Sildenafil, a drug most typically used to address erectile dysfunction, may surprisingly work wonders in staving off Alzheimer's disease, the most common cause of dementia across the world. At the moment there is no proper treatment for Alzheimer's, an incurable disease that is highly debilitating and whose burden of society is increasing every year with an aging population.
Two pathways, a single drug
After a certain age, the human brain starts to shrink considerably but surprisingly, not too many neurons die in the process. In the Alzheimer’s diseased brain, however, many neurons stop functioning, lose connections with other neurons, and eventually die. This sort of degeneration leads to memory loss and disorientation associated with the condition — though it has to be noted that Alzheimer’s starts damaging brain cells well before the first symptoms kick in.
Alzheimer’s disease is widely believed to be caused by the accumulation of beta-amyloid proteins which clump together to form plaques between neurons and disrupt cell function. Another physical characteristic of the Alzheimer’s diseased brain is the buildup of tau proteins, which tangle inside neurons, blocking their transport system.
"Many drug discovery projects focused on anti-amyloid pathways failed in the past two decades. In our project, we test a novel hypothesis of dual targeting both amyloid and Tau pathways at the same time compared to the traditional drug discovery approach targeting amyloid and Tau pathways alone. As Alzheimer’s disease (AD) is a complex disease caused by many factors, multi-target drugs or combination therapy that target multiple disease pathways may offer better clinical benefits for complex diseases, like AD," Dr. Feixiong Cheng of Cleveland Clinic’s Genomic Medicine Institute and lead author of the new study told ZME Science.
Cheng and colleagues set out to find new or existing drugs whose biological pathways may intersect with Alzheimer's. This was a challenging task that resulted in a lot of dead ends as more than 99% of proposed drugs for Alzheimer's disease have turned out to be hugely disappointing failures in clinical trials.
So the researchers decided to get back to the drawing board and try something different: target both amyloid and Tau pathways at the same time. They went to work and designed a computational model that mapped out a large network of over 350,000 human protein-protein interactions. This huge gene-mapping network allowed the researchers to single out over 1,600 FDA-approved drugs that could target both amyloid and tau, and thus potentially treat Alzheimer's disease.
The best drug candidate was sildenafil, a drug famous for treating erectile dysfunction under the brand name Viagra and pulmonary hypertension under the brand name Revatio. Previously, sildenafil has been associated with improvements in cognition and memory in preclinical models.
In order to see what kind of effect sildenafil might have on Alzheimer's, the researchers closely looked at insurance claims data from over seven million Americans. This analysis revealed that sildenafil prescriptions were associated with a 69% reduction in the risk of AD diagnosis after 6 years of follow-up.
Of particular note is that sildenafil was most likely to reduce the incidence of Alzheimer's in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with the neurodegenerative disease.
Back in the lab, the researchers used stem cells to grow Alzheimer’s patient-derived brain cells. When sildenafil was introduced in the tissue, the brain cells' rate of growth increased while the hyperphosphorylation of tau proteins (a hallmark that leads to neurofibrillary tangles) decreased.
All of these findings in combination point towards sildenafil as a worthy drug candidate for Alzheimer's, which is why the researchers are now planning a phase II randomized clinical trial to confirm the drug's clinical benefits for patients with the disease. And despite sildenafil's notorious reputation, embarrassing moments are highly unlikely.
"We don’t think daily erections are a major side effect of sildenafil as we will use sildenafil in elderly individuals and we can control this issue by adjusting dosage and other factors. We are planning a phase II trial to test the clinical benefits of sildenafil in early of AD patients in the next step. We will answer dosage issues in our future RCT (clinical trial)," Cheng said.
"AD is a complex disease and we have to use personalized treatment (precision medicine) and drug combination therapy strategies to prevent and treat AD in the future. In our project, we found that dual-targeting both Tau and amyloid pathways may offer better clinical benefits compared to the traditional approach targeting Tau and amyloid pathways alone. There are other types of endophenotypes, such as inflammatory pathways as well, and we are working on combination therapy design by combining Tau and amyloid endophenotype with anti-inflammatory therapies in the next step as well," he added.
The findings were reported in the journal Nature Aging.
