P = 0.008 and t (4) = 3.354, P = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels ( t (4) = −2.338, P = 0.079). In summary, CNS penetrance of D was…
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Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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