Sildenafil(Viagra) as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons

 

But is it the drug or the amount of sex they are having? An easy piece of research to accomplish; WHOM will do that?

Sex linked to better brain power in older age

 My doctor said it wasn't proven enough to do this.

But this for the negative view: Does Viagra really help prevent Alzheimer’s? Not so fast

The latest here:

Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons

Article type: Research Article

Authors: Gohel, Dhruv^{a; 1} | Zhang, Pengyue^{b; 1} | Gupta, Amit Kumar^{a; 1} | Li, Yichen^a | Chiang, Chien-Wei^c | Li, Lang^c | Hou, Yuan^a | Pieper, Andrew A.^{d; e; f; g; h} | Cummings, Jeffreyⁱ | Cheng, Feixiong^{a; j; k; *}

Affiliations: [a] Genomic Medicine Institute,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA | [b] Department of Biostatistics and Health Data Science, Indiana University, Indianapolis, Indiana, USA | [c] Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA | [d] Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA | [e] Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA | [f] Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA | [g] Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA | [h] Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, OH, USA | [i] Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA | [j] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA | [k] Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

Correspondence: [*] Correspondence to: Feixiong Cheng, PhD, Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Tel.: +1 216 4447654; Fax: +1 216 6361609; E-mail: chengf@ccf.org.

Note: [1] These authors contributed equally to this work.

Abstract: 

 Background: 

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. Objective: To investigate the potential therapeutic benefit of sildenafil on AD. 

Methods: 

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. 

Results:

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. 

Conclusions:

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.

Keywords: KeywordsAlzheimer’s disease, induced pluripotent stem cells, phosphodiesterase-5 (PDE5), real-world patient data, RNA-sequencing, sildenafil, tau phosphorylation

DOI: 10.3233/JAD-231391

Journal: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024

Accepted 18 January 2024

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Published: 01 March 2024

Price: EUR 27.50