Eyes are on a water retention drug called bumetanide after a recent study showed it was correlated with a lower risk of Alzheimer’s in genetically predisposed people over age 65.
Bumetanide belongs to a class of drugs called diuretics, prescribed for heart, liver, and kidney disease to treat water retention, facilitating urination. In the researchers’ analysis, people carrying the ApoE4 genetic variant had a 35 to 75 percent lower risk of developing Alzheimer’s compared to others who did not take the drug.
ApoE4 is one of the largest single risk factors for developing late-onset Alzheimer’s. “Sixty to 70 percent of Alzheimer’s disease carry at least one copy of this gene,” Dr. Yadong Huang, corresponding author on the study, told Being Patient.
In the study, the scientists first looked for differences in gene expression signatures in brain samples from individuals that developed Alzheimer’s. By identifying multiple genes that are uniquely turned on or off in ApoE4 carriers, the scientists could screen more than 1,300 approved drugs to identify if they could neutralize the aberrant gene expression.
Bumetanide was identified as the strongest candidate from this big data approach. It was then tested in animal models of Alzheimer’s as well as cell culture, verifying it neutralized aberrant gene expression. Finally, looking through health records from more than five million people over the age of 65, the researchers found that bumetanide proved protective for ApoE4 carriers, reducing the prevalence of Alzheimer’s in the group taking bumetanide compared to carriers taking another diuretic.
“Among the diuretics, we only pulled out [for the data] this particular drug,” Huang said. “So that tells me it may not be because of the [intended] function of the drug, but it may be related to other unknown functions.”
Characterizing the drug’s effects in animal and cell models of the disease, the researchers developed a theory for how the drug may work in the brain, Huang said. They believe the drug affects “a few key pathways altered in Alzheimer’s disease.” One of these is the Gamma-aminobutyric acid (GABA) signaling pathways — a neurotransmitter that tells other brain cells to stop firing. The other, Huang said, is the circadian rhythm pathway, important for regulating the sleep-wake cycle, which is frequently disrupted in Alzheimer’s, leading to insomnia.
While the effects of bumetanide need to be validated in further trials, Huang’s team believes it is a promising precision medicine approach to treating Alzheimer’s: Only a small amount of bumetanide actually makes it into the brain, he added, so future studies will also need to evaluate dosing.
“This approach will be very useful for drug repurposing for Alzheimer disease,” Huang added, “but also for other aging-related complex diseases in the central nervous system.”