Summary: Researchers identified sildenafil, known commercially as Viagra, as a promising candidate for treating Alzheimer’s disease. Leveraging artificial intelligence the team analyzed vast amounts of data, including insurance claims and brain cell observations, to highlight sildenafil’s potential benefits in reducing Alzheimer’s prevalence and neurotoxic proteins.
Their study suggests repurposing this FDA-approved drug could offer a novel therapeutic approach for a disease affecting millions. This interdisciplinary research combines computational models with real-world patient data, paving the way for future clinical trials to explore sildenafil’s effectiveness in Alzheimer’s patients.
Key Facts:
- Interdisciplinary Approach: The study integrates computational models, insurance claims data, and laboratory observations, showcasing an innovative method to identify potential Alzheimer’s treatments.
- Significant Findings: Analysis of patient data revealed a 30-54% reduction in Alzheimer’s diagnoses among sildenafil users, and laboratory tests showed decreased neurotoxic protein levels in brain cells.
- Implications for Treatment: Sildenafil, by potentially lowering Alzheimer’s risk and combating neurotoxicity, represents a significant step forward in the search for new Alzheimer’s therapies, highlighting the benefits of drug repurposing.
Source: Cleveland Clinic
New Cleveland Clinic-led research points to sildenafil (Viagra) as a potential treatment for Alzheimer’s disease. The study provides evidence from computational models, insurance claims data and observations from brain cells in Alzheimer’s patients.
Sildenafil is the main component of drugs used to treat erectile dysfunction (Viagra) and pulmonary arterial hypertension (Revatio).
“Our findings provide further weight to re-purposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” said Feixiong Cheng, Ph.D., who led the research.
“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease.”
Alzheimer’s disease currently affects over 6 million Americans and incidence is expected to triple by 2050, underscoring the need for rapid development of new prevention and treatment strategies.
Drug repurposing – use of an existing drug for new therapeutic purposes – offers a practical alternative to the costly and time-consuming traditional drug discovery process.
Published in Journal of Alzheimer’s Disease, the study builds upon the researchers’ earlier findings in 2021 that used computational models to initially identify sildenafil as a promising drug candidate to help prevent and treat Alzheimer’s disease.
In the new study, Dr. Cheng, director of the Cleveland Clinic Genome Center, and his team analyzed millions of de-identified insurance claims from two independent patient databases, which revealed a 30-54% reduced prevalence in Alzheimer’s disease diagnoses among patients who took sildenafil compared to those who did not after adjusting various possible confounding factors.
In brain cells from Alzheimer’s patients, researchers also showed that sildenafil lowers levels of neurotoxic tau proteins, which are known to be associated with Alzheimer’s disease when they build up.
They also found that neurons treated with sildenafil expressed genes related to cell growth, improved brain function, reduced inflammation and other processes known to protect against the neural degeneration associated with Alzheimer’s disease.
Dr. Cheng’s findings demonstrate the feasibility of using computer models to identify potential new drug candidates in a fast, reliable way, representing a significant step forward in Alzheimer’s drug discovery.
“After integrating this large amount of data computationally, it is rewarding to see sildenafil’s effects in human neurons and real-world patient outcomes,” said Dr. Cheng. “We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease.”
Dr. Cheng’s co-authors include Andrew A. Pieper, M.D., Ph.D., of Louis Stokes Cleveland VA Medical Center, Case Western Reserve University and University Hospitals Cleveland Medical Center; and Jeffrey Cummings, M.D., Sc.D., director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas.
Funding: Dhruv Gohel, Ph.D., and Amit Gupta, Ph.D., postdoctoral research associates in Dr. Cheng’s laboratory, are co-first authors. The study was primarily supported by the National Institute on Aging of the National Institutes of Health (NIH) under award numbers R01AG066707, U01AG073323, R01AG076448, R01AG082118, RF1AG082211, R01AG084250, R56AG074001, andR21AG083003, and the National Institute of Neurological Disorders and Stroke of NIH under award number RF1NS133812.
About this neuropharmacology and Alzheimer’s disease research news
Author: Alicia Reale
Source: Cleveland Clinic
Contact: Alicia Reale – Cleveland Clinic
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons” by Feixiong Cheng et al. Journal of Alzheimer’s Disease
Abstract
Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons
Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD.
Objective: To investigate the potential therapeutic benefit of sildenafil on AD. Methods: We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil’s mechanism-of-action.
Results: We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32– 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49– 1.00) compared to spironolactone.
We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD.
Conclusions: These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.
