When you are looking for new treatments that will either stop or slow the development of Alzheimer’s disease, where would you look?
According to a recent article in Gladstone News, researchers from the Gladstone Institutes were joined by UCSF and Mount Sinai scientists who searched a database of FDA-approved drugs. They may have come up with a winner in bumetanide which, surprisingly, is a diuretic.
Bumetanide has been used to treat conditions such as heart failure and hypertension by ridding the body of excess fluid. The drug changes the way cells absorb chloride and sodium. This is critical for the electrical signaling of the brain’s neurons.
The scientists reviewed electronic health information stored at two separate institutions. The data showed that people aged sixty-five and older who are taking bumetanide had lower incidents of Alzheimer’s than people in the same age category who had not taken the drug.
A New Approach to Drug Discovery
In 2017 Dr. Yadong-Huang launched the NIH-funded Gladstone Center for Translational Advancement. The Center repurposes previously FDA-approved drugs for new therapeutic use. This enables the expediting of safe and previously approved drugs to patients. Some consider it an alternate approach to drug discovery.
Dr. Huang, a senior author of the study that discovered bumetanide, believes that there are different causes of neurodegeneration among Alzheimer’s patients. That would mean that treatment should be specific to each patient.
However, attempting to identify the efficacy of drugs with a small number of participants (subgroups) involved in a large clinical trial is extremely difficult.
Therefore, the researchers turned to a computational method of analyzing 213 brain tissue samples to observe how genes switch on and off. The brain tissue samples were from people who did or did not have the disease. It also included patients who had various types of the APOE4 gene which presents a major risk for having Alzheimer’s.
Approximately 2000 altered gene expressions were identified from the brains of Alzheimer’s patients. By definition, an altered gene is one that is not usually expressed in that particular cell.
The next step was to search through a database of 1300 active drugs. They narrowed their search to five drugs. These drugs had the highest potential to reverse altered gene expression profiles in Alzheimer’s patients who carried two copies of the altered APOE4 gene.
Bumetanide proved to be the most promising candidate.
Typically, at about 15 months (equivalent to sixty years in humans) APOE4-altered mice would begin to experience deficits in memory and learning. But these deficits were not detected in mice that were treated with bumetanide.
Notably, bumetanide reversed the electrical activity in the brain which may be the underlying cause of cognitive deficits.
And furthermore . . .
For years amyloid plaques have been associated with Alzheimer’s. Dr. Huang and his team also studied a second group of mouse models comprised of APOE4 (two copies) and amyloid plaques.
Tests were performed on this second group of mouse models. The tests showed a decrease in amyloid plaques and restoration of normal activity in the brains of the mouse models.
Expanding Into Millions
Moving along with computer-based (silico) analysis, Dr. Huang and his team of researchers examined two electronic databases:
- A UCSF database with information recorded between 2012 and 2019 on 1.3 million people, and
- A Mount Sinai database that covers 3.9 million people recorded between 2003 and 2020.
The researchers homed in on 3,700 patients over the age of 65 who had taken bumetanide. These patients were compared to people in the same age group who had taken other diuretic drugs.
It is encouraging that thirty-five to seventy-five percent of patients who took bumetanide were not affected by Alzheimer’s disease. Dr. Huang is also a neurology professor at UCSF. He suggests the possibility that bumetanide may have an even broader effect once clinical trials have begun.
Human Clinical Trials
The research team has determined that there is now enough positive data on bumetanide to begin human clinical trials. Therefore, the team has begun to work with several medical centers in this regard.
A Word of Caution
The researchers caution doctors against prescribing bumetanide off-label pending a clinical trial confirming its efficacy.