Sildenafil shows promise as treatment for Alzheimer’s disease

Sildenafil, a phosphodiesterase type 5 inhibitor, can be a potential treatment for Alzheimer’s disease (AD), as shown in real-world data, AD patient-induced pluripotent stem cells (iPSC)-derived neuron models, and in vivo transgenic mouse model observations, according to a study presented at AAIC 2024.

“Sildenafil is a potential repurposable drug for AD,” said presenting author Dr Yichen Li from the Feixiong Cheng Lab, Cleveland Clinic, Ohio, US. However, further clinical trials are needed to confirm the causal association in the prevention and treatment of AD.

Li and his team performed new patient data analyses using the MarketScan Medicare with Supplemental database (n=7.23 million older adults) and the OPTUM database (n=11.52 million older adults) to assess the real-world evidence of sildenafil with the incidence of AD. The iPSC-derived neuron models (five iPSC lines from both familial and sporadic AD patients) were utilized to explore the “mechanism-of-action” of sildenafil’s protective effects on AD.

Finally, the research team also tested sildenafil (15 mg/kg) in a transgenic AD mouse model and carried out behavioural tests, immunofluorescence staining on mouse brain sections, and single-cell RNA-seq to examine the efficacy of the study drug and the brain target engagement.

Use of sildenafil was significantly associated with lower odds of AD incidence across four new drug cohorts, namely bumetanide, furosemide, spironolactone, and nifedipine. [AAIC 2024, abstract 49]

Specifically, treatment with sildenafil, when compared with spironolactone, resulted in a 46-percent reduced prevalence of AD in the MarketScan database (hazard ratio [HR, 0.54, 95 percent confidence interval, 0.32‒0.66; p=3.33x10⁵) and a 30-percent reduction in AD prevalence in the OPTUM database (HR, 0.70, 95 percent CI, 0.49‒1.00; p=0.05).

Mouse model

In the AD patient iPSC-derived neuron model, treatment with sildenafil led to a reduction in phosphorylated tau (pTau181 and pTau231), phosphorylated GSK-3b, and CDK5. In the animal model, use of sildenafil for 3 months resulted in significant improvements in the cognition of 5xFAD transgenic mice, particularly on novel object recognition, Morris water maze, and contextual fear condition.

These results support the therapeutic effects of sildenafil in AD from real-world patient data as well as patient iPSC model findings, according to Li.

In addition, RNA-seq analysis (bulk and single-cell) revealed potential biomarkers and brain target engagement that can be explored in future studies.

Overall, the study identified sildenafil as a candidate drug for AD [using an endophenotype-based] in silico network, demonstrated its association with a reduced risk of AD in real-world patient data, found reductions in tau phosphorylation in patient iPSC-derived neurons, and observed significant improvements in the cognition of five mice, according to Li.

“Those real-world data, patient iPSC-derived mechanic, and in vivo transgenic mouse model observations suggest that sildenafil offers a potential repurposable treatment for AD,” Li said.

Previous analysis by Li and colleagues identified sildenafil as a candidate repurposable drug for AD using in silico network medicine approach. However, the clinically meaningful size and mechanisms of the study drug in AD prevention and treatment remains unclear.