A generic drug used widely to treat swelling associated with hypertension and heart failure showed hints in early research that it may also prevent the devastating brain damage of Alzheimerʼs disease, reports STAT News.
The drug, bumetanide, reversed signs of Alzheimerʼs in mice as well as in human brain cells in lab dishes. The study, in Nature Aging, also detailed real-world data mined from millions of patientsʼ electronic health records showing that people over 65 who regularly took bumetanide were 35% to 75% less likely to be diagnosed with Alzheimerʼs.
STAT News reports that since efforts to develop drugs for the disease have been riddled with failures and controversy, the results suggest a therapeutic approach that radically departs from the one that has dominated for three decades.
Any new therapies are probably still years away — the study was in mice and human cells, which are often poor predictors of what will work in patients. And the researchers canʼt yet explain why the drug would have the purported effects on Alzheimerʼs. But the fact that bumetanide has already been approved by the Food and Drug Administration should speed up clinical testing, which the study authors are now pursuing.
“Developing new drug targets for Alzheimerʼs disease takes a lot of time and money, so we wanted to find a faster way to move drugs to patients,” said Yadong Huang, a neurobiologist at Gladstone Institutes and a co-author of the study.
In 2017, he launched a new centre to apply a computational approach for repurposing FDA-approved drugs for new uses. And from day one, his team set its sights on Alzheimerʼs.
“We didnʼt want to be biased toward any hypotheses about the mechanisms of Alzheimerʼs disease, so we took a step back and instead looked at how the whole gene expression profile altered with disease progression,” they said.
One of the hallmarks of Alzheimerʼs is the build-up of mangled beta-amyloid proteins into plaques. Many scientists believe those plaques trigger neuron death, leading to the diseaseʼs characteristic cognitive declines. Drug development has been driven by the idea that clearing out the plaques should reverse or at least slow the diseaseʼs progression. But a litany of failed clinical trials has made the idea harder and harder to defend.
Then, earlier this year, the FDA approved Aduhelm, Biogenʼs amyloid-eliminating drug, despite minimal impact on patientsʼ cognition. (A STAT investigation found that the drug was resuscitated from clinical failure in part by a secret Biogen persuasion campaign dubbed “Project Onyx”, the details of which are now being investigated by the Office of Inspector General in the Department of Health and Human Services.)
The latest study does not overturn the controversial “amyloid hypothesis”. But it did uncover a host of previously uncatalogued biological irregularities that show up inside the brains of Alzheimerʼs patients.
One of the biggest genetic risk factors for Alzheimerʼs disease is having one or more copies of the gene APOE4. About 25% of people possess one copy, which raises the risk of developing Alzheimerʼs by three- to four-fold. About 2% carry both copies, raising the risk 12 to 14 times compared with those who donʼt carry the APOE4 variant. Huangʼs group looked at what was going on inside the brains of Alzheimerʼs patients carrying one or more copies of APOE4 and found nearly 2,000 other genes whose expression had been altered compared to people without the disease. Many of these genes link back to pathways that have nothing to do with beta-amyloid metabolism, including those involved with circadian rhythms, morphine addiction, and GABA — a neurotransmitter that keeps neurons in check, preventing them from firing too often.
Huangʼs team then scanned a database of 1,300 drugs to find ones that could flip those altered genes back to a healthy state. Among the top five hits was bumetanide, a powerful diuretic first approved by the FDA in 2002.
They tested its effect first on a line of mice engineered to have two copies of the human APOE4 gene, causing them to develop memory problems and other cognitive deficits around 15 months of age — the equivalent of 60 in human years. Bumetanide treatments significantly boosted how well these mice performed on various cognitive and spatial memory tests.
They then repeated the experiment in another line of mice, who in addition to APOE4 genes also carried the human gene for APP — a protein that when broken down becomes beta-amyloid. These mice typically develop plaques at six months of age. But bumetanide treatments delivered at 10 months shrank these plaques and restored healthier brain function. Taken together, the results suggest that bumetanide is improving symptoms without specifically targeting plaques.
“There are many cellular and molecular changes in Alzheimerʼs disease patients besides plaques, but we usually donʼt talk about them,” said Huang. “These results suggest that to treat Alzheimerʼs we should probably not target only one or two but multiple genes and multiple pathways involved in the disease.”
The findings raise hopes that aiming not so narrowly at beta-amyloid, and instead at the full cascade of molecular changes, might be more effective. But this hypothesis-free approach can also be a bit unsettling. Sure, it looks like the drug might work for Alzheimerʼs disease. But why would it work? No one knows.
“The mechanism of the drug is well-known, but what the authors havenʼt addressed is how that mechanism is related to what they think might happen if they were to give this drug to Alzheimerʼs patients,” said Shilpa Kadam, a neurologist at Johns Hopkins University who studies developmental disabilities.
She has been closely following a trend of physicians prescribing bumetanide off-label to people with autism, epilepsy, and other brain disorders. But in these instances of drug repurposing, the mechanism for why the drug might provide a benefit is well-understood.
Bumetanide reduces water retention by blocking proteins that shuttle salts across cell membranes. Those proteins are also found in neurons, and if those neurons are overexcited — as occurs in conditions like epilepsy — blocking them can restore balance.
However, bumetanide can also be tricky to use because it can leave patients dehydrated and with their electrolytes off-kilter, said Jeffrey Cummings, director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada Las Vegas, who was not involved in the study.
“This drugʼs relationship to Alzheimerʼs disease is not quite proven and its side effect profile is undesirable in older people,” said Cummings. Which is one of the reasons why he thinks rushing the drug into clinical trials might not be prudent. The other is lapsed intellectual property, which will make the generic harder to profit from, and thus less appealing to biotech companies.
“I would see this much more as pointing us toward a repertoire of pathways that have not been adequately investigated,” said Cummings. “And expanding the targets that might be beneficial in human cognition strikes me as a really good outcome.”
Huang told STAT his team is now working with a number of medical research centres to launch a clinical trial for Alzheimerʼs patients who carry at least one copy of APOE4. He hopes it is a first step in overturning another idea that has long shaped Alzheimerʼs drug development; that it is just one disease treatable with one magic bullet.
“These patients may have different underlying cellular mechanisms that lead to their neurodegeneration,” he said. “If thatʼs true, then you can imagine the disease can be divided into subgroups that require different treatments. More and more people are accepting this concept, but itʼs definitely still an emerging idea.”
Study details
Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease
Alice Taubes, Phil Nova, Kelly A. Zalocusky, Idit Kosti, Mesude Bicak, Misha Y. Zilberter, Yanxia Hao, Seo Yeon Yoon, Tomiko Oskotsky, Silvia Pineda, Bin Chen, Emily A. Aery Jones, Krishna Choudhary,Brian Grone, Maureen E. Balestra, Fayzan Chaudhry, Ishan Paranjpe, Jessica De Freitas, Nicole Koutsodendris, Nuo Chen, Celine Wang, William Chang, Alice An, Benjamin S. Glicksberg, Marina Sirota & Yadong Huang
Published in Nature Aging on 11 October 2021
Abstract
The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development.
We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analysing publicly available human brain databases. We then queried these signatures against the Connectivity Map database, which contains transcriptomic perturbations of more than 1,300 drugs, to identify those that best reverse APOE genotype-specific AD signatures. Bumetanide was identified as a top drug for APOE4-related AD.
Treatment of APOE4-knock-in mice without or with amyloid β (Aβ) accumulation using bumetanide rescued electrophysiological, pathological or cognitive deficits. Single-nucleus RNA sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in APOE4 induced pluripotent stem cell (iPSC)-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two electronic health record databases, suggesting the effectiveness of bumetanide in preventing AD.
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