Bumetanide, a drug already approved to treat swelling associated with conditions such as heart failure, improved performance on cognitive tests and reduced the buildup of amyloid plaques in mice with an Alzheimer’s-like condition, researchers report. Furthermore, in cultured human neurons derived from stem cells, bumetanide reversed gene expression changes associated with Alzheimer’s, and the electronic health records of millions of patients point to a link between the drug and reduced odds of being diagnosed with the disease.

On the basis of these results, published this week (October 10) in Nature Aging, Gladstone Institutes neurobiologist and study coauthor Yadong Huang tells STAT that he and his team are now pursuing a clinical trial to test the drug in human patients with at least one copy of the APOE4 variant, a well-known risk factor for the disease.

See “Alzheimer’s Risk Gene Paradoxically Protects Against Memory Loss

Bumetanide blocks ion channels in the cell membrane, thereby altering salt balances and reducing water retention, but how this mechanism might affect neural function is not known. “The mechanism of the drug is well-known, but what the authors haven’t addressed is how that mechanism is related to what they think might happen if they were to give this drug to Alzheimer’s patients,” Johns Hopkins University neurologist Shilpa Kadam, who was not involved in the study, tells STAT.

While bumetanide did shrink amyloid plaques in a mouse model of Alzheimer’s, the drug is not thought to target these protein aggregations directly as many experimental Alzheimer’s drugs have. Many such drugs have failed, and one that was recently approved, Biogen’s Aduhelm, has been mired in controversy, with some questioning its efficacy and the legitimacy of its regulatory review.

See “Lawmakers Request Information About Alzheimer’s Drug Approval

The new study supports a growing body of evidence that amyloid plaques are but one piece of the puzzle. In Alzheimer’s patients with at least one copy of APOE4, nearly 2,000 genes showed altered expression compared with healthy controls, Huang and his colleagues found. These included genes involved with circadian rhythms, morphine addiction, and the neurotransmitter GABA.

“There are many cellular and molecular changes in Alzheimer’s disease patients besides plaques, but we usually don’t talk about them,” Huang tells STAT. He adds that “patients may have different underlying cellular mechanisms that lead to their neurodegeneration,” and thus may require different treatments. “More and more people are accepting this concept, but it’s definitely still an emerging idea.”

Jeffrey Cummings, director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada Las Vegas, tells STAT that the new study reveals “a repertoire of pathways that have not been adequately investigated,” but notes that bumetanide can cause dehydration and electrolyte imbalances. “This drug’s relationship to Alzheimer’s disease is not quite proven and its side effect profile is undesirable in older people,” he says.