The most common neurodegenerative disease is Alzheimer’s disease (AD), often known as dementia. The loss of memory, learning ability, emotional regulation, and athletic ability is common in patients, all of which have a negative impact on health, families, and society.
Currently, about 50 million people worldwide are suffering from AD. As the average human life expectancy increases and aging society intensifies, the prevalence of AD is also increasing and is expected to rise to more than 150 million by 2050, creating a huge and growing economic and disease burden on society.
The existence of beta-amyloid (Aβ) and tau amyloid deposits in the brain is a hallmark of Alzheimer’s disease pathology. However, drugs that target Aβ and tau proteins have yet to show clinical benefit in patients.
On December 6, 2021, Feixiong Cheng’s team at Cleveland Medical Center published a research paper in Nature Aging entitled “Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease”.
The study found that sildenafil, a drug used to treat pulmonary hypertension and erectile dysfunction in men, was associated with a significantly lower risk of developing AD. The findings of this study imply that sildenafil could be used in a new way to treat AD.
Several recent studies have shown that the interaction between Aβ and tau proteins has a greater impact on Alzheimer’s disease than the two themselves. Seen this way, drugs that target the intersection of molecular networks within the phenotypes of Aβ and tau proteins are likely to have the greatest potential for AD treatment.
The team used a computational approach to integrate genetic and other biological data to construct 13 disease “endophenotype modules” that characterize the biology of Alzheimer’s disease. The team mapped these modules into a large network containing 351,444 human protein interactions, and then calculated network proximity scores for 1,600 FDA-approved drugs, with higher scores indicating that the drug physically interacts with multiple molecular targets in the AD-related modules.
Previous preclinical studies indicated that sildenafil can dramatically improve cognition and memory, suggesting that the drug may be able to affect AD.
To confirm the link between sildenafil and AD, the researchers looked at insurance claims data from 7.23 million people in the United States and discovered that prescribing sildenafil was linked to a 69% lower risk of a confirmed AD diagnosis after 6 years of follow-up.
The gender component is particularly noteworthy because sildenafil is primarily used to treat erectile dysfunction in men, and thus the research team adjusted for gender and age as potential contributing factors. After correcting the data, administering sildenafil was linked to a 73% reduction in the likelihood of a confirmed AD diagnosis in males and a 35% reduction in the risk in women after 6 years of follow-up. It was linked to a 62% reduction in risk for people aged 65 to 74, and a 51% reduction in risk for people aged 75 and up.
In real-world data, these findings imply that sildenafil is significantly associated with a reduction in the incidence of AD.
The team further conducted in vitro experiments using human microglia and neurons derived from induced pluripotent stem cells (iPSCs) from AD patients and found that sildenafil was able to increase neural axon growth and reduce abnormal phosphorylation of tau proteins, mechanistically supporting a potentially beneficial role for sildenafil in reducing the risk of AD.
The team concluded that the study design did not yet show a causal association between using a specific drug and the risk of AD. To assess the efficacy of sildenafil in this scenario, randomized and controlled clinical trials in both men and women are still needed.