In a recent study led by the Cleveland Clinic in the U.S., sildenafil, approved by the U.S. Food and Drug Administration (FDA) as a treatment for erectile dysfunction (product name Viagra) and pulmonary hypertension (product name Lavatio), has been confirmed to be a promising drug candidate to help prevent and treat Alzheimer's disease.
Dr. Feixiong Cheng's team at Cleveland Clinic's Genetic Medicine Research Institute used computer analysis methods to selectively verify drugs that can treat Alzheimer's disease and announced them on the 6th of "Nature Aging."
The research team revealed that sildenafil reduced the incidence of Alzheimer's disease by 69% through a large-scale analysis of a database of more than 7 million patients. This indicates that there is a need to conduct clinical trials on how effective the drug actually is in Alzheimer's disease patients.
Looking for a change in the use of existing drugs compared to new drugs that are slow to develop.
Recent studies have shown that the interaction between amyloid and tau protein has a greater impact on causing Alzheimer's disease than by each protein itself, Dr. Cheng said. "We assumed that drugs targeting the intermolecular network intersection between amyloid and tau protein will have the greatest success."
Unless an effective new treatment is developed, 13.8 million patients in the United States alone are expected to suffer from the disease by 2050, requiring rapid development of prevention and treatment strategies.
According to data from Statistics Korea, one in 10 people aged 65 or older suffers from dementia, and the proportion of patients is expected to continue to increase as the elderly population increases.
However, it is expensive and time-consuming to develop effective new drugs through traditional new drug discovery processes. Therefore, repurposing existing drugs to new disease treatments can be a practical alternative.
"This paper is an example of a growing area in precision medical research, showing that big data is the key to connecting dots between existing drugs and complex diseases such as Alzheimer's disease," said Jean Yuan, director of the National Institute of Aging and New Drug Development Program.
He added that the study is one of NIA's many efforts to support the discovery of existing drugs or safe compounds that can be a good candidate for clinical trials of Alzheimer's disease.
With amyloid and tau as targets,
Dr. Cheng's team confirmed that understanding subtypes (internal phenotypes) of neurodegenerative diseases such as Alzheimer's disease can help identify common underlying mechanisms and discover viable targets for drug repurposing.
Figure showing the process of tau nerve fiber entanglement in the brain. © WikiCommons / NIA
When beta amyloid and tau protein accumulate in the brain, amyloid plaque and tau nerve fiber entanglement occur. These are two characteristics of Alzheimer's-related brain changes. The amount and location of these proteins in the brain can help define the inner phenotype.
However, despite numerous clinical trials over the past decade, anti-amyloid drugs or anti-tau small molecule Alzheimer's treatments that have been approved by the FDA have not yet been released.
Using a large-scale genetic mapping network, the research team integrated genetic and other biological data and identified which of the more than 1600 FDA-approved drugs was effective against Alzheimer's disease.
They found drugs that scored higher by targeting both proteins than drugs targeting only one of amyloid and tau. Dr. Cheng said, "Sildenafil, which was shown to significantly improve cognition and memory in the preclinical model, was presented as the best drug candidate."
Dr. Peichon Cheng of the Cleveland Clinic Genetic Medicine Research Institute, who led the study. Dr. Cheng's team reported that sildenafil reduced the incidence of Alzheimer's by 69%.
Sildenafil users are 69% less likely to develop than non-users.
The research team investigated the relationship between sildenafil and Alzheimer's disease by comparing sildenafil users and non-users using large-scale medical billing data from more than 7 million Americans.
The analysis also included patients who are undergoing clinical trials for Alzheimer's disease (rozartan or metformin) or who use comparative drugs (diltiazem or glymepyride) that have not yet been reported to be relevant.
After six years of follow-up, the research team found that sildenafil users were 69% less likely to develop Alzheimer's than those who did not use sildenafil. Sildenafil showed a 55% lower risk of Alzheimer's than rosartan, 63% lower than metformin, 65% lower than diltiazem, and 64% lower than glymepyride.
Dr. Cheng added, "The study found that the use of sildenafil, in particular, reduces the incidence of Alzheimer's disease in both people with coronary artery disease, high blood pressure, and type 2 diabetes, which are comorbid diseases related to Alzheimer's disease."
Developing Alzheimer's brain cell model with stem cells and experimenting with them.
To further investigate the effectiveness of sildenafil on Alzheimer's disease, the research team developed a brain cell model derived from Alzheimer's patients using stem cells.
In this model, they found that sildenafil promotes brain cell growth and reduces hyperphosphorylation of tau proteins that cause neurofiber entanglement. This presents biological insights into how sildenafil affects Alzheimer's-related brain changes.
Dr. Cheng said, "Since the results of this study have only established a link between sildenafil use and reduced incidence of Alzheimer's disease, we are currently planning a random phase 2 clinical trial with mechanical clinical trials to test causality and confirm the clinical benefits of sildenafil for Alzheimer's disease patients."
He said, "Our approach is expected to be applied to these diseases to accelerate the drug development process for other neurodegenerative diseases, including Parkinson's disease or muscular atrophic lateral sclerosis (Lugerick's disease)."
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