A large-scale study provides evidence that an FDA-approved drug may help protect brain cells from Alzheimer´s disease.
Sildenafil as a candidate drug for Alzheimer´s disease: Analysis of real-world patient data and mechanistic observations in neurons derived from patient-induced pluripotent stem cells (iPSCs)
Alzheimer´s disease (AD) is a chronic neurodegenerative condition urgently in need of effective therapies. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been suggested to have potential effects on AD.
We conducted real-world patient data analysis using the MarketScan® Medicare Supplemental and Clinformatics® databases. We performed propensity score-stratified analyses after adjusting for confounding factors (such as sex, age, race, and comorbidities). We used neurons derived from induced pluripotent stem cells (iPSCs) from patients with familial and sporadic Alzheimer´s disease to assess sildenafil’s mechanism of action.
We demonstrated that sildenafil use is associated with a reduced likelihood of Alzheimer´s disease across four new drug repurposing cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For example, sildenafil use was associated with a 54% reduced incidence of AD in the MarketScan® cohort (hazard ratio [HR] = 0.46, 95% confidence interval [CI]: 0.32-0.66) and a 30% reduced prevalence of AD in the Clinformatics® cohort (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 iPSC-derived neurons from both familial and sporadic AD patients. RNA sequencing analysis of iPSC-derived neurons from AD patients treated with sildenafil revealed that sildenafil specifically targets AD-related genes and pathobiological pathways, mechanistically supporting sildenafil’s beneficial effects in AD.
These real-world patient data and mechanistic observations from iPSC-derived neurons further suggest that sildenafil is a potentially repurposable drug for Alzheimer´s disease. However, randomized clinical trials are warranted to validate the causal effects of sildenafil treatment on AD.
New Research Led by the Cleveland Clinic Points to Sildenafil 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 medications used to treat erectile dysfunction and pulmonary arterial hypertension.
"Our findings provide further support for repurposing this FDA-approved drug as a novel treatment for Alzheimer´s, a condition in dire need of new therapies," said Feixiong Cheng, Ph.D., who led the research. "We used artificial intelligence to integrate data across multiple domains, all of which pointed to sildenafil’s potential against this devastating neurological disease."
Alzheimer´s currently affects more than 6 million Americans, with its incidence expected to triple by 2050, underscoring the need for rapid development of new prevention and treatment strategies. Drug repurposing (using an existing drug for new therapeutic purposes) offers a practical alternative to the costly and time-consuming traditional drug discovery process.
Published in the Journal of Alzheimer´s Disease, the study builds on previous findings from the researchers in 2021, when they initially identified sildenafil as a promising candidate drug to help prevent and treat Alzheimer´s using computational models.
In the new study, Dr. Cheng, director of the Cleveland Clinic´s Genomic Medicine Institute, and his team analyzed millions of de-identified insurance claims from two independent patient databases, revealing a 30-54% reduced prevalence of Alzheimer´s diagnoses among patients who took sildenafil compared to those who did not, after adjusting for various potential confounders.
In brain cells from Alzheimer´s patients, the researchers also demonstrated that sildenafil reduces levels of neurotoxic tau proteins, known to be associated with Alzheimer´s when they accumulate. 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 neurodegeneration in Alzheimer´s.
Dr. Cheng´s findings demonstrate the viability of using computational models to quickly and reliably identify potential new drug candidates, representing a significant step forward in Alzheimer´s drug discovery.
"After computationally integrating this vast amount of data, it´s rewarding to see sildenafil´s effects in human neurons and real-world patient outcomes," said Dr. Cheng. "We believe our findings provide the necessary evidence for clinical trials to further examine sildenafil’s potential efficacy in Alzheimer´s patients."
Dr. Cheng´s co-authors include Andrew A. Pieper, MD, Ph.D., from the Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, and University Hospitals Cleveland Medical Center; and Jeffrey Cummings, MD, Sc.D., director emeritus of the Cleveland Clinic´s Lou Ruvo Center for Brain Health in Las Vegas.
Dhruv Gohel, Ph.D., and Amit Gupta, Ph.D., postdoctoral research associates in Dr. Cheng’s lab, are co-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, and R21AG083003, and the NIH National Institute of Neurological Disorders and Stroke under award number RF1NS133812.
