Sildenafil use tied to reduced risk of Alzheimer’s

Reuters Health - 10/12/2021 - Sildenafil, a drug used to treat pulmonary hypertension and erectile dysfunction, may help reduce the risk of Alzheimer's disease, according to an analysis of insurance-claims data from more than 7 million people.

Using a large gene-mapping network, Dr. Feixiong Cheng with Cleveland Clinic in Ohio and colleagues integrated genetic and other biologic data to determine which of over 1,600 approved drugs might be helpful in AD.

Sildenafil, which has been shown to significantly improve cognition and memory in animal studies, emerged as the "best drug candidate," Dr. Cheng said in a statement.

In the insurance-claims analysis, across six years of follow-up, sildenafil users were 69% less likely than non-users to develop AD (hazard ratio, 0.31; 95% CI, 0.25 to 0.39), the researchers report in Nature Aging.

Sildenafil was associated with a 55% reduced risk of AD compared to losartan, 63% compared to metformin, 65% compared to diltiazem and 64% compared to glimepiride, they report.

"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," Dr. Cheng said in the statement.

"Our mechanistic studies showed that sildenafil may block GSK3B and CDK5 signaling pathways (two hallmarks in AD tau and amyloid neuropathology) in human microglia cells," Dr. Cheng told Reuters Health.

"In addition, our AD patient-derived induced pluripotent stem cell (iPSC) neuron models showed that sildenafil has potential neuroprotective effects and reduce hyperphosphorylation of tau protein (a key hallmark of AD pathology). These mechanistic findings are consistent with our real-world patient data findings that sildenafil usage is significantly with reduced likelihood of AD," Dr. Cheng said.

"This sildenafil research is an exciting illustration of the promise of repurposing existing drugs to treat Alzheimer's disease," Dr. Howard Fillit, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation (ADDF) told Reuters Health by email.

"Exploring FDA-approved drugs, which have already been proved safe, can fast-track the development of Alzheimer's drugs. We will conquer Alzheimer's through the kind of combination therapies and precision medicine that has been effective in treating cancer," Dr. Fillit said.

The Cleveland Clinic team is now planning a mechanistic trial and a phase-2 randomized clinical trial to test causality and confirm sildenafil's clinical benefits for Alzheimer's patients.

The study was supported by grants from the National Institute on Aging and National Institutes of Health (NIH) and the Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center.

SOURCE: https://go.nature.com/3lF8QUz Nature Aging, online December 6, 2021.

By Megan Brooks



Posted on 10 December 202114 December 2021