According to the CDC, an estimated 5.8 million people over age 65 suffer from Alzheimer’s disease (AD), a population predicted to triple by 2060. This statistic foreshadows a bleak future for caregivers. Over the last century, medical and technological innovations have led to the average U.S. lifespan rising from 60 to 79 years; however, 1 in 10 Americans over 65 and half of those over the age of 85 are at risk of developing AD. The increased odds of developing AD with age have led to the tragic irony of a long life with a high chance of a diagnosis of this deleterious disease. Although a personal tragedy, there will be an equally catastrophic societal impact, and the increased burden might threaten to collapse our health care systems. The startling reality of this predicted scenario has led the U.S. to pass the National Alzheimer’s Project Act in the hopes of facilitating and directing research to treat Alzheimer’s disease and related dementias through increased funding. Despite this effort having increased yearly NIH funding seven-fold over the past decade, there has been very little progress in producing novel pharmaceutical interventions. In an effort to seek out improvements in this area of study, researchers from Cleveland Clinic have set out to repurpose drugs previously approved to treat other diseases with the hope of developing an effective treatment for AD.
In their Nature Aging publication, these researchers present a computational method with which they have identified a drug used to treat erectile dysfunction, sildenafil (trade name Viagra®), to be associated with a 69% decrease of AD incidence.
From a collection of over 1,600 FDA-approved drugs, computational modules identified 66 candidate compounds. These modules make use of algorithmic computer models that simulate real-world environments, in this instance modeling pathways biologically relevant to AD. Having these target drugs allowed for a retrospective analysis of over 7 million insurance provider patient reports, with which the incidence of AD could be referenced. This retrospective case-control study revealed several drugs to be associated with decreased incidence of developing AD; sildenafil was by far the most promising candidate.
AD is characterized by deterioration in brain function leading to severe cognitive impairment and dementia, ultimately resulting in systemic dysfunction and death. Histological analysis has found AD to be associated with the pathological accumulation of amyloid-β and tau proteins. Both proteins are thought to disrupt the function of brain tissue and contribute to AD by forming aggregate amyloid-β plaques and hyperphosphorylated tau tangles. Much of AD research has targeted these individual proteins; however, as the authors note, “the predisposition to AD is complex, polygenic and pleiotropic”, and previous efforts developed to discretely target these individual proteins have not yielded any effective therapies. Therefore, the authors set out to identify drugs that might act on the multiple underlying genetic and molecular pathways involved in the formation of both amyloid-β plaques and tau tangles and further interrogate these candidate drugs for their effectiveness in preventing AD.
Retrospective studies of this kind are powerful tools to observe associations, yet these types of studies are limited in regard to uncovering mechanisms that may be causal in driving the pathogenesis of disease. In order to gain mechanistic insight beyond sildenafil’s mere association with a lower risk of AD, researchers carried out experiments using cell types known to be affected by this disease. AD patient-derived induced pluripotent stem cells were differentiated into neuronal and microglial cells, and these cultured cells were subjected to treatment with sildenafil. Treated cells were observed to have reduced accumulation of pathogenic phosphorylated tau proteins, further suggesting that sildenafil might offer a benefit in the treatment of Alzheimer’s disease.
The authors of this paper intend to bolster these findings with subsequent mechanistic studies and a phase II randomized clinical trial with the hope of finding a therapy for a disease that has had very few innovations in treatment and is increasing in incidence at an alarming rate.