"Nature Aging" Can an approved drug prevent and treat Alzheimer's disease?

Alzheimer's disease currently affects approximately 6 million Americans, and the race to develop drugs to treat Alzheimer's disease is progressing slowly

Researchers from the Gladstone Institute, in collaboration with scientists from UC San Francisco (UCSF) and Icahn School of Medicine at Mount Sinai, discovered that bumetanide was used to treat fluid retention related to hypertension and heart failure for more than 30 years to reverse bumetanide Signs of Alzheimer’s disease in mouse and human brain cells

In addition, when they analyzed electronic health records from two independent institutions, the research team found that people over 65 who took bumetanide were less likely to develop Alzheimer's than people who did not take bumetanide

Dr.

Richard J.

Another method of drug discovery

The development of new targeted drugs for complex diseases such as Alzheimer's disease is a notoriously long and expensive process

Professor Huang’s approach revolves around the idea that patients with Alzheimer’s disease may have different underlying causes of neurodegeneration, and therefore, the effects of specific treatments may vary from patient to patient—this strategy is called Precision medicine

Therefore, the research team used computational methods to identify unique gene expression profiles (or on or off levels of genes) associated with Alzheimer’s disease in the brain tissues of specific subgroups of patients

Professor Yadong Huang is combining the reuse of computational drugs with precision medicine to help bring new treatments to patients with Alzheimer's disease faster

A surprising candidate

In this new study, the researchers first analyzed a publicly available database containing 213 brain samples from Alzheimer’s and non-Alzheimer’s patients, including people with different versions of the APOE gene , APOE gene is the main genetic risk factor for Alzheimer's disease

The research team found nearly 2,000 altered gene expressions in the brains of Alzheimer's patients

Next, the researchers queried a database of more than 1,300 existing drugs to find those that could alter the altered gene expression they found in a subgroup of Alzheimer's patients

"This unbiased approach allows us to find out which drugs may be able to reverse APOE4-related Alzheimer's disease-related gene expression changes back to normal," the lead author of the study and University of California, San Francisco Marina Sirota Said Dr.

After studying the known mechanisms and previous data of the top five drugs, the researchers focused on bumetanide, a diuretic that reduces excess fluid in the body caused by heart failure, liver disease, and kidney disease

Huang and his team tested the effects of bumetanide on genetically modified mice that have the human APOE gene

The scientists also studied a second mouse model of Alzheimer's disease, in which two copies of APOE4 coexist with amyloid plaques, which are the main pathological signs of Alzheimer's disease in the brain

Finally, when the researchers studied the effect of the drug on human neurons from the skin cells of Alzheimer's patients carrying the APOE4 gene, they found that bumetanide reversed the changes in gene expression associated with the disease
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Dr.
Marina Sirota, associate professor of the Bakar Institute for Computational Health Sciences at the University of California, San Francisco, and the senior co-author of the study, said: "In traditional drug development, in addition to animal and cell research, we usually need to conduct in-depth research before conducting human clinical trials.
Safety testing
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However, with an existing FDA-approved drug, we can use real-world human data to electronically test the possible effects of the drug
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"

"This may be an effective way to find better drugs to treat Alzheimer's and other age-related complex diseases
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"

In this electronic (or computer) analysis, the researchers evaluated two large electronic health record databases, one from the University of California, San Francisco, containing information on 1.
3 million patients from 2012 to 2019, and the other from the Mount Sinai Medical System.
Covers information on 3.
9 million patients from 2003 to 2020
.
They narrowed the range of more than 3,700 patients over 65 who took bumetanide and compared them with patients of similar age and health who took different diuretics
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Strikingly, patients taking bumetanide are less likely to be diagnosed with Alzheimer's disease by 35% to 75%
.

“Since these two electronic health record databases do not distinguish patients based on the version of apolipoprotein E, these real-world data indicate that bumetanide may play a broader role in the treatment of Alzheimer’s disease, not just Only patients with two copies of APOE4," said Professor Huang of Neurology and Pathology at the University of California, San Francisco
.

Based on all these findings, Huang and his colleagues are now planning to work with multiple medical centers to directly transfer bumetanide to human clinical trials for the treatment of Alzheimer's disease, starting with APOE4 carriers
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However, the researchers warned that doctors should not prescribe bumetanide off-label until a prospective clinical trial confirms the effectiveness of bumetanide
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At the same time, the research team is also studying other drugs.
According to their computational analysis, these drugs seem to also target APOE3-related Alzheimer's disease-related gene expression changes
.

"Our research emphasizes the power of combining computational drug reuse with precision medicine, as well as the effectiveness of rapid preliminary verification using existing experimental and realistic data sets," Huang said
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"This may be an effective way to find better drugs to treat Alzheimer's and other age-related complex diseases
.
"

Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease