If the most difficult disease to overcome in modern medicine is nominated, Singularity Cake believes that Alzheimer's disease (AD) must be "on the list", and it is not known how many new drugs have been folded here for many years, from the discovery of targets to the development of new drugs, to clinical trials and marketing, it takes a long, long time, but the rising number of patients highlights the urgency of the demand for effective prevention and treatment drugs.
What to do? With the development of technology, some scientists have begun to change their thinking in recent years, turning their attention back to the "old drugs" that have been listed.
Today, in a study published in the journal Nature Aging[1], the team of Dr. Feixiong Cheng from the Cleveland Clinic's Institute for Genomic Medicine screened and validated thousands of FDA-approved drugs as potential candidates for AD, and by analyzing data from more than 7 million patients, they found that sildenafil was significantly associated with a 69% reduction in AD risk!
Screenshot of the first page of the paper
Dr. Cheng proposes that existing studies have shown that the interaction between the two pathological proteins of AD, β amyloid and tau, has a greater impact on AD than their respective effects on AD, so drugs that target their "intersections" should have the greatest potential for success [2].
Based on this finding, they began their own research. The researchers first established a dataset containing three modules, namely the experimentally validated AD-related genes, the differentiatedly expressed genes found in the transcriptomes of seven mice with the transgenic AD pattern of β amyloid or tau proteins, and the differentiatedly expressed proteins found in the proteomes of three AD-mode mice.
They mapped these modules to models of the human protein interaction group, imported information from 1608 drugs that had been approved for marketing by the FDA, quantified the drug-target interactions of these drugs, scored them, and selected the top 100.
Among these drugs, after excluding nutraceutical drugs, metal drugs and radiotherapy diagnostics, there are 66 remaining, of which the most belong to the cardiovascular system, with 14, followed by neurological drugs (11) and anti-tumor and immunomodulatory drugs (9).
Previous studies have also found that some cardiovascular disease drugs may reduce the incidence of AD [3], and nine of the 14 cardiovascular system drugs are currently undergoing preclinical studies or clinical trials of AD.
Returning to the new study, the researchers systematically retrieved the research evidence for the blood-brain barrier and anti-AD of the 66 drugs screened, of which 21 had preclinical and clinical evidence (including drugs that have been approved by the FDA for AD, such as donepezil).
Dataset module and screen out the drugs
Through the reuse of module validation and a review of known research evidence, as well as predictions of the ability to penetrate the blood-brain barrier, the final candidates were left with only dantroline, deferoxamine, and sildenafil, but the former two were less frequently used drugs and there was not enough patient data to conduct population-based validation studies.
Therefore, the researchers chose sildenafil as the final candidate. They validated sildenafil's relationship with AD using medical data from 7.23 million people covered by the U.S. Commercial Insurance and Medicare Advantage Program.
To minimize the effects of confounding factors, they conducted a total of three observational studies: sildenafil users vs. non-sildenafil users; sildenafil users vs. control drug users (diltiazem or glimepiride, no preclinical and clinical evidence of AD correlation); sildenafil users vs. control drug users (losartan or metformin, in clinical trials for the treatment of AD). As a result, 5 matching control groups (non-sildenafil users + 4 control drug users) were generated, centered on sildenafil users.
After 6 years of follow-up, sildenafil was significantly associated with a 69% lower risk of AD compared with non-sildenafil users (95% CI: 0.25-0.39, P<1x10-8). Sildenafil was associated with a 65%, 55%, 64%, and 63% lower risk of AD compared with diltiazem, losartan, glimepiride, and metformin.
The proportion of sildenafil users (green) and non-users (a), diltiazem (b), losartan (c), glimepiride (d), and metformin (e) varied over time
Sildenafil remained significantly associated with a reduced risk of AD after excluding patients with coronary artery disease, hypertension, and type 2 diabetes. This suggests that people in the cohort who do not have these AD risk factors are still able to benefit from sildenafil. In addition, the researchers excluded patients with mild cognitive impairment (MCI) and also verified the correlation between sildenafil and a reduced risk of AD.
Relationship between sildenafil and decreased risk of AD after exclusion of patients with coronary artery disease, hypertension and type 2 diabetes
In addition to underlying disease, the association of sildenafil with reduced risk of AD by sex and age is still not "rolled over". While the results of the analysis showed that the risk of AD was more significant in male sildenafil users compared to women, most men were for erectile dysfunction (ED) and women for pulmonary hypertension, which used a much higher dose than pulmonary hypertension, which may have contributed to a difference in risk reduction.
Finally, they also used induced pluripotent stem cells (iPSCs) derived from patients with AD to differentiate some forebrain neurons and treat them with sildenafil. Compared with the control group, the neurite growth of the sildenafil group became stronger, and the accumulation of phosphorylated tau 181 was significantly reduced.
Overall, this study suggests that sildenafil is associated with a significantly reduced risk of AD. Dr. Cheng revealed that they are planning a mechanism study and a Phase 2 clinical trial to further elucidate the causal relationship between sildenafil and reduced risk of AD, as well as the real clinical benefits [2].
Finally, I have to talk about it as usual, the new discovery is exciting, but don't take the medicine yourself ~ We still expect researchers to follow up with more research.
Resources:
[1] https://www.nature.com/articles/s43587-021-00138-z
[2] https://newsroom.clevelandclinic.org/2021/12/06/cleveland-clinic-research-identifies-sildenafil-as-candidate-drug-for-alzheimers-disease/
[3] Claassen J A H R. New cardiovascular targets to prevent late onset Alzheimer disease[J]. European journal of pharmacology, 2015, 763: 131-134.