Dataset Information

Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease.

ABSTRACT:

Introduction

Bumetanide, a loop diuretic, was identified as a candidate drug for repurposing for Alzheimer's disease (AD) based on its effects on transcriptomic apolipoprotein E signatures. Cross-sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, temporality between bumetanide exposure and AD development has not been established.

Methods

We evaluated Medicare claims data using Cox proportional hazards regression to evaluate the association between time-dependent use of bumetanide and time to first AD diagnosis while controlling for patient characteristics. Multiple sensitivity analyses were conducted to test the robustness of the findings.

Results

We sampled 833,561 Medicare beneficiaries, 60.8% female, with mean (standard deviation) age of 70.4 (12). Bumetanide use was not significantly associated with AD risk (hazard ratio 1.05; 95% confidence interval, 0.99-1.10).

Discussion

Using a nationwide dataset and a retrospective cohort study design, we were not able to identify a time-dependent effect of bumetanide lowering AD risk.

Highlights

Bumetanide was identified as a candidate for repurposing for Alzheimer's disease (AD). We evaluated the association between bumetanide use and risk of AD. We used Medicare data and accounted for duration of bumetanide use. Bumetanide use was not significantly associated with risk of AD.

SUBMITTER: Morales J

PROVIDER: S-EPMC11350022 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease.

Morales Jasmine J Gabriel Nico N Natarajan Loki L LaCroix Andrea Z AZ Shadyab Aladdin H AH Xu Ronghui R Silverman James J Feldman Howard H HH Hernandez Inmaculada I

Alzheimer's & dementia : the journal of the Alzheimer's Association 20240621 8

<h4>Introduction</h4>Bumetanide, a loop diuretic, was identified as a candidate drug for repurposing for Alzheimer's disease (AD) based on its effects on transcriptomic apolipoprotein E signatures. Cross-sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, temporality between bumetanide exposure and AD development has not been established.<h4>Methods</h4>We evaluated Medicare claims data using Cox proportional hazards reg ...[more]

PMID: 39030734

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Project description:BackgroundGenome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful.MethodsTo address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein-protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells.ResultsThrough this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861-0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862-0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD.ConclusionsIn summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.

Project description:Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of cognitive decline. The alarming epidemiological features of Alzheimer's disease, combined with the high failure rate of candidate drugs tested in the preclinical phase, impose more intense investigations for new curative treatments. NRF2 (Nuclear factor-erythroid factor 2-related factor 2) plays a critical role in the inflammatory response and in the cellular redox homeostasis and provides cytoprotection in several diseases including those in the neurodegeneration spectrum. These roles suggest that NRF2 and its directly associated proteins may be novel attractive therapeutic targets in the fight against AD. In this study, through a systemics perspective, we propose an in silico drug repurposing approach for AD, based on the NRF2 interactome and regulome, with the aim of highlighting possible repurposed drugs for AD. Using publicly available information based on differential expressions of the NRF2-neighborhood in AD and through a computational drug repurposing pipeline, we derived to a short list of candidate repurposed drugs and small molecules that affect the expression levels of the majority of NRF2-partners. The relevance of these findings was assessed in a four-step computational meta-analysis including i) structural similarity comparisons with currently ongoing NRF2-related drugs in clinical trials ii) evaluation based on the NRF2-diseasome iii) comparison of relevance between targeted pathways of shortlisted drugs and NRF2-related drugs in clinical trials and iv) further comparison with existing knowledge on AD and NRF2-related drugs in clinical trials based on their known modes of action. Overall, our analysis yielded in 5 candidate repurposed drugs for AD. In cell culture, these 5 candidates activated a luciferase reporter for NRF2 activity and in hippocampus derived TH22 cells they increased NRF2 protein levels and the NRF2 transcriptional signatures as determined by increased expression of its downstream target heme oxygenase 1. We expect that our proposed candidate repurposed drugs will be useful for further research and clinical translation for AD.

Dataset Information

Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease.

Introduction

Methods

Results

Discussion

Highlights

Publications

Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease.

Similar Datasets

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