Study Suggests Sildenafil Reduces Risk of Developing Alzheimer’s Disease

Study Suggests Sildenafil Reduces Risk of Developing Alzheimer’s Disease

A study conducted by researchers at the Cleveland Clinic suggests a drug used for treating erectile dysfunction and pulmonary arterial hypertension may help to reduce the risk of developing Alzheimer’s Disease.

The researchers conducted a computational study to screen and validate existing FDA-approved drugs to identify potential drug candidates for preventing and treating Alzheimer’s disease. Sildenafil, which is sold under the brand name Viagra for treating erectile dysfunction and Revatio for treating pulmonary hypertension, was associated with a 69% reduced incidence of Alzheimer’s disease and was the top drug candidate out of the 1,600 drugs screened in the study.

Alzheimer’s disease is the leading form of dementia worldwide. According to the Alzheimer’s Association, in 2021, 6.2 million Americans over the age of 65 were living with Alzheimer’s disease, which is 1 in 9 people over the age of 65. Alzheimer’s disease is characterized by the build-up of amyloid-β (Aβ) plaques and neurofibrillary tangles, which are hypothesized to trigger a range of disease-causing processes such as inflammation and synapse dysfunction. While a great deal of research over the past 25 years has focussed on targeting Aβ plaques and tau protein neurofibrillary tangles; those treatments have failed to deliver clinical benefits and the FDA has not approved any anti-amyloid or anti-tau small molecule treatment for Alzheimer’s disease.

The process of discovering new drugs for treating medical conditions is an incredibly time-consuming and expensive process. One approach to cut costs and deliver treatments faster is to repurpose existing drugs that have already been approved by the FDA for treating other diseases. The researchers screened more than 1,600 FDA-approved drugs to determine if any could be effective for treating AD patients or preventing AD from developing.

“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” said Feixiong Cheng, Ph.D., lead researcher for the study. “Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”

Since the drugs are already being used it is possible to use large-scale real-world patient data that has been collected through routine healthcare delivery. This approach “pinpointed drugs that target both amyloid and tau as having higher scores, compared with drugs that target just one or the other,” said Cheng.

The researchers used claims data from more than 7 million Americans to identify any association between Sildenafil and Alzheimer’s disease and compared users and non-users. They found 69% of patients were less likely to develop AD than non-users of the medication after 6 years of follow-up.

“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,” said Cheng.

Using a patient-derived brain cell model of Alzheimer’s disease, they found Sildenafil decreased the hyperphosphorylation of tau proteins which is associated with the growth of neurofibrillary tangles and increased brain cell growth. Sildenafil has also been shown to significantly improve cognition and memory in preclinical models.

“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.

You can read more about the study in the paper – Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease – which was recently published in Nature Aging. DOI: 10.1038/s43587-021-00138-z