Researchers at Gladstone Institutes teamed up with scientists from UC San Francisco (UCSF) and Icahn School of Medicine at Mount Sinai and discovered that bumetanide—used for more than 30 years to treat the retention of fluids associated with conditions like hypertension and heart failure—reverses signs of Alzheimer’s disease in mice, as well as in human brain cells. Moreover, when they analyzed electronic health records from two independent institutions, the team discovered that people over 65 who took bumetanide were less likely to develop Alzheimer’s disease than those who didn’t.
bumetanide, a diuretic that reduces extra fluid in the body caused by heart failure, liver disease, and kidney disease. Bumetanide is known to work by changing how cells absorb sodium and chloride—both important not only for maintaining appropriate levels of water throughout the body, but also for electrical signaling of neurons in the brain.
Based on all these findings, Huang and his colleagues are now planning to work with multiple medical centers to directly move bumetanide toward human clinical trials for treating Alzheimer’s disease, starting with APOE4 carriers.
Based on this paywalled paper:
Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease
Alice Taubes, Phil Nova, […]Yadong Huang
Nature Aging volume 1, pages 932–947 (2021)
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 analyzing 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.