With as many as 5.8 million Americans living with Alzheimer’s disease, it’s considered one of the country’s leading health epidemics. Research claims that Alzheimer’s is usually due to a combination of genetic, environmental, and lifestyle factors.
Recently, a research group used mice models and human cell lines to look into the possibility of therapeutic treatments in people that are at a genetic risk of developing Alzheimer’s disease sometime in their lifetime. What they found was that bumetanide, which is a commonly available oral diuretic drug, shows a substantial therapeutic response in treating this degenerative health condition.
Scientists have deduced that bumetanide could very well become a possible treatment and potential prevention option for the neurodegenerative disease in the near future. This shows much promise considering that it is defined as a chronic health condition that has no cure.
According to a number of studies, since Alzheimer’s is a neurodegenerative disease that usually comes from ‘complex interactions between several genetic, lifestyle, and environmental factors.’ Because of this, it’s become even harder to create and develop one drug that has the ability to treat all forms of Alzheimer’s disease.
One particular study advocates that the “precision medicine approach” could be the way to delve through the difficulty of finding the right drug.
When it comes to precision medicine, disease treatment and prevention looks at individual variances in environment, genes, and lifestyle, while being able to personalize it depending on factors that could possibly make a difference in the response to the treatment.
In recent years, scientists within America have used the precision medicine approach when aiming at particular genes that tend to raise the rise of developing this neurodegenerative disease. The focus was to look into the possible therapeutic options for Alzheimer’s disease treatment.
Their study results can be found in the Nature Aging journal.
APOE4 Hypothesis Testing
For corresponding author and associate professor at the Bakar Computational Health Sciences Institute (BCHSI) of the University of California, San Francisco (UCSF), Dr. Marina Sirota, Ph.D., she shared the motivation behind the study to Medical News Today.
According to Dr. Sirota, “[W]e agnostically queried [Alzheimer’s] disease gene expression (whether certain genes are turned on or turned off) against a database of FDA-approved drugs to see which compounds might reverse the disease effects back to the normal state.”
She added, “Here specifically, we take a precision medicine approach by focusing on individuals who have the APOE4/4 genotype as a starting point.”
“Bumetanide was one of our top hits using this computational approach, which led us to investigate this drug further,” she added.
The researchers speculated in the study that medication that overturns that expression of ‘differentially expressed genes in disease states toward normal levels’ could be advantageous against the disease.
What the scientists did first was chose the APOE genotype since this gene is the one at the greatest risk of developing late onset Alzheimer’s.
After, they took tissue samples from individual’s with Alzheimer’s disease and analyzed them to find out the APOE gene expression signatures – or to the extent ‘to which genes are turned on or off’ due to the APOE genotype carriers.
Then the team used a drug repurposing software and compared these signatures to those in a database of over 1,300 FDA-approved drugs.
They found that bumetanide surfaced as the most suitable candidate for reversing APOE4-related expressions to their normal levels in those diagnosed with Alzheimer’s disease.
After which, the research group used human cell lines, mice models, and electronic health records (EHRs) for ‘real-world validation’ of the data. Then, they genetically modified the brains of the mice models to produce APOE4-like symptoms then treated them using bumetanide.
Over a course of time, the researchers subjected the genetically modified rodents to behavorial and learning tests to check their cognitive functions, taking note of their corresponding results.
Aside from the cognitive tests, the scientists also harvested brain slices from the mice to look into the mechanism of action of bumetanide.
To further the study on human tissues, the researchers genetically derived APOE4 neurons from the skin cells of people that have the APOE4 genotype. From here, they saw that the ‘genetically “reprogrammed” cells are known as induced pluripotent stem cells (iPSC) and the ability of cells to do this is called pluripotency.
The researchers then treated the iPSC-derived human neurons with bumetanide, while also taking note of the corresponding results. They also looked at the test results in comparison to the control group.
Promising Results
From the study, the study authors found that bumetanide significantly reversed the APOE4 signature genes in the brains of the genetically modified mice.
They also saw that in the brains of the mice, the bumetanide managed to improve their memory formation while restoring the neuron ability to respond to stimuli via the reorganization of their function and connections. Additionally, ‘these processes are known as neuronal excitability and plasticity, respectively.’
The researchers also noted that during the behavioral tests, the mice with the learning deficits managed to show huge improvements.
Moreover, for the iPSC-derived human neurons, the researchers also observed a reversal in the APOE4 signature genes that was very close to those of the bumetanide-treated, genetically modified rodents.
Other studies also found that rodent and human brain cells actually share three of the same signature pathways for showing the APOE4 gene. What this indicates is an explanation for how the bumetanide generates its positive effects.
The research group even went further to test the ‘real-world efficacy’ of bumetanide by using EHRs from the UCSF and the Mount Sinai Healthy System. What they managed to confirm was for those that had bumetanide treatment exposure had substantially lower symptoms of Alzheimer’s disease than those that had no exposure to the bumetanide treatment.
From these findings, the research group was able to conclude the bumetanide treatment could truly prove effective in preventing the risk of Alzheimer’s disease.
Other experts were also questioned by MNT to better understand the study’s results.
According to program director for the Transitional Bioinformatic Program at the National Institute of Aging, Dr. Jean Yuan, Ph.D. shared about the results of the study, “[While] there are not yet clinical implications, further validation [of] this research may potentially lead to human trials to test bumetanide in [people] who may respond better to the treatment, such as [those] who are carriers of the APOE Alzheimer’s disease risk genotypes.”
Other Study Limitations and Conclusions
There were a number of limitations to the study as well. First, since there was a very limited database for the APOE4 genotype, the sample size that the researchers used was restrained to just one dataset that contained only 213 samples.
Second, the efficacy of bumetanide was validated among the top predicted drugs in animal models and human HER databases only.
And last, the two HER databases that the research group used in the study didn’t have APOE genotype information. This means that further studies are needed as well. Regardless of the limitations and conclusions, the initial results still concluded the interesting and exciting possibilities of having very positive potential in the treatment of Alzheimer’s disease in the future.
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