Experiments with old drugs suggest a new approach to Alzheimer’s disease

NS Early studies have suggested that generic drugs widely used to treat swelling associated with high blood pressure and heart failure may prevent catastrophic brain damage in Alzheimer’s disease. condition.

Investigation result, Report on Monday at Nature AgingShows how the drug, bumetanide, reversed the signs of Alzheimer’s disease in human brain cells in mice and laboratory dishes. A new study is also taken from the electronic health records of millions of patients who show that people over the age of 65 who take bumetanide on a regular basis are 35% to 75% less likely to be diagnosed with Alzheimer’s disease. Detailed real-world data.

Because the effort to develop medicines for illness is full Failure When Controversy, Results suggest a therapeutic approach that fundamentally deviates from one It has ruled for 30 years..

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New treatments may still be years away — studies have been conducted on mouse and human cells, and they are often poorly predicted what will work for patients. And researchers still can’t explain why the drug is allegedly affecting Alzheimer’s disease. However, the fact that bumetanide has already been approved by the US Food and Drug Administration should speed up the clinical trials currently being pursued by the study authors.

“Developing new drug targets for Alzheimer’s disease takes a lot of time and money, so we wanted to find a faster way to deliver the drug to patients,” said a neurobiologist at the Gladstone Institutes and co-author of a new study. Said Yadong Huang.

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In 2017, he launched a new center for applying computational approaches to divert FDA-approved drugs to new applications. And from day one, his team turned to Alzheimer’s disease. “We didn’t want to be biased towards hypotheses about the mechanism of Alzheimer’s disease, so we took a step back and instead looked at how the entire gene expression profile changes as the disease progresses.”

One of the hallmarks of Alzheimer’s disease is the accumulation of broken amyloid beta protein in plaques. Many scientists believe that these plaques cause neuronal death, leading to the characteristic cognitive decline of the disease. Drug development has been driven by the idea that plaque removal should reverse or at least slow the progression of the disease. However, a series of failed clinical trials makes it increasingly difficult to defend an idea. And this summer, the FDA approved Biogen’s amyloid-removing drug, Aduhelm, with minimal cognitive impact on patients. (((STAT survey It turns out that the drug has been revived Clinical failure Partly due to a secret biogen persuasive campaign called “Project Onyx”, details of which are now investigating According to the Inspector General’s Office of the Ministry of Health and Social Welfare. )

The new research does not overturn the controversial “amyloid hypothesis.” However, it reveals many previously uncatalogized biological irregularities that appear in the brains of patients with Alzheimer’s disease.

One of the greatest genetic risk factors for Alzheimer’s disease is having one or more copies of the APOE4 gene. About 25% of people have one copy. This increases the risk of developing Alzheimer’s disease three to four times. About 2% have both copies, which is 12-14 times more risky than those who do not have the APOE4 variant. Huang’s group investigated what was happening in the brains of patients with Alzheimer’s disease who had one or more copies of APOE4 and found about 2,000 other genes whose expression was altered compared to those without the disease. Did. Many of these genes link to pathways unrelated to amyloid beta metabolism, such as those associated with circadian rhythms, morphine poisoning, and GABA (a neurotransmitter that suppresses neurons and prevents frequent firing of neurons). I am.

Huang’s team then scanned a database of 1,300 drugs to find drugs that could restore these altered genes to a healthy state. Among the top five hits was bumetanide, a powerful diuretic first approved by the FDA in 2002.

They first tested its effects in a series of mice designed to carry two copies of the human APOE4 gene, developing memory and other cognitive deficits around the age of 15 months. This corresponds to 60 in human age. Bumetanide treatment has significantly improved how well these mice work in various cognitive and spatial memory tests.

Next, we repeated the experiment with another mouse strain that has the human gene for APP (a protein that becomes amyloid beta when degraded) in addition to the APOE4 gene. These mice usually develop plaque at 6 months of age. However, the bumetanide treatment offered at 10 months reduced these plaques and restored healthier brain function. In summary, the results suggest that bumetanide improves symptoms without specifically targeting plaque.

“Patients with Alzheimer’s disease have many other cellular and molecular changes besides plaque, but we usually don’t talk about them,” says Huang. “These results suggest that treatment of Alzheimer’s disease probably requires targeting not just one or two, but multiple genes and multiple pathways involved in the disease. . “

The findings raise the hope that amyloid beta is not so narrow and instead aiming for a complete cascade of molecular changes may be more effective. However, this hypothetical approach can also be a little disturbing. Indeed, the drug seems to have the potential to help with Alzheimer’s disease.However why Will it work? No one knows.

“The mechanism of this drug is well known, but what the author does not mention is how it relates to what they think can happen when this drug is given to patients with Alzheimer’s disease. “Is that so,” said Silpa Kadam, a Johns neurologist. Hopkins University studying developmental disabilities.She has been Follow closely Physicians’ tendency to off-label bumetanide for people with autism, epilepsy, and other brain disorders. However, in these examples of drug repositioning, the mechanism of why drugs can be beneficial is well understood. Bumetanide reduces water retention by blocking proteins that shuttle salts across cell membranes. These proteins are also found in neurons and can be rebalanced by blocking them if they are overexcited, as they occur in epilepsy-like conditions.

However, bumetanide can be difficult to use because it can dehydrate the patient and turn the electrolytes off-quilter. the study.

“The relationship between this drug and Alzheimer’s disease is not well documented and its side effect profile is undesirable for the elderly,” Cummings said. This is one of the reasons he thinks it may not be wise to rush this drug into clinical trials. The other is the expiration of intellectual property, which makes it difficult to profit from generic drugs and makes them less attractive to biotechnology companies.

“This will see much more as it directs us to a repertoire of under-researched routes,” Cummings said. “And expanding goals that may be beneficial to human cognition hits me with really good results.”

Huang told STAT that his team is currently working with a number of medical research centers to begin clinical trials in patients with Alzheimer’s disease who have at least one copy of APOE4. rice field. He hopes it is the first step in overturning another idea that has long shaped drug development for Alzheimer’s disease. It’s the only illness that can be treated with one magic bullet.

“These patients may have a variety of underlying cellular mechanisms that lead to neurodegeneration,” he said. “If that is true, you can imagine that the disease can be divided into subgroups that require different treatments. More and more people are embracing this concept, but it is definitely still It’s a new idea. “