Precision medicine data dive shows diuretic pill may be viable to test
as Alzheimer's treatment
Research reveals clinical trial candidate for those with genetic risk


Date:
October 11, 2021
Source:
NIH/National Institute on Aging
Summary:
A commonly available, FDA-approved oral diuretic pill may be a
potential candidate for an Alzheimer's disease treatment for those
who are at genetic risk, according to new findings.



FULL STORY ==========================================================================
A commonly available oral diuretic pill approved by the U.S. Food and Drug Administration may be a potential candidate for an Alzheimer's disease treatment for those who are at genetic risk, according to findings
published in Nature Aging. The research included analysis showing that
those who took bumetanide -- a commonly used and potent diuretic -- had
a significantly lower prevalence of Alzheimer's disease compared to those
not taking the drug. The study, funded by the National Institute on Aging (NIA), part of the National Institutes of Health, advances a precision
medicine approach for individuals at greater risk of the disease because
of their genetic makeup.


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The research team analyzed information in databases of brain tissue
samples and FDA-approved drugs, performed mouse and human cell
experiments, and explored human population studies to identify bumetanide
as a leading drug candidate that may potentially be repurposed to treat Alzheimer's.

"Though further tests and clinical trials are needed, this research
underscores the value of big data-driven tactics combined with more
traditional scientific approaches to identify existing FDA-approved
drugs as candidates for drug repurposing to treat Alzheimer's disease,"
said NIA Director Richard J. Hodes, M.D.

Knowing that one of the most significant genetic risk factors for
late-onset Alzheimer's is a form of the apolipoprotein E gene called
APOE4, researchers analyzed data derived from 213 brain tissue samples
and identified the Alzheimer's gene expression signatures, the levels
to which genes are turned on or off, specific to APOE4 carriers. Next,
they compared the APOE4-specific Alzheimer's signatures against those of
more than 1,300 known FDA-approved drugs. Five drugs emerged with a gene expression signature that the researchers believed might help neutralize
the disease. The strongest candidate was bumetanide, which is used to
treat fluid retention often caused by medical problems such as heart,
kidney, and liver disease.

The researchers validated the data-driven discoveries by testing
bumetanide in both mouse models of Alzheimer's and induced pluripotent
stem cell-derived human neurons. Researchers found that treating
mice which expressed the human APOE4 gene reduced learning and memory
deficits. The neutralizing effects were also confirmed in the human
cell-based models, which led to the hypothesis that people already taking bumetanide should have lower rates of Alzheimer's. To test this, the team
pared down electronic health record data sets from more than 5 million
people to two groups: adults over 65 who took bumetanide and a matching
group who did not take bumetanide. The analysis showed that those who had
the genetic risk and took bumetanide had a ~35% to 75% lower prevalence
of Alzheimer's disease compared to those not taking the drug.

"We know that Alzheimer's disease will likely require specific types
of treatments, perhaps multiple therapies, including some that may
target an individual's unique genetic and disease characteristics --
much like cancer treatments that are available today," said Jean Yuan,
M.D., Ph.D., Translational Bioinformatics and Drug Development program
director in the NIA Division of Neuroscience. "The data in this paper
make a good case to conduct a proof-of-concept trial of bumetanide in
people with genetic risk." The research team was led by scientists
at Gladstone Institutes, San Francisco, the University of California,
San Francisco, and the Icahn School of Medicine at Mount Sinai, New York
City. This group is one of more than 20 teams supported by NIA through
a program encouraging the researcher community to seek, through big data approaches, drugs that could potentially be repurposed.

========================================================================== Story Source: Materials provided by NIH/National_Institute_on_Aging. Note: Content may be edited for style and length.


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Link to news story: https://www.sciencedaily.com/releases/2021/10/211011110815.htm

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