Approved ED Drug May Help Ward Off Alzheimer’s Disease

Berg will partner with Massachusetts General Hospital and Brigham and Women's Hospital to study potential biomarkers for Alzheimer's and other neurodegenerative disorders from Harvard Biomarker Study biospecimens. [Source: ajcity.net]

A study headed by Cleveland Clinic researchers has identified sildenafil, an FDA-approved therapy for erectile dysfunction (Viagra), and for pulmonary hypertension (Ravatio), as a promising potential drug candidate for helping to prevent and treat Alzheimer’s disease (AD).

Research lead Feixiong Cheng, Ph.D., at the Cleveland Clinic Genomic Medicine Institute, and colleagues used computational methodology to screen and validate FDA-approved drugs as potential therapies for AD. Through a large-scale analysis of a database of more than seven million patients, they found that the top candidate, sildenafil, is associated with 69% reduced incidence of Alzheimer’s disease. They suggest that a follow-up clinical trial is now needed to test the drug’s efficacy in patients with AD.

“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,” said 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.”

Cheng and colleagues reported on their findings in Nature Aging, in a paper titled, “Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease.”

Alzheimer’s disease is the most prevalent form of dementia, and is anticipated to affect 16 million Americans by 2050, the authors commented. The build-up of amyloid-β (Aβ) plaques and neurofibrillary tangles consisting of hyperphosphorylated tau protein in the brain are the two primary hallmarks of Alzheimer’s-related brain changes, and represent a key focus for drug development efforts. “The aggregation of Aβ protein is hypothesized to trigger a cascade of disease-causing processes such as inflammation and synapse dysfunction, as well as contribute to tau tangle formation,” the authors continued. “The hypothesis that accumulation of Aβ and consequent tau pathology represents the main cause of AD has dominated the field for more than 25 years.”

However, as the team also noted, drug discovery approaches targeting either amyloid or tau have demonstrated a lack of clinical benefits for AD patients, and there is currently no FDA-approved, anti-amyloid or anti-tau small molecule treatment available for AD.

The amount and location of either Aβ or tau proteins in the brain may help define endophenotypes, or subtypes, and Cheng’s team has found that understanding endophenotypes of neurodegenerative diseases such as Alzheimer’s disease may help to reveal common underlying mechanisms and lead to discovery of actionable targets for drug repurposing.

Drug repurposing—the use of an existing drug for new therapeutic purposes—offers a practical alternative to the costly and time-consuming traditional drug discovery process. “Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” said Cheng. “Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”

Using a large gene-mapping network, the researchers integrated genetic and other biologic data to determine which of over 1,600 FDA-approved drugs could be an effective treatment for Alzheimer’s disease. “Network-based drug repurposing approaches focus on drugs that are already in clinical practice and hypothesis testing with this approach is possible using large-scale real-world patient data collected during routine healthcare delivery,” they wrote. This approach pinpointed drugs that target both amyloid and tau as having higher scores, compared with drugs that target just one or the other. “Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” said Cheng.

The research team then utilized a large database of claims data of more than seven million people in the United States to examine the relationship between sildenafil and Alzheimer’s disease outcomes by comparing sildenafil users to non-users. The analysis included patients using comparator drugs that were either in an active Alzheimer’s clinical trial (losartan or metformin) or were not yet reported as relevant to the disease (diltiazem or glimepiride).

They found that sildenafil users were 69% less likely to develop Alzheimer’s disease than non-sildenafil users after six years of follow-up. “Based on retrospective case–control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD,” the authors wrote. Specifically, sildenafil had a 55% reduced risk of the disease compared to losartan, 63% compared to metformin, 65% compared to diltiazem, and 64% 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,” added Cheng.

To further explore sildenafil’s effect on Alzheimer’s disease, the researchers developed an Alzheimer’s patient-derived brain cell model using stem cells. In the model, they found that sildenafil increased brain cell growth and decreased hyperphosphorylation of tau proteins. “We also found that sildenafil increases neurite growth and decreases phospho-tau expression in neuron models derived from induced pluripotent stem cells from patients with AD, supporting mechanistically its potential beneficial effect in AD,” they stated. This finding offer up some biological insights into how sildenafil may influence disease-related brain changes.

Interestingly, previous in vivo studies have shown that sildenafil improves memory, amyloid plaque burden, inflammation, and neurogenesis in an APP/PS1 mouse model of AD, and also improved memory, and tau hyperphosphorylation in the J20 mouse model, “… which is consistent with our in vitro mechanistic observation in models of iPSC neurons derived from patients with AD,” they wrote. Two pilot clinical studies also showed potential benefits of sildenafil in treatment of AD, the team noted. “Altogether, we believe that these data provide a potential mechanism of action for the protective efficacy of sildenafil in AD, complementing our endophenotype-based prediction and population-based validation.”

Noting the strengths and limitations of their research, the team concluded, “this study offers an integrated, network-based approach that incorporates endophenotype module findings, in vitro mechanistic observations and large-scale patient data analysis for the discovery of effective therapeutics to protect patients from developing AD or to reduce their risk.” They suggested that their approach can be applied to other neurodegenerative diseases, and they also noted that “ … other repurposable agents were also identified in this study that could be interrogated in greater detail to determine their anti-AD potential.”

“This paper is an example of a growing area of research in precision medicine where big data is key to connecting the dots between existing drugs and a complex disease like Alzheimer’s,” said Jean Yuan, M.D., Ph.D., program director of translational bioinformatics and drug development at the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), which funded the reported research. “This is one of many efforts we are supporting to find existing drugs or available safe compounds for other conditions that would be good candidates for Alzheimer’s disease clinical trials.”

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