The results of studies headed by teams at the Gladstone Institutes, University of California, San Francisco (UCSF), and Icahn School of Medicine at Mount Sinai, suggest that a widely available FDA-approved oral diuretic drug may potentially be repurposed to help to prevent Alzheimer’s disease (AD) in individuals who are at genetic risk.

The combined results of computational analyses of brain tissue, and drug-related transcriptomic databases, tests in mouse models and in human cells, and an analysis of electronic health records, suggested that taking bumetanide—a commonly used, potent diuretic—might significantly lower the prevalence of Alzheimer’s disease among individuals carrying the APOE4 variant of the APOE gene. The study, funded by the National Institute on Aging (NIA), represents progress in applying a precision medicine approach for individuals at greater risk of the disease because of their genetic makeup.

“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, MD. The research team, including Gladstone Institutes first author Alice Taubes, and co-corresponding author Yadong Huang, PhD, reported on their approach and results in Nature Aging, in a paper titled, “Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease.”

Alzheimer’s disease is the leading cause of dementia worldwide, and no effective therapies are available, the authors noted. “The evident genetic, pathological, and clinical heterogeneity among patients with AD poses challenges for traditional drug development, with almost all efforts to target individual AD-related pathways having failed in late human trials.” Such failures suggest that it may not be possible to develop one drug that could treat all patients with AD, the team continued, and a more “precision medicine” approach may be required, “which allows for stratification guided by known disease-associated gene mutations or polymorphisms.”

Individuals who carry either one or two copies of the APOE4 variant of the APOE gene have a much greater genetic risk for late-onset AD than those who carry the APOE3 variant. It’s also known that APOE4 and APOE3 play different roles in AD pathogenesis, the authors said, while patients with different APOE genotypes respond differently to drug therapy. “Thus, the APOE genotype represents a unique and untapped genetic guidance tool for precision medicine in AD drug development.” The investigators also suggested that using a drug-repurposing approach to target AD could make the drug discovery process faster and reduce costs, by searching among well-tolerated drugs with known targets.

For their newly reported studies, the researchers conducted a computational drug-repurposing screen for drugs to treat APOE4-related AD. “We used a computational drug-repurposing algorithm built on the well-validated hypothesis that drugs that reverse or ‘flip’ expression of differentially expressed (DE) genes in a disease state back toward normal levels may be efficacious against the disease,” they wrote.

The investigators first analyzed publicly available human brain databases to identify transcriptomic signatures in Alzheimer’s that were associated with APOE genotype. They then queried these signatures against the Connectivity Map database, which contains data on transcriptomic perturbations affected by more than 1,300 drugs, to identify compounds that might best reverse (flip) APOE genotype-specific AD transcriptomic signatures. This approach flagged bumetanide as a top drug for APOE4-related AD. Bumetanide is used to treat fluid retention often caused by medical problems such as heart, kidney, and liver disease.

The team validated the data-driven discoveries by testing bumetanide in mouse models of Alzheimer’s—APOE4 knock-in (KI) mice—and in induced pluripotent stem cell-derived human neurons. The results showed that in animals expressing the human APOE4 gene, treatment using bumetanide ameliorated learning and memory deficits. “The efficacy of a top predicted drug, bumetanide, for APOE4 AD was validated in vivo in both aged APOE4-KI (without Aβ accumulation) and J20/E4-KI (with Aβ accumulation) mouse models of AD for rescue of electrophysiological, pathological, or behavioral deficits,” the team noted in their report.

The neutralizing effects of bumetanide were also confirmed in the human cell-based models. “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,” the scientists wrote. Their collective findings led to the hypothesis that people already taking bumetanide should have lower rates of Alzheimer’s disease. To test this, the team pared down electronic health record data sets from more than five 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. “Importantly, in individuals over 65 years of age, bumetanide exposure was associated with a significantly lower AD prevalence in two independent clinical cohorts containing data on millions of people from electronic health record (EHR) databases, suggesting the potential effectiveness of bumetanide in preventing AD and warranting further tests in prospective human clinical trials,” the team concluded.

“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, MD, PhD, 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.”