Sildenafil, an FDA-approved drug for erectile dysfunction (Viagra) and pulmonary hypertension (Ravatio), has been found as a promising treatment option to help prevent and treat Alzheimer’s disease in a new Cleveland Clinic-led trial.
The research team, led by Dr. Feixiong Cheng from Cleveland Clinic’s Genomic Medicine Institute, employed computational methodology to test and validate FDA-approved drugs as a possible therapy for Alzheimer’s disease, according to findings published in Nature Aging.
They discovered that sildenafil is associated with a 69 Analysis of more than 7 million individuals’ medical records found that sildenafil is connected with a 69% lower risk of Alzheimer’s disease, highlighting the necessity for further clinical research of the drug’s efficacy in Alzheimer’s sufferers.
“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” says Dr. Cheng.
“Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”
Understanding subgroups (endophenotypes) of neurodegenerative disorders like Alzheimer’s disease may help uncover similar underlying mechanisms and lead to the discovery of actionable targets for drug repurposing, according to Dr. Cheng’s research.
Amyloid plaques and tau neurofibrillary tangles are two hallmarks of Alzheimer’s-related brain alterations caused by the buildup of beta amyloid and tau proteins in the brain. Endophenotypes may be defined by the amount and location of these proteins in the brain. However, there are currently no FDA-approved anti-amyloid or anti-tau small molecule Alzheimer’s medicines, and several clinical trials for such treatments have failed over the last decade.
“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” says Dr. Cheng.
“Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”
Researchers combined genetic and other biologic data with a huge gene-mapping network to assess which of over 1,600 FDA-approved medications could be a viable treatment for Alzheimer’s disease. They discovered that drugs that target both amyloid and tau had greater ratings than treatments that only target one of the two.
“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” adds Dr. Cheng.
The research team compared sildenafil users to non-users in a large database of claims data from more than 7 million patients in the United States to explore the association between sildenafil and Alzheimer’s disease outcomes. The analysis included patients who were using comparator drugs that were either currently enrolled in an Alzheimer’s clinical trial (losartan or metformin) or had not been previously identified as being associated with the condition (diltiazem or glimepiride).
After six years of follow-up, they discovered that sildenafil users were 69% less likely to develop Alzheimer’s disease than non-users. Specifically, sildenafil lowered the chance of developing the condition by 55% when compared to losartan, 63% when compared to metformin, 66% when compared to diltiazem, and 64% when compared to glimepiride.
“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” adds Dr. Cheng.
To do additional research on sildenafil’s influence on Alzheimer’s disease, the researchers used stem cells to create an Alzheimer’s patient-derived brain cell model. They discovered that sildenafil enhanced brain cell proliferation and lowered tau hyperphosphorylation (a hallmark of neurofibrillary tangle formation) in the model, providing molecular insight into how sildenafil may influence disease-related brain alterations.
“Because our findings only establish an association between sildenafil use and reduced incidence of Alzheimer’s disease, we are now planning a mechanistic trial and a phase II randomized clinical trial to test causality and confirm sildenafil’s clinical benefits for Alzheimer’s patients,” says Dr. Cheng.
“We also foresee our approach being applied to other neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis, to accelerate the drug discovery process.”
Source: 10.1038/s43587-021-00138-z
Image Credit: Getty
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