Model identifies sildenafil as potential candidate; real-world evidence supports link

Sildenafil emerged as a potential drug candidate for Alzheimer’s disease (AD) affecting both amyloid and tau pathologies, a drug repurposing analysis showed.

An endophenotype network-based methodology identified sildenafil as having properties that could prevent or treat AD, reported Feixiong Cheng, MD, PhD, of the Cleveland Clinic in Ohio, and co-authors, in Nature Aging.

Preliminary supportive analysis of data from 7.23 million Medicare Advantage plan beneficiaries over 6 years of follow-up also found that sildenafil usage was significantly associated with a 69% reduced risk of AD, compared with matched non-sildenafil users (HR 0.31, 95% CI 0.25–0.39, P<1 × 10−8).

“Understanding AD from the point of view of how cellular systems and molecular interactome perturbations underlie the disease is critical for therapeutic development in AD,” Cheng and colleagues wrote.

“We posited that systematic identification of underlying AD-related endophenotype modules, shared by amyloid and tauopathy, would provide a foundation for generating predictive models to characterize AD pathogenesis for efficacious therapeutic development,” they added.

“We discovered that sildenafil is associated with a reduced incidence of AD in real-world patient data,” Cheng and co-authors noted. “In vitro mechanistic observations in human microglia cells and neurons derived from induced pluripotent stem cells (iPSCs) from patients with AD support a possible mechanism for sildenafil’s beneficial effect in AD.”

Sildenafil is approved for erectile dysfunction (Viagra) and pulmonary artery hypertension (Revatio). The drug has been studied in AD previously, with evidence for improved memory and amyloid plaque load in mice. Pilot studies in humans found a single 50 mg dose decreased spontaneous right hippocampal activity and, in a separate study, increased cerebral metabolic rate of oxygen and cerebral blood flow and decreased cerebral vascular reactivity.

“Altogether, we believe that these data provide a potential mechanism of action for the protective efficacy of sildenafil in AD, complementing our endophenotype-based prediction and population-based validation,” Cheng and co-authors wrote.

The group integrated information about changes in genes, transcription, protein products, and their interactions associated with specific pathologies—e.g., amyloidosis, tauopathy, neuroinflammation, each with its own endophenotype — in a complex cellular context.

A key concept behind their approach was that “proteins that serve as drug targets for a specific disease may be suitable drug targets for another disease owing to common functional targets and pathways elucidated by the protein-protein interactions,” the researchers noted.

They used a network proximity measure to define the relationship between AD endophenotype disease modules and drug targets, and found that drugs targeting both amyloid and tau had significantly smaller network proximity (shortest path length) to AD disease modules, compared with those targeting either amyloid or tau alone.

With a series of filtering and validation steps, the group narrowed a list of 1,608 FDA-approved drugs with suitable pharmacologic properties to several top candidates: dantrolene and deferoxamine (both excluded due to infrequent use and limited available data for further validation), lansoprazole (excluded as it may increase dementia risk), and sildenafil, a phosphodisesterase inhibitor.

The Medicare Advantage claims analysis from 2012-2017 , which compared sildenafil users to non-users, also found reduced risk of AD for sildenafil compared with drugs used to treat coronary artery disease, hypertension, and type 2 diabetes. Sildenafil conferred a 65% reduced risk of AD compared with diltiazem, 55% compared with losartan, 64% compared with glimepride, and 63% compared with metformin.

Sildenafil usage was significantly associated with reduced likelihood of AD across all drug cohorts in people with coronary artery disease, hypertension, or type 2 diabetes.

Subgroup analysis by age found reduced AD risk across all drug cohorts in both mid-older (65-74 years) and older persons (75-100 years). Sex-specific subgroup analysis found sildenafil usage was more significantly associated with a reduced risk of AD in males compared with females. Most sildenafil users were men receiving treatment for erectile dysfunction who received a higher daily dose of sildenafil than women with pulmonary hypertension, which may explain the more significantly reduced risk in males, the authors noted.

Additional corroboration for sildenafil’s relevance came from in vitro cell studies. Phosphorylated levels of GSK3β and CDK5, proteins involved in human microglial mediated inflammation and AD pathology, were reduced in a dose-dependent manner in microglial cells pre-treated with sildenafil, and pre-treatment was non-toxic to cells. In pluripotent stem cells differentiated into forebrain neuron models, sildenafil treatment increased neurite growth, and reduced phosphorylated tau protein levels.

Cheng and co-authors acknowledged that using AD outcomes based on ICD codes in insurance claims data based may have influenced findings. “Combining biomarker-based confirmation of AD diagnosis and phenotyping codes should be used in the future when biomarker information (such as imaging and blood biomarkers) is available in electronic health records,” they observed.

  1. Sildenafil emerged as a potential drug candidate for Alzheimer’s disease (AD) affecting both amyloid and tau pathologies, a drug repurposing analysis showed.

  2. Preliminary supportive analysis of data from 7.23 million Medicare Advantage Plan beneficiaries over 6 years of follow-up also found that sildenafil usage was significantly associated with a 69% reduced risk of AD.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This work was primarily supported by the National Institute on Aging of the National Institutes of Health. This work was supported in part by the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center, the Brockman Foundation, Allen Initiative in Brain Health and Cognitive Impairment, the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, the Louis Stokes VA Medical Center, and the Alzheimer’s Disease Drug Discovery Foundation.

Cheng reported no disclosures.

Cat ID: 33

Topic ID: 82,33,730,33,361,192,925

Author