Genomic Medicine Institute,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Biostatistics and Health Data Science, Indiana University, Indianapolis, IN, USA.
J Alzheimers Dis. 2024;98(2):643-657. doi: 10.3233/JAD-231391.
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.
To investigate the potential therapeutic benefit of sildenafil on AD.
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.
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.
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.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，急需有效的治疗方法。西地那非是已被批准的磷酸二酯酶-5 抑制剂之一，被认为对 AD 具有潜在作用。
研究西地那非治疗 AD 的潜在益处。
我们使用 MarketScan® Medicare 补充和 Clinformatics® 数据库进行真实世界的患者数据分析。在调整混杂因素（即性别、年龄、种族和合并症）后，我们进行了倾向评分分层分析。我们使用家族性和散发性 AD 患者诱导的多能干细胞（iPSC）衍生神经元来评估西地那非的作用机制。
我们表明，西地那非的使用与四个新的药物压缩器队列中的 AD 发生率降低相关，包括布美他尼、呋塞米、螺内酯和硝苯地平。例如，与螺内酯相比，西地那非的使用与 MarketScan®中 AD 发生率降低 54%相关（风险比 [HR] = 0.46，95%CI 0.32-0.66），与 Clinformatics®中 AD 患病率降低 30%相关（HR = 0.70，95%CI 0.49-1.00）。我们发现，西地那非治疗以剂量依赖性方式降低了家族性和散发性 AD 患者 iPSC 衍生神经元中的 tau 过度磷酸化（pTau181 和 pTau205）。西地那非处理的 AD 患者 iPSC 衍生神经元的 RNA 测序数据分析表明，西地那非特异性靶向 AD 相关基因和病理生物学途径，从机制上支持西地那非在 AD 中的有益作用。
这些来自患者 iPSC 衍生神经元的真实世界患者数据验证和机制观察结果进一步表明，西地那非是 AD 的一种潜在可再利用药物。然而，需要进行随机临床试验来验证西地那非在 AD 中的因果治疗效果。
