Sildenafil as an Alzheimer’s Candidate Drug: Further Support From Insurance Database and Mechanistic Studies

New Cleveland Clinic-led research indicates that the phosphodiesterase-5 inhibitor sildenafil may be protective against Alzheimer’s disease (AD). The findings, based on large real-world patient datasets and mechanistic studies using AD patient-induced pluripotent stem cell-derived neurons, suggest that sildenafil is a potential repurposable medication for AD. The drug has long been FDA-approved for treatment of erectile dysfunction (as Viagra^®) and pulmonary arterial hypertension (as Revatio^®).

The research, published in the Journal of Alzheimer’s Disease (Epub 2024 Mar 1), details observations in brain cells from patients with AD that support earlier computational investigations that initially identified sildenafil as a potential candidate to treat AD. Both the new study and those earlier investigations were led by Feixiong Cheng, PhD,Director of the Cleveland Clinic Genome Center.

A role for systems biology and multi-omics research

Dr. Cheng and his team specialize in systems biology and multi-omics research. For their earlier investigations (Nat Aging. 2021;1[12]:1175-1188), they integrated datasets from gene expression studies, protein-based studies, anonymized patient data and anonymized insurance records to identify existing medications with potential to also treat AD. To make the leap to clinical trials, Dr. Cheng and his collaborating researchers and clinicians needed experimental proof that sildenafil specifically targets AD-related genes and processes.

“Systems biology and multi-omics research is powerful because it combines many different types of data from patients, but it’s just one part of the greater research journey,” Dr. Cheng says. “To justify using a drug like sildenafil in an Alzheimer’s disease clinical trial, we needed to get evidence that what we saw on the screen translated to real life.”

A two-pronged research effort

Real-world patient data analysis

His team set out to do so with their newly published research. They began by further analyzing millions of anonymized insurance claims from two independent patient databases. They identified pharmacy claims for sildenafil — along with claims for the calcium channel blocker nifedipine and the diuretics bumetanide, furosemide and spironolactone — and conducted propensity score-stratified analyses for association with AD risk. “We chose these four drugs as comparators for sildenafil because they are used in the treatment of hypertension or pulmonary arterial hypertension, which decreases indication confounding,” Dr. Cheng explains.

After adjusting for sex, age, race and comorbidities, the researchers found that sildenafil use correlated with significantly reduced likelihood of an AD diagnosis relative to the four comparator drugs. For example, compared with use of spironolactone, sildenafil use was associated with a 54% reduced incidence of AD in one insurance database and a 30% reduced prevalence of AD in the other independent patient database.

Mechanistic observations

While these findings confirmed the association of sildenafil with AD risk from his group’s 2021 study, Dr. Cheng needed to further explore potential mechanisms of the association. To that end, he worked closely with clinicians, including Jeffrey Cummings, MD, ScD, founding director of the Cleveland Clinic Luo Ruvo Center for Brain Health in Las Vegas, and Andrew A. Pieper, MD, PhD, who runs an outpatient psychiatry clinic at the Louis Stokes Cleveland VA Medical Center and a neurobiology laboratory at Case Western Reserve University and University Hospitals.

The group conducted tissue culture experiments using patient-induced pluripotent stem cell-derived neurons from four patients, two with familial AD and two with sporadic AD. Treatment of the neurons with sildenafil resulted in dose-dependent lowering of levels of phosphorylated tau proteins, the accumulation of which is known to be associated with AD . The researchers also found that neurons treated with sildenafil expressed genes related to neuron generation, neuroplasticity, neural function, neural inflammation and other processes known to protect against AD-associated neural degeneration.

A path toward randomized trial assessment

The researchers note that while further study is needed to confirm whether and how these changes translate to a clinical setting, the results bolster support for potential repurposing of sildenafil to prevent or treat AD — and set the stage for testing in further functional models and randomized clinical trials. For the next step, the team is working to conduct a pilot study to verify the brain target engagement of sildenafil in patients with early AD using biomarker-based observations.

“These findings also 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,” Dr. Cheng concludes.

Note: Dr. Cheng acknowledges Dhruv Gohel, PhD, and Amit Gupta, PhD, postdoctoral research associate in the Cheng lab, who served as co-first authors of this study, which was supported by the National Institute on Aging under award numbers R01AG066707, U01AG073323, R01AG076448, R01AG082118, RF1AG082211, R01AG084250, R56AG074001 and R21AG083003, and by the National Institute of Neurological Disorders and Stroke under award number RF1NS133812.